Search ((metabolize*) OR (drug metabolism)) AND (tpmt OR thiopurine methyltransferase OR thiopurine s-methyltransferase) AND (polymorphism* OR mutation*) Field: All Fields, Limits: Publication Date from 1994/01/01 to 2003/12/31 Entrez pubmed Results Items 1 - 91 of 91 1: Ma XL et al. [Relationship between single ...[PMID: 14723818] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14723818 OWN - NLM STAT- MEDLINE DA - 20040115 DCOM- 20040609 LR - 20041117 PUBM- Print IS - 0578-1310 VI - 41 IP - 12 DP - 2003 Dec TI - [Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia] PG - 929-33 AB - OBJECTIVE: For the purpose of clarifying the influence of thiopurine methyltransferase (TPMT) gene single nucleotide polymorphisms (SNPs) on the efficacy of thiopurines and risk for its toxicity and therefore improving the safety and efficacy of thiopurines, the authors investigated TPMT genotype in acute leukemia in children who were intolerant to the treatment with 6-mercap topurine (6-MP). METHODS: TPMT genotype was determined in an unrelated population of 250 Chinese healthy blood donors and 280 children with acute leukemia. TPMT genotyping assay was based on polymerase chain reaction (PCR), restriction digestion of PCR products, denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing in the TPMT * 2 (G238C), TPMT * 3A (G460A, A719G) and TPMT * 3C (A719G). RESULTS: There were 10 TPMT * 1/TPMT * 3C heterozygotes in 280 children. The frequency of the polymorphism was 3.6%. All the involved alleles were TPMT * 3C. Of the 160 children acute leukemia evaluated, 45 (26%) were intolerant to 6-MP. Presentations included hepatotoxicity and hematological toxicity. Six out of 45 children were heterozygous, while the other 39 were wild type homozygous. Before dosage adjustments for thiopurine, the hematologic toxicity and hepatotoxicity in TPMT heterozygous individuals occurred more frequently than in homozygous. Therefore, cases of TPMT heterozygotes experienced more missed doses of 6-MP. CONCLUSIONS: TPMT genotype is associated with tolerance in acute leukemia in children. The heterozygote individuals have low TPMT activity. Therefore the frequencies of hemtopoietic toxicity and hepatoxicity are high after using 6-MP. Detection of SNPs in the TPMT genes is useful in identifying children before administration of 6-MP. AD - Hematology center Beijing Children's Hospital, Capital University of Medical sciences, Beijing 100045, China. FAU - Ma, Xiao-li AU - Ma XL FAU - Zhu, Ping AU - Zhu P FAU - Wu, Min-yuan AU - Wu MY FAU - Li, Zhi-gang AU - Li ZG FAU - Hu, Ya-mei AU - Hu YM LA - chi PT - Journal Article PL - China TA - Zhonghua Er Ke Za Zhi JID - 0417427 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*therapeutic use MH - Acute Disease MH - Adolescent MH - Antimetabolites, Antineoplastic/*therapeutic use MH - Child MH - Child, Preschool MH - Chromatography, Liquid/methods MH - Comparative Study MH - Drug Resistance, Neoplasm/*genetics MH - English Abstract MH - Exons/genetics MH - Female MH - Gene Frequency MH - Genotype MH - Humans MH - Infant MH - Leukemia/drug therapy/enzymology/*genetics MH - Male MH - Methyltransferases/*genetics MH - Polymerase Chain Reaction MH - Polymorphism, Single Nucleotide/*genetics EDAT- 2004/01/16 05:00 MHDA- 2004/06/21 10:00 PST - ppublish SO - Zhonghua Er Ke Za Zhi 2003 Dec;41(12):929-33. DR -------------------------------------------------------------------------------- 2: Becquemont L. Clinical relevance of pharmac...[PMID: 14705861] Related Articles, Books, LinkOut PMID- 14705861 OWN - NLM STAT- MEDLINE DA - 20040106 DCOM- 20040812 LR - 20041117 PUBM- Print IS - 0360-2532 VI - 35 IP - 4 DP - 2003 Nov TI - Clinical relevance of pharmacogenetics. PG - 277-85 AB - Pharmacogenetics fields of research was initially restricted to drug metabolism enzymes. It has recently progressed to drug transporters, receptors, and any kind of targets that can modulate drug response. This rapid extension of pharmacogenetics to all the different medical specialties is in close relation with the recent completion of the draft sequence of the human genome and the discovery that about 0.1% of its sequence is polymorphic. The goal of pharmacogenetics for the next years is clearly to determine the clinical consequences of these 2-3 million single nucleotide polymorphisms (SNPs). Things can be schematically divided in two situations. (1) Frequent SNPs (allele frequency > 10%) which have a low impact on drug response (odds ratios < 2), even combined with other SNPs in haplotype combinations. Such situations, which are by far the most frequent, have no clinical relevance for a single patient to predict its response to a particular drug. CYP3A and MDR1 allelic variants are good examples of such frequent situations. (2) Rare SNPs, which dramatically alter the expression or the activity of a target protein, can sometimes have a real clinical relevance (odds ratios > 5), usually to predict drug side effects. Only few examples, such as TPMT and CYP2C9 genetic polymorphisms, can illustrate this rare situation. Unfortunately, less than 1% of the population is concerned by these rare SNPs, and genotyping can only explain a small part of the variability of the response to a single drug. Beside the impressive mass of data available for pharmacogenetics, it is surprising to observe its poor development in routine medical practice. This discrepancy relies mainly on educational and methodological problems, which might be solved in the decade. To promote pharmacogenetics in routine medical practice, large prospective randomized trials are needed to demonstrate that pharmacogenetic orientated prescription can sometimes predict drug response without dramatic increase in costs. AD - Pharmacology Department, Bicetre University Hospital, University Paris-Sud, Assistance Publique, Hopitaux de Paris, Paris, France. laurent.becquemont@chusa.jussieu.fr FAU - Becquemont, Laurent AU - Becquemont L LA - eng PT - Journal Article PT - Review PL - United States TA - Drug Metab Rev JID - 0322067 SB - IM MH - Animals MH - Humans MH - Pharmacogenetics/*methods/*trends MH - Polymorphism, Single Nucleotide/genetics RF - 19 EDAT- 2004/01/07 05:00 MHDA- 2004/08/13 05:00 PST - ppublish SO - Drug Metab Rev 2003 Nov;35(4):277-85. DR -------------------------------------------------------------------------------- 3: Griffiths AM. Monitoring of azathioprine/6-...[PMID: 14671489] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14671489 OWN - NLM STAT- MEDLINE DA - 20031212 DCOM- 20040304 LR - 20041117 PUBM- Print IS - 1078-0998 VI - 9 IP - 6 DP - 2003 Nov TI - Monitoring of azathioprine/6-mercaptopurine treatment in children with IBD is not necessary. PG - 389-91; discussion 392-3 AD - Pediatrics, IBD Program, The Hospital for Sick Children, University of Toronto, Ontario, Canada. anne.griffiths@sickkids.on.ca FAU - Griffiths, Anne M AU - Griffiths AM LA - eng PT - Journal Article PL - United States TA - Inflamm Bowel Dis JID - 9508162 RN - 0 (Guanine Nucleotides) RN - 0 (Immunosuppressive Agents) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - 342-69-8 (Methylthioinosine) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/adverse effects/*therapeutic use MH - Azathioprine/adverse effects/*therapeutic use MH - Child MH - Drug Monitoring MH - Guanine Nucleotides/analysis MH - Humans MH - Immunosuppressive Agents/adverse effects/*therapeutic use MH - Inflammatory Bowel Diseases/blood/*drug therapy/genetics MH - Methylthioinosine/analysis MH - Methyltransferases/analysis/genetics MH - Polymorphism, Genetic MH - Thionucleotides/analysis EDAT- 2003/12/13 05:00 MHDA- 2004/03/05 05:00 PST - ppublish SO - Inflamm Bowel Dis 2003 Nov;9(6):389-91; discussion 392-3. NR -------------------------------------------------------------------------------- 4: Dubinsky MC. Monitoring of AZA/6-MP treatm...[PMID: 14671488] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14671488 OWN - NLM STAT- MEDLINE DA - 20031212 DCOM- 20040304 LR - 20041117 PUBM- Print IS - 1078-0998 VI - 9 IP - 6 DP - 2003 Nov TI - Monitoring of AZA/6-MP treatment in children with IBD is necessary. PG - 386-8; discussion 392-3 AD - Pediatric Gastroenterology, Cedars-Sinai Hospital, Los Angeles, CA 90048, USA. marla.dubinsky@cshs.org FAU - Dubinsky, Marla C AU - Dubinsky MC LA - eng PT - Journal Article PL - United States TA - Inflamm Bowel Dis JID - 9508162 RN - 0 (Guanine Nucleotides) RN - 0 (Immunosuppressive Agents) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - 342-69-8 (Methylthioinosine) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/adverse effects/*therapeutic use MH - Azathioprine/adverse effects/*therapeutic use MH - Child MH - *Drug Monitoring MH - Guanine Nucleotides/analysis MH - Humans MH - Immunosuppressive Agents/adverse effects/*therapeutic use MH - Inflammatory Bowel Diseases/blood/*drug therapy/genetics MH - Methylthioinosine/analysis MH - Methyltransferases/analysis/genetics MH - Polymorphism, Genetic MH - Thionucleotides/analysis EDAT- 2003/12/13 05:00 MHDA- 2004/03/05 05:00 PST - ppublish SO - Inflamm Bowel Dis 2003 Nov;9(6):386-8; discussion 392-3. NR -------------------------------------------------------------------------------- 5: Haglund S et al. Pyrosequencing of TPMT allele...[PMID: 14656901] Related Articles, Books, LinkOut PMID- 14656901 OWN - NLM STAT- MEDLINE DA - 20040130 DCOM- 20040227 LR - 20041117 PUBM- Print-Electronic IS - 0009-9147 VI - 50 IP - 2 DP - 2004 Feb TI - Pyrosequencing of TPMT alleles in a general Swedish population and in patients with inflammatory bowel disease. PG - 288-95 AB - BACKGROUND: Interindividual differences in therapeutic efficacy in patients treated with thiopurines might be explained by the presence of thiopurine S-methyltransferase (TPMT) alleles that encode for reduced TPMT enzymatic activity. It is therefore of value to know an individual's inherent capacity to express TPMT. Method: We developed a pyrosequencing method to detect 10 single-nucleotide polymorphisms (SNPs) in TPMT. A Swedish population (n = 800) was examined for TPMT*3A, TPMT*3B, TPMT*3C, and TPMT*2. Patients with inflammatory bowel disease (n = 24) and healthy volunteers (n = 6), selected on the basis of TPMT enzymatic activity, were investigated for all 10 SNPs to determine the relationship between TPMT genotype and phenotype. RESULTS: In the general population we identified the following genotypes with nonfunctional alleles: TPMT*1/*3A (*3A allelic frequency, 3.75%), TPMT*1/*3C (*3C allelic frequency, 0.44%), TPMT*1/*3B (*3B allelic frequency, 0.13%), and TPMT*1/*2 (*2 allelic frequency, 0.06%). All nine individuals with normal enzymatic activity were wild-type TPMT*1/*1. Thirteen individuals with intermediate activity were either TPMT*1/*3A (n = 12) or TPMT*1/*2 (n = 1). Eight individuals with low enzymatic activity were TPMT*3A/*3A (n = 4), TPMT*3A/*3C (n = 2), or TPMT*1/*3A (n = 2). CONCLUSION: Next to wild type, the most frequent alleles in Sweden are TPMT*3A and TPMT*3C. A previously established phenotypic cutoff for distinguishing normal from intermediate metabolizers was confirmed. To identify the majority of cases (90%) with low or intermediate TPMT activity, it was sufficient to analyze individuals for only 3 of the 10 SNPs investigated. Nevertheless, this investigation indicates that other mutations might be of relevance for decreased enzymatic activity. AD - Division of Research and Development in Laboratory Medicine, Ryhov County Hospital, SE-551 85 Jonkoping, Sweden. sofie.haglund@lj.se FAU - Haglund, Sofie AU - Haglund S FAU - Lindqvist, Malin AU - Lindqvist M FAU - Almer, Sven AU - Almer S FAU - Peterson, Curt AU - Peterson C FAU - Taipalensuu, Jan AU - Taipalensuu J LA - eng PT - Journal Article DEP - 20031204 PL - United States TA - Clin Chem JID - 9421549 RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM EIN - Clin Chem. 2004 Apr;50(4):788 MH - Adult MH - Aged MH - Aged, 80 and over MH - Alleles MH - Female MH - Genetic Screening/*methods MH - Genotype MH - Humans MH - Inflammatory Bowel Diseases/*genetics MH - Male MH - Methyltransferases/*genetics MH - Middle Aged MH - Mutation MH - Phenotype MH - Polymerase Chain Reaction MH - Polymorphism, Single Nucleotide MH - Research Support, Non-U.S. Gov't MH - Sequence Analysis, DNA/methods MH - Sweden EDAT- 2003/12/06 05:00 MHDA- 2004/02/28 05:00 PHST- 2003/12/04 [aheadofprint] AID - 10.1373/clinchem.2003.023846 [doi] AID - clinchem.2003.023846 [pii] PST - ppublish SO - Clin Chem 2004 Feb;50(2):288-95. Epub 2003 Dec 4. DR -------------------------------------------------------------------------------- 6: Murphy LA et al. Azathioprine as a treatment f...[PMID: 14651577] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14651577 OWN - NLM STAT- MEDLINE DA - 20031203 DCOM- 20040408 LR - 20041117 PUBM- Print IS - 0736-8046 VI - 20 IP - 6 DP - 2003 Nov-Dec TI - Azathioprine as a treatment for severe atopic eczema in children with a partial thiopurine methyl transferase (TPMT) deficiency. PG - 531-4 AB - Azathioprine is a valuable agent in the treatment of severe childhood atopic eczema. Thiopurine methyl transferase (TPMT) exhibits autosomal codominant polymorphism and plays an important role in the metabolism of azathioprine. In most large population groups studied to date, approximately 10% of the population had intermediate activity due to heterozygosity at the TPMT locus, and about 0.33% were TPMT deficient. TPMT deficiency results in the accumulation of thioguanine nucleotides and cytotoxic 6-mercaptopurine metabolites. Previously it was considered unsafe to treat this group with azathioprine because of what was considered to be an unacceptably high risk of toxicity (profound myelosuppression). Better understanding of the pharmacogenetics of purine metabolism has changed this, and with appropriate dose adjustments, individuals who have a partial TPMT deficiency (heterozygotes) can now be treated with thiopurines. It seems probable that these individuals are more likely to have a therapeutic response while being at lower risk of developing dose-related hepatotoxicity because of the reduced doses required to effect a therapeutic response. Two patients with severe refractory atopic eczema, both of whom had a partial TPMT deficiency, have had an excellent response to treatment with azathioprine. They were treated with half-standard doses and response to treatment occurred within 2 weeks. AD - St. Johns Institute of Dermatology, London, United Kingdom. lammurphy@yahoo.com FAU - Murphy, Lesley-Ann AU - Murphy LA FAU - Atherton, David J AU - Atherton DJ LA - eng PT - Case Reports PT - Journal Article PL - United States TA - Pediatr Dermatol JID - 8406799 RN - 0 (Antimetabolites, Antineoplastic) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) SB - IM MH - Administration, Oral MH - Adolescent MH - Antimetabolites, Antineoplastic/administration & dosage/*therapeutic use MH - Azathioprine/administration & dosage/*therapeutic use MH - Child MH - Dermatitis, Atopic/*drug therapy/pathology MH - Diagnosis, Differential MH - Eczema/drug therapy/pathology MH - Humans MH - Male MH - Methyltransferases/*deficiency MH - Severity of Illness Index EDAT- 2003/12/04 05:00 MHDA- 2004/04/09 05:00 AID - 20617 [pii] PST - ppublish SO - Pediatr Dermatol 2003 Nov-Dec;20(6):531-4. PR -------------------------------------------------------------------------------- 7: Canovas D et al. Heavy metal tolerance and met...[PMID: 14641571] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14641571 OWN - NLM STAT- MEDLINE DA - 20031203 DCOM- 20040212 LR - 20041117 PUBM- Print IS - 1462-2912 VI - 5 IP - 12 DP - 2003 Dec TI - Heavy metal tolerance and metal homeostasis in Pseudomonas putida as revealed by complete genome analysis. PG - 1242-56 AB - The genome of Pseudomonas putida KT2440 encodes an unexpected capacity to tolerate heavy metals and metalloids. The availability of the complete chromosomal sequence allowed the categorization of 61 open reading frames likely to be involved in metal tolerance or homeostasis, plus seven more possibly involved in metal resistance mechanisms. Some systems appeared to be duplicated. These might perform redundant functions or be involved in tolerance to different metals. In total, P. putida was found to bear two systems for arsenic (arsRBCH), one for chromate (chrA), four to six systems for divalent cations (two cadA and two to four czc chemiosmotic antiporters), two systems for monovalent cations: pacS, cusCBA (plus one cryptic silP gene containing a frameshift mutation), two operons for Cu chelation (copAB), one metallothionein for metal(loid) binding, one system for Te/Se methylation (tpmT) and four ABC transporters for the uptake of essential Zn, Mn, Mo and Ni (one nikABCDE, two znuACB and one mobABC). Some of the metal-related clusters are located in gene islands with atypical genome signatures. The predicted capacity of P. putida to endure exposure to heavy metals is discussed from an evolutionary perspective. AD - Centro Nacional de Biotecnologia--CSIC, Campus de Cantoblanco, 28049 Madrid, Spain. FAU - Canovas, David AU - Canovas D FAU - Cases, Ildefonso AU - Cases I FAU - de Lorenzo, Victor AU - de Lorenzo V LA - eng PT - Journal Article PL - England TA - Environ Microbiol JID - 100883692 RN - 0 (Arsenicals) RN - 0 (Chromates) RN - 0 (Metals, Heavy) RN - 10049-23-7 (tellurous acid) RN - 10102-18-8 (Sodium Selenite) RN - 13494-80-9 (Tellurium) RN - 7439-96-5 (Manganese) RN - 7439-98-7 (Molybdenum) RN - 7440-02-0 (Nickel) RN - 7440-43-9 (Cadmium) RN - 7440-50-8 (Copper) RN - 7440-66-6 (Zinc) SB - IM MH - Arsenicals/metabolism MH - Cadmium/metabolism MH - Chromates/metabolism MH - Chromosomes, Bacterial/genetics MH - Computational Biology/methods MH - Copper/metabolism MH - Drug Tolerance MH - Gene Order MH - Genes, Bacterial MH - *Genome, Bacterial MH - Homeostasis MH - Manganese/metabolism MH - Metals, Heavy/*metabolism/*pharmacology MH - Molybdenum/metabolism MH - Nickel/metabolism MH - Operon MH - Pseudomonas putida/drug effects/*genetics/*metabolism MH - Research Support, Non-U.S. Gov't MH - Sodium Selenite/metabolism MH - Tellurium/metabolism MH - Zinc/metabolism EDAT- 2003/12/04 05:00 MHDA- 2004/02/13 05:00 AID - 463 [pii] PST - ppublish SO - Environ Microbiol 2003 Dec;5(12):1242-56. NR -------------------------------------------------------------------------------- 8: Carroll WL et al. Pediatric acute lymphoblastic...[PMID: 14633779] Related Articles, Books, LinkOut PMID- 14633779 OWN - NLM STAT- MEDLINE DA - 20031124 DCOM- 20040923 LR - 20041117 PUBM- Print IS - 1520-4391 DP - 2003 TI - Pediatric acute lymphoblastic leukemia. PG - 102-31 AB - The outcome for children with acute lymphoblastic leukemia (ALL) has improved dramatically with current therapy resulting in an event free survival exceeding 75% for most patients. However significant challenges remain including developing better methods to predict which patients can be cured with less toxic treatment and which ones will benefit from augmented therapy. In addition, 25% of patients fail therapy and novel treatments that are focused on undermining specifically the leukemic process are needed urgently. In Section I, Dr. Carroll reviews current approaches to risk classification and proposes a system that incorporates well-established clinical parameters, genetic lesions of the blast as well as early response parameters. He then provides an overview of emerging technologies in genomics and proteomics and how they might lead to more rational, biologically based classification systems. In Section II, Drs. Mary Relling and Stella Davies describe emerging findings that relate to host features that influence outcome, the role of inherited germline variation. They highlight technical breakthroughs in assessing germline differences among patients. Polymorphisms of drug metabolizing genes have been shown to influence toxicity and the best example is the gene thiopurine methyltransferase (TPMT) a key enzyme in the metabolism of 6-mercaptopurine. Polymorphisms are associated with decreased activity that is also associated with increased toxicity. The role of polymorphisms in other genes whose products play an important role in drug metabolism as well as cytokine genes are discussed. In Sections III and IV, Drs. James Downing and Cheryl Willman review their findings using gene expression profiling to classify ALL. Both authors outline challenges in applying this methodology to analysis of clinical samples. Dr. Willman describes her laboratory's examination of infant leukemia and precursor B-ALL where unsupervised approaches have led to the identification of inherent biologic groups not predicted by conventional morphologic, immunophenotypic and cytogenetic variables. Dr. Downing describes his results from a pediatric ALL expression database using over 327 diagnostic samples, with 80% of the dataset consisting of samples from patients treated on a single institutional protocol. Seven distinct leukemia subtypes were identified representing known leukemia subtypes including: BCR-ABL, E2A-PBX1, TEL-AML1, rearrangements in the MLL gene, hyperdiploid karyotype (i.e., > 50 chromosomes), and T-ALL as well as a new leukemia subtype. A subset of genes have been identified whose expression appears to be predictive of outcome but independent verification is needed before this type of analysis can be integrated into treatment assignment. Chemotherapeutic agents kill cancer cells by activating apoptosis, or programmed cell death. In Section V, Dr. John Reed describes major apoptotic pathways and the specific role of key proteins in this response. The expression level of some of these proteins, such as BCL2, BAX, and caspase 3, has been shown to be predictive of ultimate outcome in hematopoietic tumors. New therapeutic approaches that modulate the apoptotic pathway are now available and Dr. Reed highlights those that may be applicable to the treatment of childhood ALL. AD - Mount Sinai and New York University Schools of Medicine, New York, NY 10029-6574, USA. FAU - Carroll, William L AU - Carroll WL FAU - Bhojwani, Deepa AU - Bhojwani D FAU - Min, Dong-Joon AU - Min DJ FAU - Raetz, Elizabeth AU - Raetz E FAU - Relling, Mary AU - Relling M FAU - Davies, Stella AU - Davies S FAU - Downing, James R AU - Downing JR FAU - Willman, Cheryl L AU - Willman CL FAU - Reed, John C AU - Reed JC LA - eng GR - U01 CA88361/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - United States TA - Hematology (Am Soc Hematol Educ Program) JID - 100890099 SB - IM MH - Child MH - Gene Expression Profiling/methods MH - Gene Expression Regulation, Neoplastic MH - Humans MH - Leukemia, Lymphocytic, Acute, L1/classification/*genetics/*therapy MH - Pharmacogenetics MH - Prognosis MH - Research Support, U.S. Gov't, P.H.S. MH - Risk Assessment RF - 219 EDAT- 2003/11/25 05:00 MHDA- 2004/09/24 05:00 PST - ppublish SO - Hematology (Am Soc Hematol Educ Program) 2003;:102-31. DR -------------------------------------------------------------------------------- 9: Salavaggione OE et al. Cat red blood cell thiopurine...[PMID: 14610243] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14610243 OWN - NLM STAT- MEDLINE DA - 20040128 DCOM- 20040311 LR - 20041117 PUBM- Print-Electronic IS - 0022-3565 VI - 308 IP - 2 DP - 2004 Feb TI - Cat red blood cell thiopurine S-methyltransferase: companion animal pharmacogenetics. PG - 617-26 AB - A common genetic polymorphism for thiopurine S-methyltransferase (TPMT) is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of thiopurine drugs in humans. We set out to determine whether inheritance might also influence the level of TPMT activity in the domestic cat, Felis domesticus. As a first step, red blood cell (RBC) TPMT activity was measured in blood samples from 104 cats. The average level of cat RBC TPMT activity was lower than that observed in humans and was not related to either age or sex of the animal. We then cloned and characterized the F. domesticus TPMT cDNA and gene. Genotype-phenotype correlation analysis was performed by resequencing the cat TPMT gene using DNA samples from 12 animals with high and 12 with low levels of RBC TPMT activity. Thirty-one single nucleotide polymorphisms (SNPs) were observed in these 24 DNA samples, including five that altered the encoded amino acid, resulting in nine allozymes (six observed and three inferred). Twelve of the 31 feline TPMT SNPs were associated, collectively, with 56% of the variation in level of RBC TPMT activity in these 24 animals. When those 12 SNPs were assayed in all 89 cats for which DNA was available, 30% of the variation in level of RBC TPMT activity was associated with these 12 polymorphisms. After expression in COS-1 cells, five of the eight variant cat allozymes displayed decreased levels of both TPMT activity and immunoreactive protein compared with the wild-type allozyme. These observations are compatible with the conclusion that inheritance is an important factor responsible for variation in levels of RBC TPMT activity in the cat. They also represent a step toward the application of pharmacogenetic principles to companion animal thiopurine drug therapy. AD - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School, Mayo Clinic Mayo Foundation, Rochester, MN 55905, USA. FAU - Salavaggione, Oreste E AU - Salavaggione OE FAU - Yang, Chen AU - Yang C FAU - Kidd, Linda B AU - Kidd LB FAU - Thomae, Bianca A AU - Thomae BA FAU - Pankratz, V Shane AU - Pankratz VS FAU - Trepanier, Lauren A AU - Trepanier LA FAU - Weinshilboum, Richard M AU - Weinshilboum RM LA - eng GR - R01 GM28157/GM/NIGMS GR - R01 GM35720/GM/NIGMS GR - U01 GM61388/GM/NIGMS PT - Journal Article DEP - 20031110 PL - United States TA - J Pharmacol Exp Ther JID - 0376362 RN - 0 (DNA, Complementary) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Animals MH - COS Cells MH - Cats MH - Cloning, Molecular MH - DNA, Complementary/analysis MH - Erythrocytes/*enzymology MH - *Genome MH - Genotype MH - Methyltransferases/*genetics/metabolism MH - Pharmacogenetics MH - Phenotype MH - *Polymorphism, Genetic MH - Research Support, U.S. Gov't, P.H.S. EDAT- 2003/11/12 05:00 MHDA- 2004/03/12 05:00 PHST- 2003/11/10 [aheadofprint] AID - 10.1124/jpet.103.059055 [doi] AID - jpet.103.059055 [pii] PST - ppublish SO - J Pharmacol Exp Ther 2004 Feb;308(2):617-26. Epub 2003 Nov 10. DR -------------------------------------------------------------------------------- 10: Krynetski E et al. Drug methylation in cancer th...[PMID: 14576848] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 14576848 OWN - NLM STAT- MEDLINE DA - 20031024 DCOM- 20031121 LR - 20041117 PUBM- Print IS - 0950-9232 VI - 22 IP - 47 DP - 2003 Oct 20 TI - Drug methylation in cancer therapy: lessons from the TPMT polymorphism. PG - 7403-13 AB - The genetic polymorphism of thiopurine methyltransferase (TPMT) is one of the most developed examples of pharmacogenetics, spanning from molecular genetics to clinical diagnostics for individualizing thiopurine therapy (i.e. azathioprine, mercaptopurine, and thioguanine). Elucidation of the molecular mechanisms and biochemical consequences of TPMT deficiency demonstrates how pharmacogenetic traits can be identified, characterized, and translated to the bedside. Insights gained from studies of the TPMT polymorphism illustrate the potential of pharmacogenomics to optimize cancer therapy by avoiding toxic side effects in genetically distinct subgroups of patients. AD - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA. FAU - Krynetski, Eugene AU - Krynetski E FAU - Evans, William E AU - Evans WE LA - eng GR - CA 21765/CA/NCI GR - R37 CA 36401/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Oncogene JID - 8711562 RN - 0 (Antineoplastic Agents) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Amino Acid Sequence MH - Animals MH - Antineoplastic Agents/*metabolism MH - Evolution, Molecular MH - Humans MH - Methylation MH - Methyltransferases/chemistry/*genetics/*metabolism MH - Molecular Sequence Data MH - Neoplasms/*drug therapy/*enzymology/genetics MH - Pharmacogenetics MH - Polymorphism, Genetic/*genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. RF - 84 EDAT- 2003/10/25 05:00 MHDA- 2003/12/03 05:00 AID - 10.1038/sj.onc.1206944 [doi] AID - 1206944 [pii] PST - ppublish SO - Oncogene 2003 Oct 20;22(47):7403-13. DR -------------------------------------------------------------------------------- 11: Abbott A. With your genes? Take one of ...[PMID: 14574377] Related Articles, Substance via MeSH, Books, LinkOut PMID- 14574377 OWN - NLM STAT- MEDLINE DA - 20031023 DCOM- 20031117 LR - 20041117 PUBM- Print IS - 1476-4687 VI - 425 IP - 6960 DP - 2003 Oct 23 TI - With your genes? Take one of these, three times a day. PG - 760-2 FAU - Abbott, Alison AU - Abbott A LA - eng PT - News PL - England TA - Nature JID - 0410462 RN - 0 (Pharmaceutical Preparations) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM EIN - Nature. 2003 Sep 25;425(6956):337 MH - Clinical Trials/trends MH - Cost-Benefit Analysis MH - Cytochrome P-450 Enzyme System/genetics/metabolism MH - Databases, Genetic MH - Drug Labeling/legislation & jurisprudence/trends MH - Drug Toxicity/genetics/prevention & control MH - Genetic Predisposition to Disease/genetics MH - Genetic Screening/trends MH - Genomics/*trends MH - Humans MH - Methyltransferases/genetics/metabolism MH - Oligonucleotide Array Sequence Analysis MH - Pharmaceutical Preparations/*adverse effects/metabolism MH - Pharmacogenetics/*trends MH - Polymorphism, Single Nucleotide/genetics MH - Predictive Value of Tests MH - United States MH - United States Food and Drug Administration/legislation & jurisprudence EDAT- 2003/10/24 05:00 MHDA- 2003/12/03 05:00 AID - 10.1038/425760a [doi] AID - 425760a [pii] PST - ppublish SO - Nature 2003 Oct 23;425(6960):760-2. PR -------------------------------------------------------------------------------- 12: Clunie GP et al. Relevance of thiopurine methy...[PMID: 14566029] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 14566029 OWN - NLM STAT- MEDLINE DA - 20031218 DCOM- 20040310 LR - 20041117 PUBM- Print-Electronic IS - 1462-0324 VI - 43 IP - 1 DP - 2004 Jan TI - Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. PG - 13-8 AB - Azathioprine (AZA) is widely used in the management of rheumatological diseases. Despite its efficacy, AZA can often cause bone marrow suppression, notably leucopenia, which has been recorded in up to 17% of patients taking AZA for rheumatoid arthritis, though this can be considered clinically significant in about 3% overall. Severe myelosuppression, associated with abnormal AZA metabolism, is linked to the thiopurine methyltransferase (TPMT) genetic polymorphism. TPMT status can be assessed prior to AZA treatment by measuring enzyme activity or genotyping techniques. Analysis of recent data suggests that by optimizing the AZA dose on the basis of TPMT status testing (with a substantial reduction in dose for patients homozygous for mutant TPMT alleles), a reduction in drug-induced morbidity and cost savings can be made by avoiding hospitalization and rescue therapy for leucopenic events. In this article we review the pharmacogenetic and clinical implications of the TPMT polymorphism, emphasizing its relevance to rheumatologists managing diseases with AZA. AD - Rheumatology Department, Ipswich Hospital NHS Trust, Ipswich, UK. gavin.clunie@doctors.org.uk FAU - Clunie, G P R AU - Clunie GP FAU - Lennard, L AU - Lennard L LA - eng PT - Journal Article PT - Review DEP - 20031017 PL - England TA - Rheumatology (Oxford) JID - 100883501 RN - 0 (Antirheumatic Agents) RN - 0 (Biological Markers) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM MH - 6-Mercaptopurine/adverse effects/therapeutic use MH - Antirheumatic Agents/adverse effects/therapeutic use MH - Arthritis, Rheumatoid/blood/drug therapy/*genetics MH - Azathioprine/adverse effects/therapeutic use MH - Biological Markers/blood MH - Erythrocytes/enzymology MH - Genotype MH - Humans MH - Leukopenia/diagnosis/etiology MH - Methyltransferases/blood/*genetics MH - Pharmacogenetics MH - *Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't RF - 90 EDAT- 2003/10/21 05:00 MHDA- 2004/03/11 05:00 PHST- 2003/10/17 [aheadofprint] AID - 10.1093/rheumatology/keg442 [doi] AID - keg442 [pii] PST - ppublish SO - Rheumatology (Oxford) 2004 Jan;43(1):13-8. Epub 2003 Oct 17. DR -------------------------------------------------------------------------------- 13: Scheuermann TH et al. Tertiary structure of thiopur...[PMID: 14556746] Related Articles, Protein, Structure, 3D Domains, Books, LinkOut PMID- 14556746 OWN - NLM STAT- MEDLINE DA - 20031014 DCOM- 20031120 LR - 20041117 PUBM- Print IS - 0022-2836 VI - 333 IP - 3 DP - 2003 Oct 24 TI - Tertiary structure of thiopurine methyltransferase from Pseudomonas syringae, a bacterial orthologue of a polymorphic, drug-metabolizing enzyme. PG - 573-85 AB - In humans, the enzyme thiopurine methyltransferase (TPMT) metabolizes 6-thiopurine (6-TP) medications, including 6-thioguanine, 6-mercaptopurine and azathioprine, commonly used for immune suppression and for the treatment of hematopoietic malignancies. S-Methylation by TPMT prevents the intracellular conversion of these drugs into active 6-thioguanine nucleotides (6-TGNs). Genetic polymorphisms in the TPMT protein sequence have been associated with decreased tissue enzymatic activities and an increased risk of life-threatening myelo-suppression from standard doses of 6-TP medications. Biochemical studies have demonstrated that TPMT deficiency is primarily associated with increased degradation of the polymorphic proteins through an ubiquitylation and proteasomal-dependent pathway. We have now determined the tertiary structure of the bacterial orthologue of TPMT from Pseudomonas syringae using NMR spectroscopy. Bacterial TPMT similarly catalyzes the S-adenosylmethionine (SAM)-dependent transmethylation of 6-TPs and shares 45% similarity (33% identity) with the human enzyme. Initial studies revealed an unstructured N terminus, which was removed for structural studies and subsequently determined to be required for enzymatic activity. Despite lacking sequence similarity to any protein of known three-dimensional structure, the tertiary structure of bacterial TPMT reveals a classical SAM-dependent methyltransferase topology, consisting of a seven-stranded beta-sheet flanked by alpha-helices on both sides. However, some deviations from the consensus topology, along with multiple insertions of structural elements, are evident. A review of the many experimentally determined tertiary structures of SAM-dependent methyltransferases demonstrates that such structural deviations from the consensus topology are common and often functionally important. AD - Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA. FAU - Scheuermann, Thomas H AU - Scheuermann TH FAU - Lolis, Elias AU - Lolis E FAU - Hodsdon, Michael E AU - Hodsdon ME LA - eng SI - PDB/1PJZ GR - K08-AI01806/AI/NIAID GR - R01-AI43838/AI/NIAID PT - Journal Article PL - England TA - J Mol Biol JID - 2985088R RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Amino Acid Sequence MH - Binding Sites MH - Biotransformation MH - Humans MH - Methyltransferases/*chemistry/*metabolism MH - Models, Molecular MH - Molecular Sequence Data MH - Nuclear Magnetic Resonance, Biomolecular MH - Protein Structure, Quaternary MH - Pseudomonas/*enzymology MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Homology, Amino Acid MH - Structure-Activity Relationship EDAT- 2003/10/15 05:00 MHDA- 2003/12/03 05:00 AID - S0022283603010829 [pii] PST - ppublish SO - J Mol Biol 2003 Oct 24;333(3):573-85. PR -------------------------------------------------------------------------------- 14: Indjova D et al. Phenotypic and genotypic anal...[PMID: 14508387] Related Articles, Books, LinkOut PMID- 14508387 OWN - NLM STAT- MEDLINE DA - 20030925 DCOM- 20040105 LR - 20041117 PUBM- Print IS - 0163-4356 VI - 25 IP - 5 DP - 2003 Oct TI - Phenotypic and genotypic analysis of thiopurine s-methyltransferase polymorphism in the bulgarian population. PG - 631-6 AB - Genetic polymorphism of TPMT activity is an important factor responsible for large individual differences in thiopurine toxicity and therapeutic efficacy. The aim of this study was to determine the distribution of TPMT activity as well as the types and frequencies of mutant alleles in a Bulgarian population sample. TPMT activity was measured in 313 Bulgarians, using an established HPLC procedure. All individuals with TPMT activity less than 12.0 nmol/(mL Ery.h) (n = 76) were additionally genotyped using a color multiplex hybridization assay. The samples were tested for TPMT*2, *3A, *3B, *3C, *3D, *4, and *6 mutant alleles. TPMT activities varied from 1.1 to 24.0 nmol/(mL Ery.h) [mean 14.2 +/- 3.2 nmol/(mL Ery.h)]: 92.3% of the individuals investigated had high TPMT activity [>10 nmol/(mL Ery. h)], whereas 7.4% were intermediate [2.8-10 nmol/(mL Ery.h)], and 0.3% were low metabolizers [< 2.8 nmol/(mL Ery.h)]. A significant gender-related difference in TPMT activity (P = 0.02) was observed with 6.2% higher values in men than in women. There was no significant correlation between age and enzyme activity (r = 0.06, P = 0.27). Genotype analysis revealed three mutant TPMT alleles: 2, 3A, and 3C. The frequency of these alleles among the TPMT-deficient individuals was 2.17%, 30.4%, and 2.17%, respectively. These data show a similar distribution of TPMT activity among the Bulgarian population investigated as in most other white populations with the frequency of intermediate metabolizers being somewhat lower (7.4% versus approximately 11%) in the Bulgarians. The most common variant allele was TPMT-3A, as in other white populations. AD - Department of Clinical Laboratory, Medical University Sofia, Sofia, Bulgaria. dindjova@yahoo.com FAU - Indjova, Dessislava AU - Indjova D FAU - Atanasova, Srebrena AU - Atanasova S FAU - Shipkova, Maria AU - Shipkova M FAU - Armstrong, Victor W AU - Armstrong VW FAU - Oellerich, Michael AU - Oellerich M FAU - Svinarov, Dobrin AU - Svinarov D LA - eng PT - Journal Article PL - United States TA - Ther Drug Monit JID - 7909660 RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Aged, 80 and over MH - Alleles MH - Child MH - Genotype MH - Humans MH - Methyltransferases/*genetics/metabolism MH - Middle Aged MH - Phenotype MH - *Polymorphism, Genetic EDAT- 2003/09/26 05:00 MHDA- 2004/01/06 05:00 PST - ppublish SO - Ther Drug Monit 2003 Oct;25(5):631-6. DR -------------------------------------------------------------------------------- 15: Baker DE. Pharmacogenomics of azathiopr...[PMID: 14502119] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 14502119 OWN - NLM STAT- MEDLINE DA - 20030922 DCOM- 20031119 LR - 20041117 PUBM- Print IS - 1533-001X VI - 3 IP - 3 DP - 2003 Summer TI - Pharmacogenomics of azathioprine and 6-mercaptopurine in gastroenterologic therapy. PG - 150-7 AB - The elimination of azathioprine and 6-mercaptopurine is greatly influenced by polymorphisms in the enzymes responsible for their metabolism. Patients who are deficient in thiopurine methyltransferase (TPMT) are at an increased risk for azathioprine- and 6-mercaptopurine-induced toxicities because of the accumulation of toxic metabolites, and patients with high TPMT activity may not receive maximum benefit because of the increased clearance. Therefore, routine TPMT genotyping prior to the initiation of azathioprine or 6-mercaptopurine therapy should be considered to decrease the risk of severe and possibly preventable adverse effects and to identify patients who might benefit from higher doses. However, measuring the TPMT activity at baseline is not a substitute for monitoring white blood cell counts throughout therapy because drug therapy and/or other conditions may still cause myelosuppression in these patients. AD - College of Pharmacy, Washington State University, Spokane, Washington, USA. FAU - Baker, Danial E AU - Baker DE LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - United States TA - Rev Gastroenterol Disord JID - 101140143 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) SB - IM MH - 6-Mercaptopurine/administration & dosage/*adverse effects MH - Azathioprine/administration & dosage/*adverse effects MH - Clinical Trials MH - Female MH - Follow-Up Studies MH - Gastrointestinal Diseases/*drug therapy/*genetics MH - Genetic Screening MH - Humans MH - Immunosuppressive Agents/administration & dosage/*adverse effects MH - Male MH - Pharmacogenetics MH - Polymorphism, Genetic MH - Prospective Studies MH - Risk Assessment MH - Treatment Outcome RF - 38 EDAT- 2003/09/23 05:00 MHDA- 2003/12/03 05:00 PST - ppublish SO - Rev Gastroenterol Disord 2003 Summer;3(3):150-7. PR -------------------------------------------------------------------------------- 16: Wang L et al. Thiopurine S-methyltransferas...[PMID: 12972954] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 12972954 OWN - NLM STAT- MEDLINE DA - 20030915 DCOM- 20040430 LR - 20041117 PUBM- Print IS - 0960-314X VI - 13 IP - 9 DP - 2003 Sep TI - Thiopurine S-methyltransferase pharmacogenetics: chaperone protein association and allozyme degradation. PG - 555-64 AB - Thiopurine S-methyltransferase (TPMT) catalyses the S-methylation of thiopurine drugs such as 6-mercaptopurine. A common genetic polymorphism for TPMT is associated with large individual variations in thiopurine drug toxicity and therapeutic efficacy. TPMT*3A, the most common variant allele in Caucasians, has two alterations in amino acid sequence, resulting in striking decreases in TPMT protein levels. This phenomenon results, in part, from rapid degradation through a ubiquitin-proteasome-mediated process. We set out to test the hypothesis that chaperone proteins might be involved in targeting TPMT for degradation. As a first step, hsp90, hsp70 and the cochaperone hop were immunoprecipitated from a rabbit reticulocyte lysate (RRL) that included radioactively labelled *3A and wild-type TPMT. TPMT*3A was much more highly associated with all three chaperones than was the wild-type enzyme. The RRL was also used to confirm the accelerated degradation of *3A compared to wild-type TPMT. Treatment of RRL with the hsp90 inhibitor geldanamycin resulted in enhanced association of hsp90 with wild-type TPMT, an observation that correlated with accelerated ubiquitin-dependent degradation of wild-type TPMT. Geldanamycin treatment of COS-1 cells transfected with FLAG-tagged wild-type also resulted in a time and geldanamycin concentration-dependent decrease in TPMT activity and protein, which was compatible with results obtained in the RRL. These observations indicate that TPMT is a client protein for hsp90 and suggest that chaperone proteins, especially hsp90, are involved in targeting both TPMT*3A and, in the presence of geldanamycin, the wild-type allozyme for degradation. Therefore, chaperone proteins play an important mechanistic role in this clinically significant example of pharmacogenetic variation in drug metabolism. AD - Departments of Molecular Pharmacology and Experimental Therapeutics, Mayo Graduate School-Mayo Clinic-Mayo Foundation, Rochester, Minnesota 55905, USA. FAU - Wang, Liewei AU - Wang L FAU - Sullivan, William AU - Sullivan W FAU - Toft, David AU - Toft D FAU - Weinshilboum, Richard AU - Weinshilboum R LA - eng GR - R01 DK46249/DK/NIDDK GR - R01 GM28157/GM/NIGMS GR - R01 GM35720/GM/NIGMS GR - U01 GM61388/GM/NIGMS PT - Journal Article PL - England TA - Pharmacogenetics JID - 9211735 RN - 0 (Enzyme Inhibitors) RN - 0 (Heat-Shock Proteins) RN - 0 (Heat-Shock Proteins 70) RN - 0 (Heat-Shock Proteins 90) RN - 0 (Isoenzymes) RN - 0 (Quinones) RN - 0 (STIP1 protein, human) RN - 30562-34-6 (geldanamycin) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Alleles MH - Animals MH - COS Cells MH - Cercopithecus aethiops MH - Comparative Study MH - Enzyme Inhibitors/pharmacology MH - European Continental Ancestry Group MH - Heat-Shock Proteins/*metabolism MH - Heat-Shock Proteins 70/metabolism MH - Heat-Shock Proteins 90/drug effects/metabolism MH - Humans MH - Isoenzymes/*metabolism MH - Methyltransferases/*genetics/metabolism MH - *Pharmacogenetics MH - Polymorphism, Genetic MH - Quinones/pharmacology MH - Rabbits MH - Research Support, U.S. Gov't, P.H.S. MH - Reticulocytes/chemistry MH - Variation (Genetics) EDAT- 2003/09/16 05:00 MHDA- 2004/05/01 05:00 AID - 10.1097/01.fpc.0000054124.14659.99 [doi] PST - ppublish SO - Pharmacogenetics 2003 Sep;13(9):555-64. DR -------------------------------------------------------------------------------- 17: Gearry RB et al. Thiopurine S-methyltransferas...[PMID: 12940924] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12940924 OWN - NLM STAT- MEDLINE DA - 20030827 DCOM- 20031007 LR - 20041117 PUBM- Print IS - 0269-2813 VI - 18 IP - 4 DP - 2003 Aug 15 TI - Thiopurine S-methyltransferase (TPMT) genotype does not predict adverse drug reactions to thiopurine drugs in patients with inflammatory bowel disease. PG - 395-400 AB - BACKGROUND: Azathioprine and mercaptopurine (MP) are well established treatments for inflammatory bowel disease but they have severe adverse effects that prevent their use in some patients. The likelihood and type of adverse effect may relate to thiopurine methyltransferase (TPMT) enzyme activity and genotype. AIM: To compare the TPMT genotype frequencies in patients with inflammatory bowel disease who have had severe adverse effects to those who tolerate azathioprine or MP (controls). METHODS: Patients with inflammatory bowel disease who had been treated with azathioprine or MP in Christchurch between 1996 and 2002 were identified. Patients with adverse effects, and controls, were invited to provide a peripheral blood sample for analysis of TPMT genotype. The genotype frequencies were then compared between the two groups. RESULTS: Fifty-six patients were identified with adverse effects requiring cessation of therapy, of which 50 were genotyped. Reactions included allergic-type (25%), hepatitis (33%), nausea/vomiting (14%), bone marrow suppression (10%), pancreatitis (6%) and other (12%). Five of 50 patients with reactions had TPMT genotype *1/*3, one had *3/*3, and the rest had the wildtype genotype *1/*1. The patient with genotype *3/*3 had severe pancytopenia requiring hospitalization. Three of 50 controls had the *1/*3 genotype and the rest were *1/*1. CONCLUSIONS: The TPMT allele frequency in our population with inflammatory bowel disease is similar to that reported elsewhere. There was a slight trend for more frequent TPMT mutations in the patients with adverse reactions, but this was not statistically significant. Most patients with reactions did not have gene mutations. AD - Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand. richard.geary@cdhb.govt.nz FAU - Gearry, R B AU - Gearry RB FAU - Barclay, M L AU - Barclay ML FAU - Burt, M J AU - Burt MJ FAU - Collett, J A AU - Collett JA FAU - Chapman, B A AU - Chapman BA FAU - Roberts, R L AU - Roberts RL FAU - Kennedy, M A AU - Kennedy MA LA - eng PT - Clinical Trial PT - Controlled Clinical Trial PT - Journal Article PL - England TA - Aliment Pharmacol Ther JID - 8707234 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*adverse effects MH - Adolescent MH - Adult MH - Aged MH - Azathioprine/*adverse effects MH - Comparative Study MH - Female MH - Genotype MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Inflammatory Bowel Diseases/*drug therapy/enzymology MH - Methyltransferases/*genetics MH - Middle Aged MH - Research Support, Non-U.S. Gov't EDAT- 2003/08/28 05:00 MHDA- 2003/10/08 05:00 AID - 1690 [pii] PST - ppublish SO - Aliment Pharmacol Ther 2003 Aug 15;18(4):395-400. PR -------------------------------------------------------------------------------- 18: Schaeffeler E et al. A novel TPMT missense mutatio...[PMID: 12835738] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12835738 OWN - NLM STAT- MEDLINE DA - 20030701 DCOM- 20030807 LR - 20041117 PUBM- Print IS - 0887-6924 VI - 17 IP - 7 DP - 2003 Jul TI - A novel TPMT missense mutation associated with TPMT deficiency in a 5-year-old boy with ALL. PG - 1422-4 FAU - Schaeffeler, E AU - Schaeffeler E FAU - Stanulla, M AU - Stanulla M FAU - Greil, J AU - Greil J FAU - Schrappe, M AU - Schrappe M FAU - Eichelbaum, M AU - Eichelbaum M FAU - Zanger, U M AU - Zanger UM FAU - Schwab, M AU - Schwab M LA - eng PT - Case Reports PT - Letter PL - England TA - Leukemia JID - 8704895 RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/metabolism/therapeutic use MH - Child, Preschool MH - Family Health MH - Humans MH - Leukemia, Lymphocytic, Acute/drug therapy/*enzymology/genetics MH - Male MH - Methyltransferases/deficiency/*genetics MH - Mutation, Missense MH - Pedigree EDAT- 2003/07/02 05:00 MHDA- 2003/08/09 05:00 AID - 10.1038/sj.leu.2402981 [doi] AID - 2402981 [pii] PST - ppublish SO - Leukemia 2003 Jul;17(7):1422-4. DR -------------------------------------------------------------------------------- 19: van Aken J et al. Prospects and limits of pharm...[PMID: 12814323] Related Articles, Books, LinkOut PMID- 12814323 OWN - NLM STAT- MEDLINE DA - 20030619 DCOM- 20040227 LR - 20041117 PUBM- Print IS - 1175-2203 VI - 3 IP - 3 DP - 2003 TI - Prospects and limits of pharmacogenetics: the thiopurine methyl transferase (TPMT) experience. PG - 149-55 AB - Thiopurine drug metabolism is a quintessential case of pharmacogenetics. A wealth of experimental and clinical data on polymorphisms in the thiopurine metabolizing enzyme thiopurine methyl transferase (TPMT) has been generated in the past decade. Pharmacogenetic testing prior to thiopurine treatment is already being practiced to some extent in the clinical context, and it is likely that it will be among the first pharmacogenetic tests applied on a regular basis. We analyzed the published TPMT data and identified some lessons to be learned for the future implementation of pharmacogenetics for thiopurines as well as in other fields. These include the need for comprehensive and unbiased data on allele frequencies relevant to a broad range of populations worldwide. The nature and frequency of TPMT gene polymorphisms in some ethnic groups is still a matter of speculation, as the vast majority of studies on TPMT allele distribution are limited to only a small subset of alleles and populations. Secondly, an appreciation of the limits of pharmacogenetics is warranted, as pharmacogenetic testing can help in avoiding some, but by far not all adverse effects of drug therapy. An analysis of six clinical studies correlating adverse thiopurine effects and TPMT genotype revealed that an average of 78% of adverse drug reactions were not associated with TPMT polymorphisms. Pharmacogenetic testing will thus not eliminate the need for careful clinical monitoring of adverse drug reactions. Finally, a careful approach toward dose increases for patients with high enzyme activity is necessary, as TPMT-mediated methylation of thiopurines generates a possibly hepatotoxic byproduct. AD - Research Center for Biotechnology, Society and the Environment, University of Hamburg, Hamburg, Germany. FAU - van Aken, Jan AU - van Aken J FAU - Schmedders, Mechtild AU - Schmedders M FAU - Feuerstein, Gunter AU - Feuerstein G FAU - Kollek, Regine AU - Kollek R LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - New Zealand TA - Am J Pharmacogenomics JID - 100967746 RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Animals MH - Gene Frequency/physiology MH - Humans MH - Methyltransferases/*genetics/metabolism MH - Pharmacogenetics/*methods/*trends MH - Research Support, Non-U.S. Gov't RF - 39 EDAT- 2003/06/20 05:00 MHDA- 2004/02/28 05:00 AID - 331 [pii] PST - ppublish SO - Am J Pharmacogenomics 2003;3(3):149-55. PR -------------------------------------------------------------------------------- 20: El-Azhary RA. Azathioprine: current status ...[PMID: 12755967] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12755967 OWN - NLM STAT- MEDLINE DA - 20030520 DCOM- 20031030 LR - 20041117 PUBM- Print IS - 0011-9059 VI - 42 IP - 5 DP - 2003 May TI - Azathioprine: current status and future considerations. PG - 335-41 AD - Department of Dermatology, Mayo Clinic, Rochester, Minnesota 55905, USA. elazhary.rokea2@mayo.edu FAU - El-Azhary, Rokea A AU - El-Azhary RA LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - United States TA - Int J Dermatol JID - 0243704 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Dermatologic Agents) RN - 154-42-7 (Thioguanine) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Antimetabolites, Antineoplastic/blood MH - Azathioprine/chemistry/pharmacokinetics/*pharmacology MH - Dermatologic Agents/chemistry/pharmacokinetics/*pharmacology MH - Drug Interactions MH - Erythrocytes/metabolism MH - Humans MH - Methyltransferases/drug effects/*genetics/metabolism MH - Molecular Structure MH - Polymorphism, Genetic MH - Thioguanine/blood RF - 69 EDAT- 2003/05/21 05:00 MHDA- 2003/10/31 05:00 AID - 1823 [pii] PST - ppublish SO - Int J Dermatol 2003 May;42(5):335-41. NR -------------------------------------------------------------------------------- 21: Oscarson M. Pharmacogenetics of drug meta...[PMID: 12747605] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12747605 OWN - NLM STAT- MEDLINE DA - 20030515 DCOM- 20030625 LR - 20041117 PUBM- Print IS - 1434-6621 VI - 41 IP - 4 DP - 2003 Apr TI - Pharmacogenetics of drug metabolising enzymes: importance for personalised medicine. PG - 573-80 AB - The number of polymorphisms identified in genes encoding drug metabolising enzymes, drug transporters, and receptors is rapidly increasing. In many cases, these genetic factors have a major impact on the pharmacokinetics and pharmacodynamics of a particular drug and thereby influence the sensitivity to such drug in an individual patient with a certain genotype. The highest impact is seen for drugs with a narrow therapeutic index, with important examples emerging from treatment with antidepressants, oral anticoagulants, and cytostatics, which are metabolised by the polymorphic enzymes cytochrome P450 2D6 (CYP2D6), cytochrome P450 2C9 (CYP2C9), and thiopurine-S-methyltransferase (TPMT), respectively. In order to apply the increasing amount of pharmacogenetic knowledge to clinical practise, specific dosage recommendations based on genotypes will have to be developed to guide the clinician, and these recommendations will have to be evaluated in prospective clinical studies. Such development will lead to a patient-tailored drug therapy which hopefully would be more efficient and will result in fewer adverse drug reactions. AD - Division of Pharmacology/Neurobiology, Biozentrum, University of Basel, Basel, Switzerland. Mikael.Oscarson@unibas.ch FAU - Oscarson, Mikael AU - Oscarson M LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Germany TA - Clin Chem Lab Med JID - 9806306 RN - 0 (Pharmaceutical Preparations) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Cytochrome P-450 Enzyme System/*genetics/metabolism MH - Genotype MH - Humans MH - Methyltransferases/*genetics/metabolism MH - Neoplasms/drug therapy MH - Pharmaceutical Preparations/metabolism MH - *Pharmacogenetics MH - Pharmacology, Clinical MH - Polymorphism, Genetic/*genetics RF - 64 EDAT- 2003/05/16 05:00 MHDA- 2003/06/26 05:00 PST - ppublish SO - Clin Chem Lab Med 2003 Apr;41(4):573-80. NR -------------------------------------------------------------------------------- 22: Scherl E et al. Optimization and individualiz...[PMID: 12746731] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12746731 OWN - NLM STAT- MEDLINE DA - 20030514 DCOM- 20040107 LR - 20041117 PUBM- Print IS - 1470-269X VI - 3 IP - 2 DP - 2003 TI - Optimization and individualization of thiopurine therapy in inflammatory bowel disease: the great variability among drug responses. PG - 66-8 AD - Division of Gastroenterology and Hepatology, The Weill Medical College of Cornell University, The New York Presbyterian Hospital, 425 E 61st Street, New York, NY 10021, USA. FAU - Scherl, E AU - Scherl E FAU - Subbaramiah, K AU - Subbaramiah K LA - eng PT - Comment PT - Journal Article PL - United States TA - Pharmacogenomics J JID - 101083949 RN - 0 (Immunosuppressive Agents) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM CON - Pharmacogenetics. 2002 Aug;12(6):429-36. PMID: 12172211 MH - 6-Mercaptopurine/administration & dosage/adverse effects/*therapeutic use MH - Genotype MH - Humans MH - Immunosuppressive Agents/administration & dosage/adverse effects/*therapeutic use MH - Inflammatory Bowel Diseases/*drug therapy MH - Methyltransferases/genetics/metabolism MH - Phenotype MH - Polymorphism, Genetic/genetics MH - Research Support, Non-U.S. Gov't EDAT- 2003/05/15 05:00 MHDA- 2004/01/08 05:00 AID - 10.1038/sj.tpj.6500162 [doi] AID - 6500162 [pii] PST - ppublish SO - Pharmacogenomics J 2003;3(2):66-8. PR -------------------------------------------------------------------------------- 23: Seidman EG. Clinical use and practical ap...[PMID: 12684587] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12684587 OWN - NLM STAT- MEDLINE DA - 20030409 DCOM- 20030610 LR - 20041117 PUBM- Print IS - 1533-001X VI - 3 Suppl 1 DP - 2003 TI - Clinical use and practical application of TPMT enzyme and 6-mercaptopurine metabolite monitoring in IBD. PG - S30-8 AB - 6-mercaptopurine (6-MP) and its parent drug azathioprine (AZA) have been proven to be effective for both steroid-dependent and chronically active, or steroid-resistant inflammatory bowel disease, as well as for the prevention of relapse. Concerns about toxicity, delayed onset of action, and therapeutic failure (1 out of 3 patients) have restricted their use. Recent pharmacogenetic advances have led to the development of novel strategies to optimize and individualize therapy with AZA and 6-MP, maximizing efficacy while minimizing toxicity. We have defined a range of optimal therapeutic 6-MP metabolite levels, as well as an association of metabolite levels with medication-induced toxicity and the genotype of the main catabolic enzyme, thiopurine methyltransferase (TPMT). Measurement of 6-MP metabolite levels and TPMT molecular analysis provide clinicians with useful tools for optimizing therapeutic response to 6-MP/AZA, as well as for identifying individuals at increased risk for drug-induced toxicity. AD - Division of Gastroenterology, Hepatology, and Nutrition, Faculty of Medicine, University of Montreal, Montreal, Canada. FAU - Seidman, Ernest G AU - Seidman EG LA - eng PT - Journal Article PL - United States TA - Rev Gastroenterol Disord JID - 101140143 RN - 0 (Antimetabolites) RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/adverse effects/metabolism/*therapeutic use MH - Antimetabolites/adverse effects/metabolism/*therapeutic use MH - Azathioprine/adverse effects/*therapeutic use MH - Evidence-Based Medicine MH - Genotype MH - Humans MH - Immunosuppressive Agents/adverse effects/*therapeutic use MH - Inflammatory Bowel Diseases/*drug therapy/*metabolism MH - Liver/drug effects MH - Methyltransferases/genetics/*metabolism MH - Pharmacogenetics MH - Polymorphism, Genetic MH - Remission Induction EDAT- 2003/04/10 05:00 MHDA- 2003/06/11 05:00 PST - ppublish SO - Rev Gastroenterol Disord 2003;3 Suppl 1:S30-8. DR -------------------------------------------------------------------------------- 24: Watters JW et al. Cancer pharmacogenomics: curr...[PMID: 12618310] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 12618310 OWN - NLM STAT- MEDLINE DA - 20030305 DCOM- 20030610 LR - 20041117 PUBM- Print IS - 0006-3002 VI - 1603 IP - 2 DP - 2003 Mar 17 TI - Cancer pharmacogenomics: current and future applications. PG - 99-111 AB - Heterogeneity in patient response to chemotherapy is consistently observed across patient populations. Pharmacogenomics is the study of inherited differences in interindividual drug disposition and effects, with the goal of selecting the optimal drug therapy and dosage for each patient. Pharmacogenomics is especially important for oncology, as severe systemic toxicity and unpredictable efficacy are hallmarks of cancer therapies. In addition, genetic polymorphisms in drug metabolizing enzymes and other molecules are responsible for much of the interindividual differences in the efficacy and toxicity of many chemotherapy agents. This review will discuss clinically relevant examples of gene polymorphisms that influence the outcome of cancer therapy, and whole-genome expression studies using microarray technology that have shown tremendous potential for benefiting cancer pharmacogenomics. The power and utility of the mouse as an experimental system for pharmacogenomic discovery will also be discussed in the context of cancer therapy. CI - Copyright 2003 Elsevier Science B.V. AD - Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave-Campus Box 8069, St Louis, MO 63110, USA. FAU - Watters, James W AU - Watters JW FAU - McLeod, Howard L AU - McLeod HL LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Netherlands TA - Biochim Biophys Acta JID - 0217513 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Agents, Phytogenic) RN - 0 (DNA Adducts) RN - 0 (Organoplatinum Compounds) RN - 100286-90-6 (irinotecan) RN - 50-44-2 (6-Mercaptopurine) RN - 51-21-8 (Fluorouracil) RN - 7689-03-4 (Camptothecin) RN - EC 1. (Oxidoreductases) RN - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP)) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.45 (Thymidylate Synthase) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.4.1.- (phenol glucuronosyltransferase) RN - EC 2.4.1.17 (Glucuronosyltransferase) RN - EC 2.5.1.18 (Glutathione Transferase) SB - IM MH - 6-Mercaptopurine/metabolism MH - Animals MH - Antimetabolites, Antineoplastic/metabolism MH - Antineoplastic Agents, Phytogenic/metabolism MH - Camptothecin/adverse effects/*analogs & derivatives/metabolism MH - DNA Adducts/metabolism MH - DNA Repair/genetics MH - Dihydrouracil Dehydrogenase (NADP) MH - Disease Models, Animal MH - Fluorouracil/adverse effects/metabolism MH - Glucuronosyltransferase/biosynthesis/genetics MH - Glutathione Transferase/genetics/metabolism MH - Humans MH - Methyltransferases/genetics/metabolism MH - Neoplasms/drug therapy/*genetics/metabolism MH - Organoplatinum Compounds/metabolism MH - Oxidoreductases/metabolism MH - Pharmacogenetics/*trends MH - Polymorphism, Genetic MH - Thymidylate Synthase/antagonists & inhibitors/genetics RF - 88 EDAT- 2003/03/06 04:00 MHDA- 2003/06/11 05:00 AID - S0304419X03000039 [pii] PST - ppublish SO - Biochim Biophys Acta 2003 Mar 17;1603(2):99-111. DR -------------------------------------------------------------------------------- 25: Daly AK. Pharmacogenetics of the major...[PMID: 12588628] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12588628 OWN - NLM STAT- MEDLINE DA - 20030217 DCOM- 20031003 LR - 20041117 PUBM- Print IS - 0767-3981 VI - 17 IP - 1 DP - 2003 Feb TI - Pharmacogenetics of the major polymorphic metabolizing enzymes. PG - 27-41 AB - There is increasing information available on the existence of polymorphisms in genes encoding xenobiotic metabolizing enzymes and the functional significance of many of these. In addition to genes long recognized as being polymorphic, such as CYP2D6, CYP2C19 and CYP2C9, there is now information available on the existence of polymorphisms in other cytochrome P450 genes such as CYP2A6, CYP2B6 and CYP2C8. With respect to phase II metabolism, polymorphisms in GSTM1, GSTT1, NAT2 and TPMT are well understood but information is also emerging on other GST polymorphisms and on polymorphisms in the UDP-glucuronosyltransferases and sulfotransferases. The availability of comprehensive information on the occurrence and functional significance of polymorphisms affecting drug metabolism should facilitate their application to pharmacogenomic profiling. AD - Department of Pharmacological Sciences, University of Newcastle, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK. A.K.Daly@ncl.ac.uk FAU - Daly, A K AU - Daly AK LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Fundam Clin Pharmacol JID - 8710411 RN - 0 (Enzymes) RN - 0 (Xenobiotics) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Cytochrome P-450 Enzyme System/classification/genetics/metabolism MH - Enzymes/*genetics/metabolism MH - Humans MH - *Pharmacogenetics MH - *Polymorphism, Genetic MH - Xenobiotics/*metabolism RF - 139 EDAT- 2003/02/18 04:00 MHDA- 2003/10/04 05:00 AID - 119 [pii] PST - ppublish SO - Fundam Clin Pharmacol 2003 Feb;17(1):27-41. PR -------------------------------------------------------------------------------- 26: Nagasubramanian R et al. Pharmacogenetics in cancer tr...[PMID: 12525681] Related Articles, Cited in PMC, Books, LinkOut PMID- 12525681 OWN - NLM STAT- MEDLINE DA - 20030114 DCOM- 20030603 LR - 20041117 PUBM- Print-Electronic IS - 0066-4219 VI - 54 DP - 2003 TI - Pharmacogenetics in cancer treatment. PG - 437-52 AB - Interindividual variability in the efficacy and toxicity of drug therapy is associated with polymorphisms in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Pharmacogenetics aims to identify individuals predisposed to high risk of toxicity from conventional doses of cancer chemotherapeutic agents. We review the role of genetic polymorphisms in UGT1A1 and TPMT, as well as mutations in DPD, in influencing drug disposition and toxicity. Recent studies show that pharmacogenetic determinants may also influence treatment outcomes. We discuss the clinical significance of polymorphisms in TS, MTHFR, and FCGR3A, as well as the polymorphic DNA repair genes XPD and XRCC1, in influencing response to chemotherapy and survival outcomes. Finally, the potential implications of transporter pharmacogenetics in influencing drug bioavailability are addressed. AD - Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA. rnagasub@peds.bsd.uchicago.edu FAU - Nagasubramanian, R AU - Nagasubramanian R FAU - Innocenti, F AU - Innocenti F FAU - Ratain, M J AU - Ratain MJ LA - eng GR - GM61393/GM/NIGMS PT - Journal Article PT - Review DEP - 20011203 PL - United States TA - Annu Rev Med JID - 2985151R RN - 0 (Antineoplastic Agents) SB - IM MH - Antineoplastic Agents/adverse effects/pharmacokinetics/*therapeutic use MH - Biotransformation/genetics MH - Humans MH - Metabolic Detoxication, Drug/genetics MH - Neoplasms/*drug therapy/genetics MH - *Pharmacogenetics MH - Polymorphism, Genetic/genetics MH - Research Support, U.S. Gov't, P.H.S. MH - Treatment Outcome RF - 75 EDAT- 2003/01/15 04:00 MHDA- 2003/06/05 05:00 PHST- 2001/12/03 [aheadofprint] AID - 10.1146/annurev.med.54.101601.152352 [doi] AID - 101601.152352 [pii] PST - ppublish SO - Annu Rev Med 2003;54:437-52. Epub 2001 Dec 3. DR -------------------------------------------------------------------------------- 27: Corominas H et al. Is thiopurine methyltransfera...[PMID: 12509611] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12509611 OWN - NLM STAT- MEDLINE DA - 20030101 DCOM- 20030221 LR - 20041117 PUBM- Print IS - 1462-0324 VI - 42 IP - 1 DP - 2003 Jan TI - Is thiopurine methyltransferase genetic polymorphism a major factor for withdrawal of azathioprine in rheumatoid arthritis patients? PG - 40-5 AB - OBJECTIVE: To determine whether the presence of thiopurine methyltransferase (TPMT) alleles associated with reduced or absent activity of thiopurine methyltransferase is a major factor for withdrawal of azathioprine (AZA) in rheumatoid arthritis (RA) patients. METHODS: The TPMT genotype, including the variable number of tandem repeats (VNTR) pattern in the 5' untranslated region, was analysed in 111 patients with long-standing RA. Azathioprine (AZA) therapy was used in 40 patients (36%) as a disease-modifying anti-rheumatic drug. RESULTS: Seven out of 111 RA patients (6.3%) were carriers of a mutant allele, TPMT3A (G(460)-->A, A(719)-->G) being the mutant allele observed most frequently. In the group of 40 AZA-treated patients, therapy was discontinued in six patients because of side-effects and in 26 patients because of lack of efficacy. Three patients presented moderate side-effects and were homozygous for the wild-type TPMT allele, whereas the remaining three patients, who developed gastrointestinal effects with severe nausea and vomiting, were TPMT3A carriers. CONCLUSION: In this observational study, the absence of response, probably due to the low-dose scheme used, was the major cause of AZA withdrawal in our series of RA patients. TPMT genotyping may allow the use of high doses of AZA in patients with normal TPMT alleles to improve the efficacy of this immunosuppressive drug. Our data support the relationship between gastrointestinal intolerance and thiopurine metabolic imbalance. AD - Unitat de Reumatologia, Servei de Medicina Interna, Hospital Universitari de la Santa Creu i Sant Pau, Avda Sant Antoni M. Claret 167, 08025 Barcelona, Spain. FAU - Corominas, H AU - Corominas H FAU - Domenech, M AU - Domenech M FAU - Laiz, A AU - Laiz A FAU - Gich, I AU - Gich I FAU - Geli, C AU - Geli C FAU - Diaz, C AU - Diaz C FAU - de Cuevillas, F AU - de Cuevillas F FAU - Moreno, M AU - Moreno M FAU - Vazquez, G AU - Vazquez G FAU - Baiget, M AU - Baiget M LA - eng PT - Journal Article PL - England TA - Rheumatology (Oxford) JID - 100883501 RN - 0 (5' Untranslated Regions) RN - 0 (Antirheumatic Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM MH - 5' Untranslated Regions MH - Antirheumatic Agents/adverse effects/*contraindications MH - Arthritis, Rheumatoid/drug therapy/*enzymology/genetics MH - Azathioprine/adverse effects/*contraindications MH - Case-Control Studies MH - Chi-Square Distribution MH - Heterozygote MH - Homozygote MH - Humans MH - Methyltransferases/*genetics MH - Minisatellite Repeats MH - Nausea/chemically induced MH - *Polymorphism, Genetic MH - Vomiting/chemically induced EDAT- 2003/01/02 04:00 MHDA- 2003/02/22 04:00 PST - ppublish SO - Rheumatology (Oxford) 2003 Jan;42(1):40-5. DR -------------------------------------------------------------------------------- 28: Marra CA et al. Practical pharmacogenetics: t...[PMID: 12465143] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12465143 OWN - NLM STAT- MEDLINE DA - 20021204 DCOM- 20030507 LR - 20041117 PUBM- Print IS - 0315-162X VI - 29 IP - 12 DP - 2002 Dec TI - Practical pharmacogenetics: the cost effectiveness of screening for thiopurine s-methyltransferase polymorphisms in patients with rheumatological conditions treated with azathioprine. PG - 2507-12 AB - OBJECTIVE: Thiopurine S-methyltransferase (TPMT), which catalyzes the inactivation of azathioprine (AZA), exhibits genetic polymorphism that results in dose related, serious toxicities (mainly hematological cytopenias) in 10-15% of individuals treated with AZA. Polymerase chain reaction (PCR) tests provide a sensitive, specific means of prospectively identifying these patients before AZA therapy and minimizing toxicity through dosage reduction. Our objective was to model the cost effectiveness of the 2 alternative AZA treatment strategies in rheumatologic conditions: (1) utilizing PCR to determine polymorphisms leading to TPMT deficiencies prior to AZA therapy with a reduction in dose; and (2) no testing. The analysis was conducted from a third party payer perspective over one year. METHODS: A decision analytic model was applied to map the costs and outcomes of patients under both strategies. Data applied to the model included the positive and negative predictive values of the PCR, the probabilities of adverse events due to AZA, and the costs associated with their management. Sources of data included published clinical trials, diagnostic test evaluations, surveillance trials, and economic evaluations. RESULTS: Dose related toxicities resulted in AZA discontinuation rates of 10-20%. The usual dosing strategy cost $677 Cdn per patient, whereas the genotype directed dosing strategy cost $663 Cdn per patient. In the genotype dosing strategy, the number needed to treat to avoid one adverse event over 6 months was 20. Thus, the genotype based dosing strategy dominated the usual dosing strategy. One-way sensitivity analyses revealed that the estimates were robust to ranges of +/- 30% for the costs, the properties of the PCR test, and the probability of adverse events. CONCLUSION: The introduction of PCR testing to identify TPMT polymorphisms prior to AZA treatment may represent good value in certain health care settings. AD - Department of Health Care and Epidemiology, University of British Columbia, Vancouver, Canada. FAU - Marra, Carlo A AU - Marra CA FAU - Esdaile, John M AU - Esdaile JM FAU - Anis, Aslam H AU - Anis AH LA - eng PT - Journal Article PL - Canada TA - J Rheumatol JID - 7501984 RN - 0 (Antirheumatic Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Antirheumatic Agents/pharmacokinetics/*therapeutic use MH - Arthritis, Rheumatoid/drug therapy/economics/enzymology/genetics MH - Azathioprine/pharmacokinetics/*therapeutic use MH - Cost-Benefit Analysis MH - Decision Support Techniques MH - Genetic Screening/*economics/methods MH - Health Care Costs MH - Humans MH - Lupus Erythematosus, Systemic/drug therapy/economics/enzymology/genetics MH - Methyltransferases/*genetics MH - Pancytopenia/chemically induced/economics/genetics/prevention & control MH - Pharmacogenetics/*economics/methods MH - Polymerase Chain Reaction MH - *Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Rheumatic Diseases/drug therapy/*economics/enzymology/genetics EDAT- 2002/12/05 04:00 MHDA- 2003/05/08 05:00 AID - 0315162X-29-2507 [pii] PST - ppublish SO - J Rheumatol 2002 Dec;29(12):2507-12. DR -------------------------------------------------------------------------------- 29: Salavaggione OE et al. Canine red blood cell thiopur...[PMID: 12464800] Related Articles, Gene, HomoloGene, UniGene, Nucleotide, Protein, Books, LinkOut PMID- 12464800 OWN - NLM STAT- MEDLINE DA - 20021204 DCOM- 20030707 LR - 20041117 PUBM- Print IS - 0960-314X VI - 12 IP - 9 DP - 2002 Dec TI - Canine red blood cell thiopurine S-methyltransferase: companion animal pharmacogenetics. PG - 713-24 AB - Thiopurine S-methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs. In humans, a common genetic polymorphism for TPMT is a major factor responsible for individual variation in the toxicity and therapeutic efficacy of these drugs. Dogs (Canis familiaris) are also treated with thiopurine drugs and, similar to humans, they display large individual variations in thiopurine toxicity and efficacy. We set out to determine whether dogs might also display genetically determined variation in TPMT activity. As a first step, we observed that canine red blood cell (RBC) TPMT activity in samples from 145 dogs varied over a nine-fold range. That variation was not associated with either the age or sex of the animal. Subsequently, we cloned the canine TPMT cDNA and gene. The canine cDNA encoded a protein that was 81.2% identical to the enzyme encoded by the most common TPMT allele in humans. A genotype-phenotype correlation analysis was performed by resequencing the canine gene using DNA samples from 39 animals selected for high, low or intermediate levels of RBC TPMT activity. We observed nine polymorphisms in these 39 DNA samples, including three insertion/deletion events and six single nucleotide polymorphisms (SNPs), one of which was a nonsynonymous cSNP (Arg97Gln). However, when the variant allozyme at codon 97 was expressed in COS-1 cells, it did not display significant differences in either basal levels of TPMT activity or in substrate kinetics compared with the wild-type allozyme. Six of the nine canine TPMT polymorphisms were associated with 67% of the variation in level of RBC TPMT activity in these 39 blood samples. When those six SNPs were assayed using DNA from all 145 animals studied, 40% of the phenotypic variance in the entire population sample could be explained by these polymorphisms. Therefore, inheritance is a major factor involved in the regulation of variation in RBC TPMT in the dog, just as it is in humans. These observations represent a step towards the application of pharmacogenetic and pharmacogenomic principles to companion animal drug therapy. CI - Copyright 2002 Lippincott Williams & Wilkins AD - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School-Mayo Clinic-Mayo Foundation, Rochester, Minnesota 55905, USA. FAU - Salavaggione, Oreste E AU - Salavaggione OE FAU - Kidd, Linda AU - Kidd L FAU - Prondzinski, Janel L AU - Prondzinski JL FAU - Szumlanski, Carol L AU - Szumlanski CL FAU - Pankratz, V Shane AU - Pankratz VS FAU - Wang, Liewei AU - Wang L FAU - Trepanier, Lauren AU - Trepanier L FAU - Weinshilboum, Richard M AU - Weinshilboum RM LA - eng SI - GENBANK/AY057077 SI - GENBANK/AY057078 SI - GENBANK/AY057087 GR - R01 GM28157/GM/NIGMS GR - R01 GM35720/GM/NIGMS GR - U01 GM61388/GM/NIGMS PT - Journal Article PL - England TA - Pharmacogenetics JID - 9211735 RN - 0 (DNA Primers) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Animals MH - COS Cells MH - Cercopithecus aethiops MH - Cloning, Molecular MH - Comparative Study MH - DNA Primers/chemistry MH - Dogs/*blood MH - Erythrocytes/*enzymology MH - Exons MH - Gene Frequency MH - Genotype MH - Introns MH - Methyltransferases/*genetics MH - Molecular Sequence Data MH - Mutagenesis, Site-Directed MH - Pharmacogenetics MH - Phenotype MH - Phylogeny MH - Polymerase Chain Reaction MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. EDAT- 2002/12/05 04:00 MHDA- 2003/07/08 05:00 PST - ppublish SO - Pharmacogenetics 2002 Dec;12(9):713-24. DR -------------------------------------------------------------------------------- 30: Ansari A et al. Thiopurine methyltransferase ...[PMID: 12269967] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12269967 OWN - NLM STAT- MEDLINE DA - 20020924 DCOM- 20030129 LR - 20041117 PUBM- Print IS - 0269-2813 VI - 16 IP - 10 DP - 2002 Oct TI - Thiopurine methyltransferase activity and the use of azathioprine in inflammatory bowel disease. PG - 1743-50 AB - BACKGROUND: Azathioprine therapy is discontinued in one-third of patients with inflammatory bowel disease because of toxicity or a lack of clinical response. Patients with thiopurine methyltransferase (TPMT) deficiency are intolerant to azathioprine, whilst carriers are at increased risk of side-effects. AIM: To evaluate the importance of TPMT activity in the management of azathioprine therapy in inflammatory bowel disease. METHODS: Clinical response, adverse effects and haematological parameters were determined and correlated with TPMT enzyme activity and genotype in 106 patients with inflammatory bowel disease. RESULTS: Ninety-six patients had high TPMT activity, and 10 had intermediate activity. Nineteen patients (18%) were intolerant to azathioprine. Fifteen (16%) of those with high TPMT activity were intolerant, compared with five (50%) with intermediate activity [odds ratio (OR), 5.4; 95% confidence interval (CI), 1.5-19.8]. Complete remission was achieved in 63% of cases, and complete or partial remission in 79%. Interestingly, very high TPMT activity (> 14 units/mL red blood cells) was significantly associated with non-response, irrespective of the time on azathioprine (OR, 0.21; 95% CI, 0.07-0.68). TPMT gene mutations correlated with TPMT activity. CONCLUSIONS: Inflammatory bowel disease patients with intermediate TPMT activity have an increased risk of azathioprine toxicity. Conversely, very high TPMT activity predicts treatment failure. TPMT genotype predicted TPMT phenotype in this study. AD - Department of Public Health Medicine, GKT School of Medicine, London, UK. FAU - Ansari, A AU - Ansari A FAU - Hassan, C AU - Hassan C FAU - Duley, J AU - Duley J FAU - Marinaki, A AU - Marinaki A FAU - Shobowale-Bakre, E-M AU - Shobowale-Bakre EM FAU - Seed, P AU - Seed P FAU - Meenan, J AU - Meenan J FAU - Yim, A AU - Yim A FAU - Sanderson, J AU - Sanderson J LA - eng PT - Journal Article PL - England TA - Aliment Pharmacol Ther JID - 8707234 RN - 0 (Biological Markers) RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adult MH - Azathioprine/adverse effects/*therapeutic use MH - Biological Markers/blood MH - Erythrocytes/enzymology MH - Female MH - Genotype MH - Humans MH - Immunosuppressive Agents/adverse effects/*therapeutic use MH - Inflammatory Bowel Diseases/*drug therapy/enzymology MH - Leukocyte Count MH - Logistic Models MH - Male MH - Methyltransferases/*blood/genetics MH - Middle Aged MH - Odds Ratio MH - Research Support, Non-U.S. Gov't MH - Retrospective Studies MH - Treatment Failure EDAT- 2002/09/25 06:00 MHDA- 2003/01/30 04:00 AID - 1353 [pii] PST - ppublish SO - Aliment Pharmacol Ther 2002 Oct;16(10):1743-50. DR -------------------------------------------------------------------------------- 31: Wood TC et al. Cefazolin administration and ...[PMID: 12228189] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12228189 OWN - NLM STAT- MEDLINE DA - 20020913 DCOM- 20030226 LR - 20041117 PUBM- Print IS - 0090-9556 VI - 30 IP - 10 DP - 2002 Oct TI - Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue: possible relationship to hypoprothrombinemia. PG - 1123-8 AB - Cephalosporin antibiotics with structures that include the heterocyclic leaving group 1-methyltetrazole-5-thiol (MTT) can cause hypoprothrombinemia and hemorrhage as a result of MTT-dependent inhibition of the gamma-carboxylation of glutamate. The structure of cefazolin also includes a heterocyclic thiol, 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), and this compound can also inhibit the gamma-carboxylation of glutamate. However, unlike MTT, which is known to be present in vivo after the administration of drugs that include this structure, there have been no reports that MTD is present in vivo after cefazolin administration. We set out to determine whether MTD might be present in the tissues of patients treated with cefazolin prior to surgery. To do that, we took advantage of the fact that heterocyclic thiols can undergo S-methylation catalyzed by the genetically polymorphic drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT). Initially, we tested recombinant human TPMT as a "reagent" to S-methylate MTD. MTD was a substrate for TPMT-catalyzed S-methylation, with an apparent K(m) value of 63 micro M. Recombinant TPMT, with [(14)C-methyl]S-adenosyl-L-methionine as a cosubstrate, was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol preparations from patients who had been treated preoperatively with cefazolin. Pooled renal cytosol from 10 of those patients was used to purify and isolate the methylated product by reverse-phase high-performance liquid chromatography. That methylated compound coeluted with S-methyl MTD. When the methylated product was subjected to tandem mass spectrometry, it was identified as S-methyl MTD. Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway. AD - Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Medical School, Mayo Clinic, Mayo Foundation, Rochester, Minnesota 55905, USA. FAU - Wood, Thomas C AU - Wood TC FAU - Johnson, Kenneth L AU - Johnson KL FAU - Naylor, Stephen AU - Naylor S FAU - Weinshilboum, Richard M AU - Weinshilboum RM LA - eng GR - R01 GM28157/GM/NIGMS GR - R01 GM35720/GM/NIGMS GR - U01 GM61388/GM/NIGMS PT - Journal Article PL - United States TA - Drug Metab Dispos JID - 9421550 RN - 0 (Thiadiazoles) RN - 25953-19-9 (Cefazolin) RN - 36988-21-3 (2-methyl-1,3,4-thiadiazole-5-thiol) SB - IM MH - Animals MH - COS Cells MH - Cefazolin/administration & dosage/chemistry/*metabolism MH - Cercopithecus aethiops MH - Humans MH - Hypoprothrombinemias/*chemically induced/*metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Thiadiazoles/*metabolism MH - Tissue Distribution/drug effects/physiology EDAT- 2002/09/14 10:00 MHDA- 2003/02/27 04:00 PST - ppublish SO - Drug Metab Dispos 2002 Oct;30(10):1123-8. PR -------------------------------------------------------------------------------- 32: Langley PG et al. Thiopurine methyltransferase ...[PMID: 12217596] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12217596 OWN - NLM STAT- MEDLINE DA - 20020909 DCOM- 20031001 LR - 20041117 PUBM- Print IS - 0168-8278 VI - 37 IP - 4 DP - 2002 Oct TI - Thiopurine methyltransferase phenotype and genotype in relation to azathioprine therapy in autoimmune hepatitis. PG - 441-7 AB - BACKGROUND/AIMS: Toxicity and efficacy of azathioprine is governed partly by the activity of thiopurine methyltransferase (TPMT). Azathioprine has been used for many years, with corticosteroids or alone, for the treatment of autoimmune hepatitis (AIH) but no studies of TPMT phenotype and genotype in relation to response to the drug in AIH have been published. METHODS: Erythrocyte TPMT activities were measured by a radioincorporation assay in 72 consecutive outpatients with AIH, 53 of whom were genotyped for the commonest defective alleles in Europeans (TPMT*3A, *3B and *3C) by restriction fragment length polymorphism analysis. RESULTS: TPMT activities were significantly lower in patients intolerant of azathioprine (group I, n=15) than in those who sustained remission on azathioprine alone (group II, n=28; P=0.003) and those who tolerated azathioprine but continued to require corticosteroids (group III, n=29; P<0.0001), and were higher in group III than in group II (P=0.034). Ten patients with defective alleles (all heterozygotes) had significantly lower TPMT activities (P=0.002). However, in 25% there was discordance between phenotype and/or genotype and response to azathioprine. CONCLUSIONS: TPMT phenotyping or genotyping may be advisable before institution of azathioprine therapy in AIH but neither approach invariably predicts response to the drug. AD - Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9RS, UK. FAU - Langley, Peter G AU - Langley PG FAU - Underhill, James AU - Underhill J FAU - Tredger, J Michael AU - Tredger JM FAU - Norris, Suzanne AU - Norris S FAU - McFarlane, Ian G AU - McFarlane IG LA - eng PT - Clinical Trial PT - Journal Article PL - England TA - J Hepatol JID - 8503886 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Azathioprine/*administration & dosage MH - Erythrocytes/enzymology MH - Female MH - Genotype MH - Hepatitis, Autoimmune/*drug therapy/*genetics/metabolism MH - Humans MH - Immunosuppressive Agents/*administration & dosage MH - Male MH - Methyltransferases/*genetics MH - Middle Aged MH - Phenotype MH - Polymorphism, Genetic MH - Treatment Outcome EDAT- 2002/09/10 10:00 MHDA- 2003/10/02 05:00 AID - S0168827802002143 [pii] PST - ppublish SO - J Hepatol 2002 Oct;37(4):441-7. DR -------------------------------------------------------------------------------- 33: Schwab M et al. Azathioprine therapy and adve...[PMID: 12172211] Related Articles, Compound via MeSH, Substance via MeSH, OMIM, Books, LinkOut PMID- 12172211 OWN - NLM STAT- MEDLINE DA - 20020812 DCOM- 20030220 LR - 20041117 PUBM- Print IS - 0960-314X VI - 12 IP - 6 DP - 2002 Aug TI - Azathioprine therapy and adverse drug reactions in patients with inflammatory bowel disease: impact of thiopurine S-methyltransferase polymorphism. PG - 429-36 AB - The efficacy of the immunosuppressants azathioprine and 6-mercaptopurine has been well established in the therapy of inflammatory bowel diseases (IBD). However, its use has been complicated by a high incidence of serious adverse drug reactions such as hematotoxicity, hepatotoxicity, pancreatitis and gastrointestinal disturbances. Whereas azathioprine-related pancytopenia has been clearly linked to thiopurine S-methyltransferase (TPMT) polymorphism limited data are available to explain gastrointestinal side effects. In a retrospective analysis of 93 adults with IBD and azathioprine therapy both phenotyping and genotyping was used to explore systematically the relationship between TPMT and azathioprine-related adverse reactions. At time of inclusion, 69 patients were still receiving azathioprine therapy and had never experienced side effects. Azathioprine had been withdrawn in 10 patients for non-medical reasons or lack of response and 14 patients (15%) had stopped medication or were on reduced dose due to severe azathioprine-related side effects. Nine of these 14 patients had developed gastrointestinal side effects (hepatotoxicity, n = 3; pancreatitis, n = 3; others, n = 3), but their normal red blood cell TPMT activities were in accordance to TPMT wild-type. TPMT deficiency in one patient had led to pancytopenia whereas only two of the remaining four patients with hematotoxicity displayed an intermediate phenotype of TPMT. This study demonstrates that azathioprine-related gastrointestinal side effects are independent of the TPMT polymorphism. Nevertheless pharmacogenetic testing for TPMT prior to commencing thiopurine therapy should become routine practice in order to avoid severe hematotoxicity in TPMT deficient patients and lowering the incidence of hematological side effects in individuals heterozygous for TPMT. AD - Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany. matthias.schwab@ikp-stuttgart.de FAU - Schwab, Matthias AU - Schwab M FAU - Schaffeler, Elke AU - Schaffeler E FAU - Marx, Claudia AU - Marx C FAU - Fischer, Christine AU - Fischer C FAU - Lang, Thomas AU - Lang T FAU - Behrens, Christoph AU - Behrens C FAU - Gregor, Michael AU - Gregor M FAU - Eichelbaum, Michel AU - Eichelbaum M FAU - Zanger, Ulrich M AU - Zanger UM FAU - Kaskas, Bernd A AU - Kaskas BA LA - eng PT - Journal Article PL - England TA - Pharmacogenetics JID - 9211735 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM CIN - Pharmacogenetics. 2002 Aug;12(6):421-3. PMID: 12172209 CIN - Pharmacogenomics J. 2003;3(2):66-8. PMID: 12746731 MH - Adult MH - Aged MH - Azathioprine/*adverse effects MH - Colitis, Ulcerative/drug therapy/*enzymology MH - Crohn Disease/drug therapy/*enzymology MH - Female MH - Genotype MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Male MH - Methyltransferases/*genetics/metabolism MH - Middle Aged MH - Neutropenia/chemically induced MH - Phenotype MH - *Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Retrospective Studies EDAT- 2002/08/13 10:00 MHDA- 2003/02/21 04:00 PST - ppublish SO - Pharmacogenetics 2002 Aug;12(6):429-36. DR -------------------------------------------------------------------------------- 34: Evans WE. Thiopurine S-methyltransferas...[PMID: 12172209] Related Articles, Compound via MeSH, Substance via MeSH, OMIM, Books, LinkOut PMID- 12172209 OWN - NLM STAT- MEDLINE DA - 20020812 DCOM- 20030220 LR - 20041117 PUBM- Print IS - 0960-314X VI - 12 IP - 6 DP - 2002 Aug TI - Thiopurine S-methyltransferase: a genetic polymorphism that affects a small number of drugs in a big way. PG - 421-3 AD - St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. william.evans@stjude.org FAU - Evans, William E AU - Evans WE LA - eng PT - Comment PT - Journal Article PL - England TA - Pharmacogenetics JID - 9211735 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM CON - Pharmacogenetics. 2002 Aug;12(6):429-36. PMID: 12172211 MH - Azathioprine/*adverse effects MH - Colitis, Ulcerative/drug therapy/*enzymology MH - Crohn Disease/drug therapy/*enzymology MH - Genotype MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Methyltransferases/*genetics/metabolism MH - Neutropenia/chemically induced MH - Phenotype MH - *Polymorphism, Genetic EDAT- 2002/08/13 10:00 MHDA- 2003/02/21 04:00 PST - ppublish SO - Pharmacogenetics 2002 Aug;12(6):421-3. DR -------------------------------------------------------------------------------- 35: Hiratsuka M. [Development of simplified an...[PMID: 12136641] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12136641 OWN - NLM STAT- MEDLINE DA - 20020724 DCOM- 20020829 LR - 20041118 PUBM- Print IS - 0031-6903 VI - 122 IP - 7 DP - 2002 Jul TI - [Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications] PG - 451-63 AB - Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations. Routine genotyping before drug therapy may enable the identification of responders, nonresponders, or patients at increased risk of toxicity. Automated, high-throughput detecting methods for single-nucleotide polymorphisms (SNPs) are highly desirable in many clinical laboratories. The aim of this study is to develop a high-throughput genotyping method for detecting SNPs influencing drug response in the Japanese population. We have developed three real-time PCR assays for detecting SNPs in the human drug-metabolizing enzymes and drug targets. The assay for simultaneously detecting CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A5, NAT2, TPMT, DPYD, UGT1A1, ALDH2, ADH2, MDR1, CETP, DCP-1, ADRB2, HTR2A, INPP1, SDF1, and mitochondrial DNA polymorphisms takes less than 1.5 h. With the clinical application of NAT2 genotyping, we found statistically significant difference between the incidence of adverse drug reactions (ADRs) and the NAT2 genotype. The incidence of the ADRs was significantly higher in the slow type than the in other two types, as 5 of the 6 patients were of the slowtype, and the other was the intermediatetype, while no patients of the rapidtype has developed any ADRs. AD - Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. FAU - Hiratsuka, Masahiro AU - Hiratsuka M LA - jpn PT - Case Reports PT - Journal Article PT - Review PT - Review, Tutorial PL - Japan TA - Yakugaku Zasshi JID - 0413613 RN - 0 (Aminoglycosides) RN - 0 (Anti-Bacterial Agents) RN - 0 (DNA, Mitochondrial) RN - 50-44-2 (6-Mercaptopurine) RN - 54-85-3 (Isoniazid) RN - 64-77-7 (Tolbutamide) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1.5 (Arylamine N-Acetyltransferase) RN - EC 2.3.1.5 (N-acetyltransferase 2 (arylamine N-acetyltransferase), human) SB - IM MH - 6-Mercaptopurine/adverse effects MH - Adult MH - Aminoglycosides MH - Anti-Bacterial Agents/adverse effects MH - Arylamine N-Acetyltransferase/genetics MH - Biotransformation/*genetics MH - Cytochrome P-450 Enzyme System/genetics MH - DNA, Mitochondrial/genetics MH - English Abstract MH - Genotype MH - Humans MH - Isoniazid/adverse effects MH - Male MH - Methyltransferases/genetics MH - Pharmacogenetics/*methods MH - Polymerase Chain Reaction/methods MH - *Polymorphism, Single Nucleotide MH - Tolbutamide/adverse effects RF - 18 EDAT- 2002/07/26 10:00 MHDA- 2002/08/30 10:01 PST - ppublish SO - Yakugaku Zasshi 2002 Jul;122(7):451-63. DR -------------------------------------------------------------------------------- 36: Tribut O et al. Pharmacogenomics....[PMID: 12119546] Related Articles, Substance via MeSH, Books, LinkOut PMID- 12119546 OWN - NLM STAT- MEDLINE DA - 20020716 DCOM- 20030318 LR - 20041117 PUBM- Print IS - 1234-1010 VI - 8 IP - 7 DP - 2002 Jul TI - Pharmacogenomics. PG - RA152-63 AB - Pharmacogenomics, a revolutionary chapter in the history of pharmacology, has received new impetus from the development and accessibility of molecular biotechnologies, notably DNA chips. The longstanding notion of responders/non-responders has given way to a more organic approach, where idiosyncrasy becomes an obsolete concept. This is a major step towards predictive, individualized medicine. In this review, several applications of pharmacogenomics are considered. Genetic polymorphisms of metabolization reactions, mainly with cytochrome P450, explain most of the cases described today. More fundamental and innovative studies have tried to link the structure of receptors or transporters and drug response. A leading topic in neuropsychopharmacology is the relation between the polymorphism of dopaminergic receptors and the efficacy of, or adverse reaction to, neuroleptics. In asthma, the structure of the beta2-adrenergic receptor has been associated with response to treatment. Intrinsic genetic predisposition also plays an important role in cardiovascular diseases, and the role of ion channel mutations will be discussed. Research in oncological molecular epidemiology has explored the connection between the predisposition to certain cancers and specific enzymatic equipment hindering the detoxification of potentially carcinogenic exogenous compounds, or, on the contrary, promoting metabolic activation implicated in the formation of reactive compounds. The search for determinants of addictive behavior is another vast field of pharmacogenomics. Finally, we consider the impact of pharmacogenomics on the methodology of drug development in preclinical and clinical trials. Progress in methods of phenotyping/genotyping should promote diagnosis, guide the choice of drug for an individual (benefit/risk ratio), and determine dosage and regimen. AD - Department of Pharmacology, Medical Faculty, Rennes I University, France. FAU - Tribut, Olivier AU - Tribut O FAU - Lessard, Yvon AU - Lessard Y FAU - Reymann, Jean-Michael AU - Reymann JM FAU - Allain, Herve AU - Allain H FAU - Bentue-Ferrer, Daniele AU - Bentue-Ferrer D LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Poland TA - Med Sci Monit JID - 9609063 RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Cardiovascular Physiology MH - Central Nervous System/physiology MH - Clinical Trials MH - Cytochrome P-450 Enzyme System/metabolism MH - Drug Design MH - Genotype MH - Humans MH - Methyltransferases/metabolism MH - Neoplasms/metabolism MH - *Pharmacogenetics MH - Phenotype MH - *Polymorphism, Genetic MH - Respiratory Physiology MH - Substance-Related Disorders/physiopathology RF - 103 EDAT- 2002/07/18 10:00 MHDA- 2003/03/19 04:00 AID - 2280 [pii] PST - ppublish SO - Med Sci Monit 2002 Jul;8(7):RA152-63. PR -------------------------------------------------------------------------------- 37: Daly AK et al. Pharmacogenetics of cytotoxic...[PMID: 12113035] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12113035 OWN - NLM STAT- MEDLINE DA - 20020712 DCOM- 20020813 LR - 20041117 PUBM- Print IS - 1473-7140 VI - 1 IP - 2 DP - 2001 Aug TI - Pharmacogenetics of cytotoxic drugs. PG - 301-8 AB - The main genetic polymorphisms affecting the metabolism and transport of cytotoxic drugs are discussed in this review. Likely future approaches to pharmacogenetics and emerging technologies, such as tumor classification using microarray analysis, are also considered. AD - Department of Pharmacological Sciences, University of Newcastle Medical School, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, UK. FAU - Daly, A K AU - Daly AK FAU - Hall, A G AU - Hall AG LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - England TA - Expert Rev Anticancer Ther JID - 101123358 RN - 0 (Antineoplastic Agents) RN - 0 (Cytotoxins) RN - 0 (Dihydropyridines) RN - 3337-17-5 (1,4-dihydropyridine) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1. (Oxidoreductases) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1.5 (Arylamine N-Acetyltransferase) RN - EC 2.4.1.17 (Glucuronosyltransferase) SB - IM MH - Antineoplastic Agents/*metabolism/*pharmacology MH - Arylamine N-Acetyltransferase/genetics/metabolism MH - Cytochrome P-450 Enzyme System/genetics/metabolism MH - Cytotoxins/*metabolism/*pharmacology MH - Dihydropyridines/metabolism MH - Glucuronosyltransferase/genetics/metabolism MH - Humans MH - Methyltransferases/genetics/metabolism MH - Neoplasms/*drug therapy/enzymology/*genetics/metabolism MH - Oxidoreductases/genetics/metabolism MH - *Pharmacogenetics MH - Polymorphism, Genetic/*genetics RF - 55 EDAT- 2002/07/13 10:00 MHDA- 2002/08/14 10:01 AID - ERA010215 [pii] PST - ppublish SO - Expert Rev Anticancer Ther 2001 Aug;1(2):301-8. PR -------------------------------------------------------------------------------- 38: Loennechen T et al. [New techniques for optimizat...[PMID: 12043054] Related Articles, Books, LinkOut PMID- 12043054 OWN - NLM STAT- MEDLINE DA - 20020604 DCOM- 20020813 LR - 20041117 PUBM- Print IS - 0029-2001 VI - 122 IP - 11 DP - 2002 Apr 30 TI - [New techniques for optimization of thiopurine therapy in leukemia and transplantation] PG - 1107-10 AB - BACKGROUND: The majority of chemotherapeutic agents are administered at fixed doses that are close to those maximally tolerated. MATERIAL AND METHODS: This review is based on current knowledge about the metabolism of thiopurines and the clinical implications of genetic polymorphism in thiopurine-S-methyltransferase (TPMT). RESULTS: Intracellularly thiopurines, e.g. 6-MP, are anabolized to cytotoxic 6-thioguanine nucleotides (6-TGN) that are incorporated into DNA and RNA. A competing pathway is S-methylation of 6-MP and its initial nucleotide metabolites by TPMT. In childhood acute lymphocytic leukaemia, high erythrocyte concentrations of 6-TGN correlate with the degree of leukopenia and a good prognosis, while low concentrations appear to be associated with higher risk of relapse. In most populations studied, approximately 10% have intermediate TPMT activity and 1/300 lacks TPMT activity due to one or two mutant TPMT alleles, respectively. INTERPRETATION: Phenotyping or genotyping may be used to identify patients as deficient or intermediate thiopurine metabolizers. This suggests that they should receive a profound or moderate reduction in dosage to avoid haematopoietic toxicity. AD - Avdeling for farmakologi Institutt for farmasi, Universitetet i Tromso 9037 Troms. thrinal@farmasi.uit.no FAU - Loennechen, Thrina AU - Loennechen T FAU - Lysaa, Roy Andre AU - Lysaa RA FAU - Giverhaug, Trude AU - Giverhaug T FAU - Sylte, Ingebrigt AU - Sylte I FAU - Mathiesen, Lars-Eirik AU - Mathiesen LE FAU - Aarbakke, Jarle AU - Aarbakke J LA - nor PT - Journal Article PT - Review PT - Review, Tutorial TT - Nye styringsverktoy for tiopuriner i leukemi- og transplantasjonsbehandling. PL - Norway TA - Tidsskr Nor Laegeforen JID - 0413423 RN - 0 (Antimetabolites) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Immunosuppressive Agents) RN - 0 (Purines) RN - EC 2.1.1. (Methyltransferases) SB - IM MH - Adult MH - Antimetabolites/*administration & dosage/metabolism MH - Antimetabolites, Antineoplastic/*administration & dosage/metabolism MH - Child MH - English Abstract MH - Genotype MH - Humans MH - Immunosuppressive Agents/*administration & dosage/metabolism MH - Leukemia, Lymphocytic, Acute/*drug therapy/genetics/metabolism MH - Methyltransferases/genetics/metabolism MH - *Organ Transplantation MH - *Pharmacogenetics MH - Phenotype MH - Polymorphism, Genetic MH - Purines/*administration & dosage/metabolism RF - 30 EDAT- 2002/06/05 10:00 MHDA- 2002/08/14 10:01 PST - ppublish SO - Tidsskr Nor Laegeforen 2002 Apr 30;122(11):1107-10. PR -------------------------------------------------------------------------------- 39: Pettersson B et al. Differences between children ...[PMID: 12021625] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 12021625 OWN - NLM STAT- MEDLINE DA - 20020521 DCOM- 20021114 LR - 20041117 PUBM- Print IS - 0163-4356 VI - 24 IP - 3 DP - 2002 Jun TI - Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy: possible role of concomitant methotrexate. PG - 351-8 AB - This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients.The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex. AD - Department of Clinical Pharmacology, University Hospital, SE-58185 Linkoping, Sweden. FAU - Pettersson, Birgitta AU - Pettersson B FAU - Almer, Sven AU - Almer S FAU - Albertioni, Freidoun AU - Albertioni F FAU - Soderhall, Stefan AU - Soderhall S FAU - Peterson, Curt AU - Peterson C LA - eng PT - Clinical Trial PT - Controlled Clinical Trial PT - Journal Article PL - United States TA - Ther Drug Monit JID - 7909660 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Immunosuppressive Agents) RN - 0 (Thionucleotides) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - 574-25-4 (Thioinosine) RN - 59-05-2 (Methotrexate) RN - 7021-52-5 (6-methylthiopurine ribonucleoside-5'-phosphate) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/blood/*therapeutic use MH - Adult MH - Age Factors MH - Antimetabolites, Antineoplastic/blood/therapeutic use MH - Azathioprine/blood/*therapeutic use MH - Child MH - Drug Therapy, Combination MH - Erythrocytes/*enzymology MH - Female MH - Humans MH - Immunosuppressive Agents/blood/therapeutic use MH - Inflammatory Bowel Diseases/*drug therapy MH - Leukemia, Lymphocytic, Acute/*drug therapy MH - Male MH - Methotrexate/blood/therapeutic use MH - Methyltransferases/blood/*genetics MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Thioinosine/*analogs & derivatives/metabolism MH - Thionucleotides/metabolism EDAT- 2002/05/22 10:00 MHDA- 2002/11/26 04:00 PST - ppublish SO - Ther Drug Monit 2002 Jun;24(3):351-8. DR -------------------------------------------------------------------------------- 40: Cara Terribas CJ et al. [Hypomethylation and multiple...[PMID: 11927101] Related Articles, Gene, HomoloGene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 11927101 OWN - NLM STAT- MEDLINE DA - 20020402 DCOM- 20021106 LR - 20041117 PUBM- Print IS - 0213-4853 VI - 17 IP - 3 DP - 2002 Mar TI - [Hypomethylation and multiple sclerosis, the susceptibility factor?] PG - 132-5 AB - BACKGROUND: Azathioprine, off-label used long time ago to treat multiple sclerosis (MS) patients, has recently received approval from the Spanish Medicine Agency (Agencia Espanola del Medicamento) in relapsing-remitting (RR) forms of this condition. Clinical efficacy of azathioprine is due to the enzymatic conversion to 6-thioguanine (the active metabolite). The key enzyme in this process is thio purine methyl transferase (TPMT), converting 6-MP to 6-methylMP. A specific genetic polymorphism has been described affecting this enzyme. With the aim of optimizing purine therapy in a variety of autoimmune diseases, monitoring of TPMT phenotype has been performed in a vast number of patients. The TPMT activity frequency distribution histogram from a Spanish population sample has been compared with the corresponding ones to Crohn's disease, ulcerative colitis and MS patients. METHODS AND RESULTS: TPMT activity has been studied in red blood cells obtained from 3,640 clinical laboratory samples in Spain of which 1,249 corresponded to patients affected by Crohn's disease, 589 to ulcerative colitis, 348 to MS, 487 to several autoimmune diseases apart from the previously mentioned and 967 to a group of blood donors. The mean TPMT activity in the MS group (17.1 6.1 U/ml) was significantly lower (p < 0.001) than in Crohn's disease (20.0 5.8 U/ml), ulcerative colitis (19.7 6.1 U/ml) and donors group (19.9 6.3 U/ml). CONCLUSION: Defective methylation profile and subsequent hyperhomocysteinemia leading to a widespread impairment of the methyl-transferase activity (in this case affecting MBP methylation) is a vicious circle we propose as a MS susceptibility factor. AD - Celltech Pharma Espana, Departamento Cientifico, Madrid, Spain. carlos.cara@celltechgroup.com FAU - Cara Terribas, C J AU - Cara Terribas CJ FAU - Gonzalez Guijarro, L AU - Gonzalez Guijarro L LA - eng PT - Journal Article PL - Spain TA - Neurologia JID - 9005460 RN - 0 (Immunosuppressive Agents) RN - 0 (Purines) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Autoimmune Diseases/enzymology MH - Azathioprine/therapeutic use MH - Comparative Study MH - Genetic Predisposition to Disease MH - Humans MH - Immunosuppressive Agents/therapeutic use MH - Inflammatory Bowel Diseases/enzymology MH - Methylation MH - Methyltransferases/genetics/*metabolism MH - Multiple Sclerosis/drug therapy/*enzymology/genetics MH - Phenotype MH - Polymorphism, Genetic MH - Purines/metabolism MH - Spain EDAT- 2002/04/03 10:00 MHDA- 2002/11/26 04:00 AID - 13028625 [pii] PST - ppublish SO - Neurologia 2002 Mar;17(3):132-5. NR -------------------------------------------------------------------------------- 41: Relling MV et al. Pharmacogenetics and cancer t...[PMID: 11905809] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11905809 OWN - NLM STAT- MEDLINE DA - 20020321 DCOM- 20020416 LR - 20041117 PUBM- Print IS - 1474-175X VI - 1 IP - 2 DP - 2001 Nov TI - Pharmacogenetics and cancer therapy. PG - 99-108 AB - Pharmacogenetics is the study of how genetic variations affect drug response. These variations can affect a patient's response to cancer drugs, for which there is usually a fine line between a dosage that has a therapeutic effect and one that produces toxicity. Gaining better insight into the genetic elements of both the patient and the tumour that affect drug efficacy will eventually allow for individualized dosage determination and fewer adverse effects. AD - Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. mary.relling@stjude.org FAU - Relling, M V AU - Relling MV FAU - Dervieux, T AU - Dervieux T LA - eng PT - Journal Article PT - Review PL - England TA - Nat Rev Cancer JID - 101124168 RN - 0 (ATP-Binding Cassette Transporters) RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Folic Acid Antagonists) RN - 0 (Receptors, Drug) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2. (Transferases) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase) SB - IM MH - ATP-Binding Cassette Transporters/genetics MH - Antimetabolites, Antineoplastic/pharmacokinetics MH - Antineoplastic Agents/adverse effects/classification/pharmacokinetics MH - Biotransformation/genetics MH - Cytochrome P-450 Enzyme System/genetics MH - Enzyme Inhibitors/pharmacokinetics MH - Folic Acid Antagonists/pharmacokinetics MH - Forecasting MH - Genetic Predisposition to Disease MH - Genotype MH - Humans MH - Hypoxanthine Phosphoribosyltransferase/genetics MH - Methyltransferases/genetics MH - Neoplasms/*drug therapy/genetics MH - *Pharmacogenetics MH - Polymorphism, Single Nucleotide MH - Receptors, Drug/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Transferases/genetics MH - Variation (Genetics) RF - 133 EDAT- 2002/03/22 10:00 MHDA- 2002/04/17 10:01 AID - 10.1038/35101056 [doi] PST - ppublish SO - Nat Rev Cancer 2001 Nov;1(2):99-108. PR -------------------------------------------------------------------------------- 42: Steiner M et al. Elevated serum pancreatic enz...[PMID: 11834908] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11834908 OWN - NLM STAT- MEDLINE DA - 20020208 DCOM- 20020326 LR - 20041117 PUBM- Print IS - 0042-1138 VI - 68 IP - 2 DP - 2002 TI - Elevated serum pancreatic enzyme activities in kidney transplant recipients and azathioprine drug therapy: is thiopurine methyltransferase polymorphism one missing link? PG - 135-6 FAU - Steiner, Michael AU - Steiner M FAU - Burmeister, Dirk AU - Burmeister D FAU - Bastian, Manuela AU - Bastian M FAU - Seiter, Hansjorg AU - Seiter H FAU - Schuff-Werner, Peter AU - Schuff-Werner P LA - eng PT - Letter PL - Switzerland TA - Urol Int JID - 0417373 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 3.1.1.3 (Lipase) RN - EC 3.2.1.- (Amylases) SB - IM MH - Alleles MH - Amylases/blood MH - Azathioprine/*therapeutic use MH - Comparative Study MH - Female MH - Humans MH - Immunosuppressive Agents/*therapeutic use MH - *Kidney Transplantation MH - Lipase/blood MH - Male MH - Methyltransferases/*genetics MH - Middle Aged MH - Pancreatitis/chemically induced MH - Polymorphism, Genetic EDAT- 2002/02/09 10:00 MHDA- 2002/03/27 10:01 AID - uin68135 [pii] PST - ppublish SO - Urol Int 2002;68(2):135-6. PR -------------------------------------------------------------------------------- 43: Sekine I et al. Polymorphisms of metabolizing...[PMID: 11822749] Related Articles, Books, LinkOut PMID- 11822749 OWN - NLM STAT- MEDLINE DA - 20020201 DCOM- 20020716 LR - 20041117 PUBM- Print IS - 0923-7534 VI - 12 IP - 11 DP - 2001 Nov TI - Polymorphisms of metabolizing enzymes and transporter proteins involved in the clearance of anticancer agents. PG - 1515-25 AB - BACKGROUND: The efficacies and toxicities of anticancer agents vary greatly among patients. This is attributable to the activities of drug-metabolizing enzymes and membrane transporters, primarily determined by polymorphisms of the functions of genes encoding these proteins. DESIGN: We reviewed the available literature on drug-metabolizing enzymes and membrane transporters, especially their physiological functions, genetic and functional polymorphisms, and involvement in metabolism, pharmacokinetics and toxicity of anticancer agents. RESULTS: Nine enzymes metabolizing anticancer agents have been shown to have genetic polymorphisms: dihydropyrimidine dehydrogenase, cytochrome P450, NAD(P)H:quinone oxidoreductase 1, N-acetyltransferase 2, thiopurine methyltransferase, glutathione S-transferase, and uridine diphosphate glucuronosyltransferase. Decreased activities of these proteins can cause not only inherited metabolic disorders, but also extraordinarily severe toxicity in cancer patients given chemothearpy. Transporter proteins mediate cellular uptake and secretion of organic anions and cations. These proteins have recently been shown to play critical roles in the clearance of anticancer agents, although relations between patients' genetics backgrounds and the clinical significance of drug actions are poorly understood. CONCLUSIONS: Further studies should be focused on dosing and selection of anticancer agents, based on the type and extent of metabolic variation among individuals, in order to avoid adverse reactions and therapeutic failure. AD - Internal Medicine & Thoracic Oncology Division, National Cancer Center Hospital, Tokyo, Japan. isekine@gan2.ncc.go.jp FAU - Sekine, I AU - Sekine I FAU - Saijo, N AU - Saijo N LA - eng PT - Journal Article PT - Review PL - England TA - Ann Oncol JID - 9007735 RN - 0 (Antineoplastic Agents) RN - 0 (Carrier Proteins) RN - EC 1. (Oxidoreductases) SB - IM MH - Antineoplastic Agents/*metabolism MH - Carrier Proteins/*genetics MH - Humans MH - Metabolic Detoxication, Drug/genetics MH - Oxidoreductases/*genetics MH - Polymorphism, Genetic RF - 110 EDAT- 2002/02/02 10:00 MHDA- 2002/07/18 10:01 PST - ppublish SO - Ann Oncol 2001 Nov;12(11):1515-25. DR -------------------------------------------------------------------------------- 44: Brouwer C et al. Thiopurine methyl transferase...[PMID: 11783509] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11783509 OWN - NLM STAT- MEDLINE DA - 20020109 DCOM- 20020225 LR - 20041117 PUBM- Print IS - 0065-2598 VI - 486 DP - 2000 TI - Thiopurine methyl transferase: activity and genotyping in patients with acute lymphoblastic leukemia. PG - 327-31 AD - Center for Pediatric Oncology S.E. Netherlands, University Medical Center St Radboud, Department of Pediatrics, Nijmegen. FAU - Brouwer, C AU - Brouwer C FAU - Keizer-Garritsen, J J AU - Keizer-Garritsen JJ FAU - Lambooy, L H AU - Lambooy LH FAU - Ament, K AU - Ament K FAU - Ter Riet, P G AU - Ter Riet PG FAU - De Abreu, R A AU - De Abreu RA FAU - Bokkerink, J P AU - Bokkerink JP FAU - Van Wering, E R AU - Van Wering ER FAU - Van Der Does-Van Den Berg, A AU - Van Der Does-Van Den Berg A FAU - Veerman, A J AU - Veerman AJ FAU - Trijbels, J P AU - Trijbels JP LA - eng PT - Journal Article PL - United States TA - Adv Exp Med Biol JID - 0121103 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - 59-05-2 (Methotrexate) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/therapeutic use MH - Alleles MH - Antimetabolites, Antineoplastic/therapeutic use MH - Child MH - Female MH - Genetic Screening MH - Genotype MH - Humans MH - Leukemia, Lymphocytic, Acute/drug therapy/*enzymology/genetics MH - Male MH - Methotrexate/therapeutic use MH - Methyltransferases/*genetics/*metabolism MH - Mutation MH - Research Support, Non-U.S. Gov't EDAT- 2002/01/11 10:00 MHDA- 2002/02/28 10:01 PST - ppublish SO - Adv Exp Med Biol 2000;486:327-31. DR -------------------------------------------------------------------------------- 45: Steimer W et al. Pharmacogenetic screening and...[PMID: 11728416] Related Articles, Books, LinkOut PMID- 11728416 OWN - NLM STAT- MEDLINE DA - 20011130 DCOM- 20020122 LR - 20041117 PUBM- Print IS - 0009-8981 VI - 315 IP - 1-2 DP - 2002 Jan TI - Pharmacogenetic screening and therapeutic drugs. PG - 137-55 AB - BACKGROUND: Pharmacogenetics is the science of the influence of heredity on pharmacological response. ISSUES: The cost of severe adverse drug reactions in individuals has been estimated in the US alone to be in excess of US$4 billion. It has been argued that in a significant proportion of cases, the efficacy and toxicity profiles of drug therapy would be substantially improved in individuals if characteristics due to genetic variation were taken into account. Methods are now available, which make screening for susceptibility feasible. CONCLUSIONS: There are several therapeutic areas in which screening may give rise to significant improvements in outcome with cost-benefits to both the individual and the community. However, there is currently a lack of data on which cost-benefit analysis can be based. The challenge is to provide this information for new drugs, and for drugs with established therapeutic roles. AD - Institute for Clinical Chemistry and Pathobiochemistry, Munich University of Technology, Klinikum rechts der Isar, Ismaningerstrasse 22, D-81675 Munich, Germany. Steimer@KlinChem.med.TU-Muenchen.de FAU - Steimer, Werner AU - Steimer W FAU - Potter, Julia M AU - Potter JM LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Netherlands TA - Clin Chim Acta JID - 1302422 RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1.5 (Arylamine N-Acetyltransferase) RN - EC 3.1.1.- (Butyrylcholinesterase) SB - IM MH - Arylamine N-Acetyltransferase/deficiency/genetics MH - Butyrylcholinesterase/deficiency/genetics MH - Cost-Benefit Analysis MH - Cytochrome P-450 CYP2D6/genetics MH - Drug Therapy/*adverse effects/economics MH - *Genetic Screening MH - Humans MH - Methyltransferases/deficiency/genetics MH - *Pharmacogenetics MH - Pharmacokinetics MH - Phenotype MH - Polymorphism, Genetic RF - 123 EDAT- 2001/12/01 10:00 MHDA- 2002/01/23 10:01 AID - S0009898101007136 [pii] PST - ppublish SO - Clin Chim Acta 2002 Jan;315(1-2):137-55. PR -------------------------------------------------------------------------------- 46: Pillans PI. Increasing relevance of pharm...[PMID: 11720061] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11720061 OWN - NLM STAT- MEDLINE DA - 20011126 DCOM- 20020417 LR - 20041117 PUBM- Print IS - 1444-0903 VI - 31 IP - 8 DP - 2001 Nov TI - Increasing relevance of pharmacogenetics of drug metabolism in clinical practice. PG - 476-8 AB - Much of the individual variation in drug response is due to genetic drug metabolic polymorphisms. Clinically relevant examples include acetylator status; cytochrome P450 2D6, 2C9 and 2C19 polymorphisms; and thiopurine methyltransferase deficiency. It is important to be aware of which drugs are subject to pharmacogenetic variability. In the future, population-based pharmacogenetic testing will allow more individualized drug treatment and will avoid the current empiricism. AD - Department of Clinical Pharmacology, Princess Alexandra Hospital, Brisbane, Queensland, Australia. peter_pillans@health.qld.gov.au FAU - Pillans, P I AU - Pillans PI LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - Australia TA - Intern Med J JID - 101092952 RN - 0 (Enzymes) RN - 0 (Pharmaceutical Preparations) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.14.- (Steroid Hydroxylases) RN - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - EC 1.14.14.1 (Steroid 16-alpha-Hydroxylase) RN - EC 1.14.14.1 (testosterone 16-alpha-hydroxylase, mouse) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1. (Acetyltransferases) SB - IM MH - Acetyltransferases/genetics/metabolism MH - *Aryl Hydrocarbon Hydroxylases MH - Cytochrome P-450 CYP2D6/genetics/metabolism MH - Cytochrome P-450 Enzyme System/genetics/metabolism MH - Drug Therapy/*methods MH - Enzymes/*genetics/metabolism MH - Genotype MH - Humans MH - Methyltransferases/genetics/metabolism MH - Pharmaceutical Preparations/*metabolism MH - Pharmacogenetics MH - *Steroid 16-alpha-Hydroxylase MH - Steroid Hydroxylases/genetics/metabolism RF - 16 EDAT- 2001/11/27 10:00 MHDA- 2002/04/18 10:01 PST - ppublish SO - Intern Med J 2001 Nov;31(8):476-8. PR -------------------------------------------------------------------------------- 47: Evans WE et al. Pharmacogenomics: the inherit...[PMID: 11701642] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11701642 OWN - NLM STAT- MEDLINE DA - 20011109 DCOM- 20020102 LR - 20041117 PUBM- Print IS - 1527-8204 VI - 2 DP - 2001 TI - Pharmacogenomics: the inherited basis for interindividual differences in drug response. PG - 9-39 AB - It is well recognized that most medications exhibit wide interpatient variability in their efficacy and toxicity. For many medications, these interindividual differences are due in part to polymorphisms in genes encoding drug metabolizing enzymes, drug transporters, and/or drug targets (e.g., receptors, enzymes). Pharmacogenomics is a burgeoning field aimed at elucidating the genetic basis for differences in drug efficacy and toxicity, and it uses genome-wide approaches to identify the network of genes that govern an individual's response to drug therapy. For some genetic polymorphisms (e.g., thiopurine S-methyltransferase), monogenic traits have a marked effect on pharmacokinetics (e.g., drug metabolism), such that individuals who inherit an enzyme deficiency must be treated with markedly different doses of the affected medications (e.g., 5%-10% of the standard thiopurine dose). Likewise, polymorphisms in drug targets (e.g., beta adrenergic receptor) can alter the sensitivity of patients to treatment (e.g., beta-agonists), changing the pharmacodynamics of drug response. Recognizing that most drug effects are determined by the interplay of several gene products that govern the pharmacokinetics and pharmacodynamics of medications, pharmacogenomics research aims to elucidate these polygenic determinants of drug effects. The ultimate goal is to provide new strategies for optimizing drug therapy based on each patient's genetic determinants of drug efficacy and toxicity. This chapter provides an overview of the current pharmacogenomics literature and offers insights for the potential impact of this field on the safe and effective use of medications. AD - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. william.evans@stjude.org FAU - Evans, W E AU - Evans WE FAU - Johnson, J A AU - Johnson JA LA - eng GR - CA36401/CA/NCI GR - R01 HL64691/HL/NHLBI GR - R37 CA36401/CA/NCI GR - RO1 CA78224/CA/NCI PT - Journal Article PT - Review PL - United States TA - Annu Rev Genomics Hum Genet JID - 100911346 RN - 0 (Pharmaceutical Preparations) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Cytochrome P-450 Enzyme System/genetics/metabolism MH - Humans MH - Mutation MH - Pharmaceutical Preparations/metabolism MH - *Pharmacogenetics MH - Pharmacokinetics MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. RF - 164 EDAT- 2001/11/10 10:00 MHDA- 2002/01/05 10:01 AID - 2/1/9 [pii] AID - 10.1146/annurev.genom.2.1.9 [doi] PST - ppublish SO - Annu Rev Genomics Hum Genet 2001;2:9-39. DR -------------------------------------------------------------------------------- 48: Dervieux T et al. Possible implication of thiop...[PMID: 11681411] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11681411 OWN - NLM STAT- MEDLINE DA - 20011029 DCOM- 20011204 LR - 20041117 PUBM- Print IS - 0887-6924 VI - 15 IP - 11 DP - 2001 Nov TI - Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine. PG - 1706-12 AB - 6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P= 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P< 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides. AD - Service de Pharmacologie Pediatrique et Pharmacogenetique, Hopital Robert Debre, Paris, France. FAU - Dervieux, T AU - Dervieux T FAU - Medard, Y AU - Medard Y FAU - Verpillat, P AU - Verpillat P FAU - Guigonis, V AU - Guigonis V FAU - Duval, M AU - Duval M FAU - Lescoeur, B AU - Lescoeur B FAU - Suciu, S AU - Suciu S FAU - Vilmer, E AU - Vilmer E FAU - Jacqz-Aigrain, E AU - Jacqz-Aigrain E LA - eng PT - Clinical Trial PT - Journal Article PL - England TA - Leukemia JID - 8704895 RN - 0 (Antimetabolites, Antineoplastic) RN - 154-42-7 (Thioguanine) RN - 50-44-2 (6-Mercaptopurine) RN - 50-66-8 (6-methylthiopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/administration & dosage/*adverse effects/*analogs & derivatives/metabolism/pharmacokinetics MH - Adolescent MH - Antimetabolites, Antineoplastic/administration & dosage/*adverse effects/pharmacokinetics MH - Child MH - Child, Preschool MH - Dose-Response Relationship, Drug MH - Erythrocytes/metabolism MH - Female MH - Genotype MH - Humans MH - Infant MH - Infection/*etiology MH - Leukemia, Lymphocytic, Acute/*complications/metabolism/prevention & control MH - Leukocyte Count MH - Male MH - Methyltransferases/genetics/*physiology MH - Research Support, Non-U.S. Gov't MH - Thioguanine/metabolism EDAT- 2001/10/30 10:00 MHDA- 2002/01/05 10:01 PST - ppublish SO - Leukemia 2001 Nov;15(11):1706-12. DR -------------------------------------------------------------------------------- 49: Wedlund PJ. Practical considerations for ...[PMID: 11569125] Related Articles, Books, LinkOut PMID- 11569125 OWN - NLM STAT- MEDLINE DA - 20010924 DCOM- 20011101 LR - 20041117 PUBM- Print IS - 0580-7247 VI - 33 IP - 9 DP - 2001 Sep TI - Practical considerations for pharmacogenetic testing. PG - 16-21, 23; quiz 24-5 FAU - Wedlund, P J AU - Wedlund PJ LA - eng PT - Journal Article PL - United States TA - MLO Med Lab Obs JID - 0225602 RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - H MH - Cost-Benefit Analysis MH - Cytochrome P-450 CYP2D6/genetics/metabolism MH - Drug Therapy/standards MH - Education, Continuing MH - Genetic Screening/*economics MH - Humans MH - Methyltransferases/genetics/metabolism MH - Pharmacogenetics/*economics MH - Polymorphism, Genetic MH - Treatment Outcome MH - United States EDAT- 2001/09/25 10:00 MHDA- 2001/11/03 10:01 PST - ppublish SO - MLO Med Lab Obs 2001 Sep;33(9):16-21, 23; quiz 24-5. PR -------------------------------------------------------------------------------- 50: Dervieux T et al. Differing contribution of thi...[PMID: 11479220] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11479220 OWN - NLM STAT- MEDLINE DA - 20010731 DCOM- 20010816 LR - 20041117 PUBM- Print IS - 0008-5472 VI - 61 IP - 15 DP - 2001 Aug 1 TI - Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. PG - 5810-6 AB - Thioguanine and mercaptopurine are prodrugs requiring conversion into thiopurine nucleotides to exert cytotoxicity. Thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism, catabolizes thiopurines into inactive methylated bases, but also produces methylthioguanine nucleotides and methylmercaptopurine nucleotides from thioguanine and mercaptopurine nucleotides, respectively. To study the effect of TPMT on activation versus inactivation of mercaptopurine and thioguanine, we used a retroviral gene transfer technique to develop human CCRF-CEM cell lines that did (TPMT+) and did not (MOCK) overexpress TPMT. After transduction, TPMT activities were 14-fold higher in the TPMT+ versus the MOCK cell lines (P < 0.001). TPMT+ cells were less sensitive to thioguanine than MOCK cells (IC(50) = 1.10+/- 0.12 microM versus 0.55 +/- 0.19 microM; P = 0.02); in contrast, TPMT+ cells were more sensitive to mercaptopurine than MOCK cells (IC(50) = 0.52 +/- 0.20 microM versus 1.50 +/- 0.23 microM; P < 0.01). The lower sensitivity of TPMT+ versus MOCK cells to thioguanine was associated with lower thioguanine nucleotide concentrations (917 +/- 282 versus 1515 +/- 183 pmol/5 x 10(6) cells; P = 0.01), higher methylthioguanine nucleotide concentrations (252 +/- 34 versus 27 +/- 10 pmol/5 x 10(6) cells; P = 0.01), less inhibition of de novo purine synthesis (13 versus 95%; P < 0.01), and lower deoxythioguanosine incorporation into DNA (2.0 +/- 0.6% versus 7.2 +/- 2.0%; P < 0.001). The higher sensitivity of TPMT+ cells to mercaptopurine was associated with higher concentrations of methylmercaptopurine nucleotide (2601 +/- 1055 versus 174 +/- 77 pmol/5 x 10(6) cells; P = 0.01) and greater inhibition of de novo purine synthesis (>99% versus 74%; P < 0.01) compared with MOCK cells. We conclude that methylation of mercaptopurine contributes to the antiproliferative properties of the drug, probably through inhibition of de novo purine synthesis by methylmercaptopurine nucleotides, whereas thioguanine is inactivated primarily by TPMT. AD - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. FAU - Dervieux, T AU - Dervieux T FAU - Blanco, J G AU - Blanco JG FAU - Krynetski, E Y AU - Krynetski EY FAU - Vanin, E F AU - Vanin EF FAU - Roussel, M F AU - Roussel MF FAU - Relling, M V AU - Relling MV LA - eng GR - CA21765/CA/NCI GR - CA36401/CA/NCI GR - CA51001/CA/NCI GR - CA56819/CA/NCI PT - Journal Article PL - United States TA - Cancer Res JID - 2984705R RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (DNA, Neoplasm) RN - 0 (Purine Nucleotides) RN - 0 (Purines) RN - 0 (Thionucleosides) RN - 0 (Thionucleotides) RN - 154-42-7 (Thioguanine) RN - 50-44-2 (6-Mercaptopurine) RN - 50-66-8 (6-methylthiopurine) RN - 961-07-9 (Deoxyguanosine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 3T3 Cells MH - 6-Mercaptopurine/*analogs & derivatives/pharmacokinetics/*pharmacology MH - Animals MH - Antimetabolites, Antineoplastic/pharmacokinetics/*pharmacology MH - Biotransformation MH - Comparative Study MH - Cytosol/metabolism MH - DNA, Neoplasm/metabolism MH - Deoxyguanosine/metabolism MH - Gene Transfer Techniques MH - Hela Cells MH - Humans MH - Leukemia, T-Cell, Acute/*drug therapy/*enzymology/genetics MH - Methyltransferases/biosynthesis/genetics/*metabolism MH - Mice MH - Purine Nucleotides/metabolism MH - Purines/biosynthesis MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Retroviridae/genetics MH - Thioguanine/pharmacokinetics/*pharmacology MH - Thionucleosides/metabolism MH - Thionucleotides/metabolism MH - Tumor Cells, Cultured EDAT- 2001/08/02 10:00 MHDA- 2001/08/17 10:01 PST - ppublish SO - Cancer Res 2001 Aug 1;61(15):5810-6. PR -------------------------------------------------------------------------------- 51: Ando M et al. Genetic polymorphisms of thio...[PMID: 11337943] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11337943 OWN - NLM STAT- MEDLINE DA - 20010507 DCOM- 20010913 LR - 20041117 PUBM- Print IS - 0960-314X VI - 11 IP - 3 DP - 2001 Apr TI - Genetic polymorphisms of thiopurine S-methyltransferase and 6-mercaptopurine toxicity in Japanese children with acute lymphoblastic leukaemia. PG - 269-73 AD - First Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsurumai-cho, Showaku, Nagoya 466-8550, Japan. FAU - Ando, M AU - Ando M FAU - Ando, Y AU - Ando Y FAU - Hasegawa, Y AU - Hasegawa Y FAU - Sekido, Y AU - Sekido Y FAU - Shimokata, K AU - Shimokata K FAU - Horibe, K AU - Horibe K LA - eng PT - Journal Article PL - England TA - Pharmacogenetics JID - 9211735 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*adverse effects MH - Adolescent MH - Antimetabolites, Antineoplastic/*adverse effects MH - Bone Marrow/*drug effects MH - Child MH - Child, Preschool MH - Comparative Study MH - Female MH - Heterozygote MH - Humans MH - Japan/epidemiology MH - Leukemia, Lymphocytic, Acute/drug therapy/*enzymology/ethnology MH - Male MH - Methyltransferases/*genetics MH - Polymerase Chain Reaction MH - *Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't EDAT- 2001/05/08 10:00 MHDA- 2001/09/14 10:01 PST - ppublish SO - Pharmacogenetics 2001 Apr;11(3):269-73. DR -------------------------------------------------------------------------------- 52: Evans WE et al. Preponderance of thiopurine S...[PMID: 11304783] Related Articles, Compound via MeSH, Substance via MeSH, OMIM, Books, LinkOut PMID- 11304783 OWN - NLM STAT- MEDLINE DA - 20010417 DCOM- 20010517 LR - 20041117 PUBM- Print IS - 0732-183X VI - 19 IP - 8 DP - 2001 Apr 15 TI - Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. PG - 2293-301 AB - PURPOSE: To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management. PATIENTS AND METHODS: TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography. RESULTS: Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity. CONCLUSION: There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity. AD - St Jude Children's Research Hospital and University of Tennessee, Memphis 38101-0318, USA. william.evans@stjude.org FAU - Evans, W E AU - Evans WE FAU - Hon, Y Y AU - Hon YY FAU - Bomgaars, L AU - Bomgaars L FAU - Coutre, S AU - Coutre S FAU - Holdsworth, M AU - Holdsworth M FAU - Janco, R AU - Janco R FAU - Kalwinsky, D AU - Kalwinsky D FAU - Keller, F AU - Keller F FAU - Khatib, Z AU - Khatib Z FAU - Margolin, J AU - Margolin J FAU - Murray, J AU - Murray J FAU - Quinn, J AU - Quinn J FAU - Ravindranath, Y AU - Ravindranath Y FAU - Ritchey, K AU - Ritchey K FAU - Roberts, W AU - Roberts W FAU - Rogers, Z R AU - Rogers ZR FAU - Schiff, D AU - Schiff D FAU - Steuber, C AU - Steuber C FAU - Tucci, F AU - Tucci F FAU - Kornegay, N AU - Kornegay N FAU - Krynetski, E Y AU - Krynetski EY FAU - Relling, M V AU - Relling MV LA - eng GR - CA21765/CA/NCI GR - R01 CA78224/CA/NCI GR - R37 CA36401/CA/NCI PT - Journal Article PL - United States TA - J Clin Oncol JID - 8309333 RN - 0 (Antimetabolites, Antineoplastic) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*adverse effects MH - Adolescent MH - Adult MH - Antimetabolites, Antineoplastic/*adverse effects MH - Azathioprine/*adverse effects MH - Child MH - Child, Preschool MH - Female MH - Genotype MH - Hospitalization MH - Humans MH - Infant MH - Male MH - Methyltransferases/*deficiency/*genetics/metabolism MH - Neoplasms/drug therapy MH - Phenotype MH - Platelet Transfusion MH - *Polymorphism, Restriction Fragment Length MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Risk Factors MH - Thrombocytopenia/*chemically induced/genetics EDAT- 2001/04/17 10:00 MHDA- 2001/05/18 10:01 PST - ppublish SO - J Clin Oncol 2001 Apr 15;19(8):2293-301. DR -------------------------------------------------------------------------------- 53: Weinshilboum R. Thiopurine pharmacogenetics: ...[PMID: 11259360] Related Articles, Books, LinkOut PMID- 11259360 OWN - NLM STAT- MEDLINE DA - 20010322 DCOM- 20010614 LR - 20041117 PUBM- Print IS - 0090-9556 VI - 29 IP - 4 Pt 2 DP - 2001 Apr TI - Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. PG - 601-5 AB - Thiopurine drugs are used to treat patients with neoplasia and autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best examples of the potential importance of pharmacogenetics for clinical medicine. Specifically, it is now known that patients with inherited very low levels of TPMT activity are at greatly increased risk for thiopurine-induced toxicity such as myelosuppression when treated with standard doses of these drugs, while subjects with very high activity may be undertreated. Furthermore, recent reports indicate that TPMT may be the target for clinically significant drug interactions and that this common genetic polymorphism might be a risk factor for the occurrence of therapy-dependent secondary leukemia. In parallel with these clinical reports, the molecular basis for the TPMT polymorphism has been determined as a result of cloning and characterization of the human TPMT cDNA and gene. Those advances led to the description and characterization of a series of single nucleotide polymorphisms that result in low levels of enzyme activity as well as a polymorphic variable number tandem repeat within the 5'-flanking region of the TPMT gene that may "modulate" level of enzyme activity. As a result of these observations, the TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is developed and applied to clinical medicine. AD - Department of Pharmacology, Mayo Medical School/Mayo Graduate School/Mayo Clinic, Rochester, Minnesota 55905, USA. weinshilboum.richard@mayo.edu FAU - Weinshilboum, R AU - Weinshilboum R LA - eng GR - RO1 GM 28157/GM/NIGMS GR - RO1 GM 35720/GM/NIGMS PT - Congresses PL - United States TA - Drug Metab Dispos JID - 9421550 RN - 0 (Purines) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Humans MH - Methyltransferases/*genetics MH - *Pharmacogenetics MH - Polymorphism, Genetic MH - Purines/*therapeutic use MH - Research Support, U.S. Gov't, P.H.S. EDAT- 2001/03/22 10:00 MHDA- 2001/06/23 10:01 PST - ppublish SO - Drug Metab Dispos 2001 Apr;29(4 Pt 2):601-5. DR -------------------------------------------------------------------------------- 54: Krynetskaia NF et al. [Targets of antileukemia agen...[PMID: 11186004] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11186004 OWN - NLM STAT- MEDLINE DA - 20001218 DCOM- 20010215 LR - 20041117 PUBM- Print IS - 0026-8984 VI - 34 IP - 6 DP - 2000 Nov-Dec TI - [Targets of antileukemia agents: molecular mechanisms of mercaptopurine action] PG - 1046-53 AD - natalia.krynetskaia@stjude.org FAU - Krynetskaia, N F AU - Krynetskaia NF FAU - Krynetskii, E Iu AU - Krynetskii EIu LA - rus PT - Journal Article PT - Review PT - Review, Tutorial TT - Misheni antileikoznykh agentov: molekuliarnye mekhanizmy deistviia merkaptopurina. PL - Russia TA - Mol Biol (Mosk) JID - 0105454 RN - 0 (Antineoplastic Agents, Alkylating) RN - 0 (DNA, Neoplasm) RN - 0 (Nucleic Acid Heteroduplexes) RN - 118-00-3 (Guanosine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*pharmacology/therapeutic use MH - Antineoplastic Agents, Alkylating/*pharmacology/therapeutic use MH - DNA, Neoplasm/metabolism MH - Guanosine/metabolism MH - Humans MH - Leukemia/*drug therapy MH - Methyltransferases/genetics/metabolism MH - Nucleic Acid Heteroduplexes MH - Phylogeny MH - Polymorphism, Genetic RF - 47 EDAT- 2001/02/24 12:00 MHDA- 2001/03/03 10:01 PST - ppublish SO - Mol Biol (Mosk) 2000 Nov-Dec;34(6):1046-53. NR -------------------------------------------------------------------------------- 55: Hall AG et al. The use of denaturing high-pr...[PMID: 11179762] Related Articles, Cited in PMC, Books, LinkOut PMID- 11179762 OWN - NLM STAT- MEDLINE DA - 20010222 DCOM- 20010521 LR - 20041117 PUBM- Print IS - 0165-022X VI - 47 IP - 1-2 DP - 2001 Jan 30 TI - The use of denaturing high-pressure liquid chromatography for the detection of mutations in thiopurine methyltransferase. PG - 65-71 AB - The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of drugs used both in the treatment of acute leukaemia (6-mercaptopurine and 6-thioguanine) and as an immunosuppressant in patients with autoimmune diseases or following organ transplantation (azathioprine). Studies of enzyme activity in red blood cells have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. Patients with biallelic mutations and undetectable enzyme activity suffer life-threatening myelosuppression when treated with conventional doses of these drugs. Patients with intermediate activity have an increased risk of drug-associated toxicity. In the Caucasian populations studied to date, intermediate activity is associated with mutations at two sites of the TPMT gene, G460A and A719G (designated TPMT*3A), in 80% of cases. Detection of these mutations has, to date, been based on the analysis of restriction digests of PCR products. In order to simplify this process we have investigated the ability of denaturing high pressure liquid chromatography (DHPLC) to detect the A719G mutation. DHPLC of PCR products from 15 known heterozygotes (TPMT*3A/TPMT*1) and 18 known homozygotes (TPMT*1/TPMT*1) gave a clear pattern difference between the groups and 100% concordance with the results of restriction digests. These results suggest DHPLC represents a valuable technique for accurate and rapid detection of pharmacologically important mutations in the TPMT gene. AD - Leukaemia Research Fund Laboratory, University of Newcastle Upon Tyne, Newcastle Upon Tyne, UK. a.g.hall@ncl.ac.uk FAU - Hall, A G AU - Hall AG FAU - Hamilton, P AU - Hamilton P FAU - Minto, L AU - Minto L FAU - Coulthard, S A AU - Coulthard SA LA - eng PT - Journal Article PL - Netherlands TA - J Biochem Biophys Methods JID - 7907378 RN - 0 (Antineoplastic Agents) RN - 0 (Immunosuppressive Agents) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Antineoplastic Agents/adverse effects/metabolism MH - Chromatography, High Pressure Liquid/*methods MH - DNA Mutational Analysis/*methods MH - Humans MH - Immunosuppressive Agents/adverse effects/metabolism MH - Methyltransferases/blood/*genetics MH - Nucleic Acid Denaturation MH - Point Mutation MH - Polymerase Chain Reaction MH - Research Support, Non-U.S. Gov't EDAT- 2001/02/17 11:00 MHDA- 2001/05/25 10:01 AID - S0165022X00001524 [pii] PST - ppublish SO - J Biochem Biophys Methods 2001 Jan 30;47(1-2):65-71. DR -------------------------------------------------------------------------------- 56: Thervet E et al. Clinical consequences of the ...[PMID: 11134802] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11134802 OWN - NLM STAT- MEDLINE DA - 20010119 DCOM- 20010126 LR - 20041117 PUBM- Print IS - 0041-1345 VI - 32 IP - 8 DP - 2000 Dec TI - Clinical consequences of the polymorphism of azathioprine metabolism. PG - 2780 AD - Service de Nephrologie, Hopital Saint Louis, Paris, France. FAU - Thervet, E AU - Thervet E FAU - Anglicheau, D AU - Anglicheau D FAU - Toledano, N AU - Toledano N FAU - Kreis, H AU - Kreis H FAU - Legendre, C AU - Legendre C FAU - Beaune, P AU - Beaune P LA - eng PT - Journal Article PL - UNITED STATES TA - Transplant Proc JID - 0243532 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 59865-13-3 (Cyclosporine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Azathioprine/*blood/therapeutic use MH - Cyclosporine/therapeutic use MH - Drug Therapy, Combination MH - Erythrocytes/*enzymology MH - Follow-Up Studies MH - Humans MH - Immunosuppressive Agents/blood/therapeutic use MH - Kidney Transplantation/immunology/*physiology MH - Methyltransferases/*blood/genetics MH - *Polymorphism, Genetic MH - Postoperative Period MH - Prospective Studies EDAT- 2001/01/03 11:00 MHDA- 2001/02/28 10:01 AID - S0041134500018820 [pii] PST - ppublish SO - Transplant Proc 2000 Dec;32(8):2780. DR -------------------------------------------------------------------------------- 57: Meisel C et al. How to manage individualized ...[PMID: 11097342] Related Articles, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 11097342 OWN - NLM STAT- MEDLINE DA - 20010307 DCOM- 20010607 LR - 20041117 PUBM- Print IS - 1434-6621 VI - 38 IP - 9 DP - 2000 Sep TI - How to manage individualized drug therapy: application of pharmacogenetic knowledge of drug metabolism and transport. PG - 869-76 AB - Significant fractions of health budgets must be spent for treatment of drug side effects and for inefficient drug therapy. Hereditary variants in drug metabolizing enzymes, drug transporters, and drug targets are important determinants of drug response and toxicity and may therefore aid in selection and dosage of drugs. Today there is extensive knowledge of genetic polymorphisms of cytochrome P450 (CYP) enzymes 2A6, 2C9, 2C19, and 2D6; of phase-2 enzymes such as thiopurine S-methyltransferase; and more recently of drug transporters such as the MDR-1 gene-product P-glycoprotein, affecting a significant share of currently used drugs. However, application of pharmacogenetic knowledge to clinical routine is limited in current practice. To promote the application of pharmacogenetic knowledge in clinical routine, research on genotype-based dose adjustments is still necessary - as is the promotion of faster and cheaper genotype analyses. Furthermore, the benefits of CYP genotype-directed drug therapy should be evaluated in properly designed prospective studies. Once such steps have been successfully taken, drug therapy could well become more prevention-directed and patient-tailored than it is possible today, replacing the current "one drug in one dose for one disease" strategy by a more individualized approach. AD - Institute of Clinical Pharmacology, Charite University Medical Center, Humboldt University of Berlin, Germany. FAU - Meisel, C AU - Meisel C FAU - Roots, I AU - Roots I FAU - Cascorbi, I AU - Cascorbi I FAU - Brinkmann, U AU - Brinkmann U FAU - Brockmoller, J AU - Brockmoller J LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - GERMANY TA - Clin Chem Lab Med JID - 9806306 RN - 0 (Enzymes) RN - 0 (Pharmaceutical Preparations) RN - 0 (Xenobiotics) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) SB - IM MH - Cytochrome P-450 Enzyme System/*genetics/metabolism MH - Drug Therapy/*methods MH - Enzymes/*genetics/metabolism MH - Genotype MH - Humans MH - Pharmaceutical Preparations/*metabolism MH - Pharmacogenetics/*methods MH - Research Support, Non-U.S. Gov't MH - Xenobiotics/*pharmacokinetics RF - 58 EDAT- 2000/11/30 11:00 MHDA- 2001/06/08 10:01 PST - ppublish SO - Clin Chem Lab Med 2000 Sep;38(9):869-76. PR -------------------------------------------------------------------------------- 58: Corominas H et al. [Aplasia after azathioprine a...[PMID: 11093885] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11093885 OWN - NLM STAT- MEDLINE DA - 20001207 DCOM- 20001214 LR - 20041117 PUBM- Print IS - 0025-7753 VI - 115 IP - 8 DP - 2000 Sep 16 TI - [Aplasia after azathioprine administration: role of the thiopurine methyltransferase genetic polymorphism] PG - 299-301 AB - BACKGROUND: Azathioprine is an immunosuppressor drug widely used in the treatment of autoimmune diseases. Adverse effects during treatment are related to the activity of thiopurine methyltransferase (TPMT), an enzyme which plays a role in azathioprine metabolism. The presence of the allelic variants of the TPMT gene allows us to classify patients into three different groups: high, moderate and low risk of myelosuppression after receiving standard doses of azathioprine. PATIENTS AND METHODS: Study of the allelic variants of the TPMT gene in the positions 460 and 719 with PCR methods in a patient with Crohn's disease, who developed aplasia after receiving azathioprine. The study was extended to his relatives. RESULTS: The patient under study carried the most frequent variant allele of the TPMT gene associated with low enzymatic activity. The mother and one sister of the patient were also carriers of this allelic variant. CONCLUSIONS: Genotyping the allelic variants of the TPMT gene is a useful method to identify patients at moderate or high risk of myelosuppression after administration of azathioprine. AD - Medicina Interna Hospital de la Santa Creu i Sant Pau. Barcelona. FAU - Corominas, H AU - Corominas H FAU - Domenech, M AU - Domenech M FAU - Gonzalez-Juan, D AU - Gonzalez-Juan D FAU - Gonzalez-Suarez, B AU - Gonzalez-Suarez B FAU - Diaz, C AU - Diaz C FAU - Pujol, J AU - Pujol J FAU - Vazquez, G AU - Vazquez G FAU - Baiget, M AU - Baiget M LA - spa PT - Case Reports PT - Journal Article TT - Aplasia medular tras administracion de azatioprina: papel de polimorfismo genetico de la tiopurina metiltransferasa. PL - SPAIN TA - Med Clin (Barc) JID - 0376377 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adult MH - Azathioprine/*adverse effects MH - Crohn Disease/drug therapy MH - English Abstract MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Male MH - Methyltransferases/*genetics MH - *Polymorphism, Genetic MH - Red-Cell Aplasia, Pure/*chemically induced MH - Research Support, Non-U.S. Gov't EDAT- 2000/11/30 11:00 MHDA- 2001/02/28 10:01 PST - ppublish SO - Med Clin (Barc) 2000 Sep 16;115(8):299-301. DR -------------------------------------------------------------------------------- 59: Hiratsuka M et al. High throughput detection of ...[PMID: 11041238] Related Articles, Substance via MeSH, Books, LinkOut PMID- 11041238 OWN - NLM STAT- MEDLINE DA - 20010220 DCOM- 20010222 LR - 20041117 PUBM- Print IS - 0918-6158 VI - 23 IP - 10 DP - 2000 Oct TI - High throughput detection of drug-metabolizing enzyme polymorphisms by allele-specific fluorogenic 5' nuclease chain reaction assay. PG - 1131-5 AB - We have developed an allele-specific fluorogenic 5' nuclease chain reaction assay for detecting polymorphisms in the following human drug-metabolizing enzyme genes: CYP2C9 (CYP2C9*2 and *3), CYP2C19 (CYP2C19*2 and *3), CYP2D6 (CYP2D6*4, *10, *14, *18, and *21(C8)), N-acetyltransferase 2 (NAT2*5B, *6A, and *7B), thiopurine methyltransferase (TPMT*3C), and aldehyde dehydrogenase2 (ALDH2*2). This method is a marriage of two emerging technologies, the use of allele-specific amplification primers for target DNA and hybridization of the TaqMan probe. The TaqMan probe is labeled with both a fluorescent reporter dye and a quencher dye. Genotypes are separated according to the different threshold cycles of the wild-type and mutant primers. All assays are performed using a single thermocycling protocol. This genotyping method is rapid and highly sensitive and yields a high throughput. It could be applied toward automated large-scale genotyping. AD - Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan. FAU - Hiratsuka, M AU - Hiratsuka M FAU - Agatsuma, Y AU - Agatsuma Y FAU - Omori, F AU - Omori F FAU - Narahara, K AU - Narahara K FAU - Inoue, T AU - Inoue T FAU - Kishikawa, Y AU - Kishikawa Y FAU - Mizugaki, M AU - Mizugaki M LA - eng PT - Journal Article PL - JAPAN TA - Biol Pharm Bull JID - 9311984 RN - 0 (Enzymes) RN - 0 (Oligonucleotides) RN - 0 (Pharmaceutical Preparations) RN - 9007-49-2 (DNA) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 3.1.- (Exodeoxyribonucleases) RN - EC 3.1.11.5 (Exodeoxyribonuclease V) SB - IM MH - Aldehyde Dehydrogenase/genetics MH - Alleles MH - Cytochrome P-450 Enzyme System/genetics MH - DNA/genetics MH - Enzymes/*genetics MH - Exodeoxyribonuclease V MH - Exodeoxyribonucleases/*genetics MH - Genotype MH - Japan MH - Methyltransferases/genetics MH - Oligonucleotides/diagnostic use MH - Pharmaceutical Preparations/*metabolism MH - Polymerase Chain Reaction MH - Polymorphism, Genetic/genetics MH - Research Support, Non-U.S. Gov't EDAT- 2000/10/21 11:00 MHDA- 2001/03/03 10:01 PST - ppublish SO - Biol Pharm Bull 2000 Oct;23(10):1131-5. NR -------------------------------------------------------------------------------- 60: Foster AP et al. Demonstration of thiopurine m...[PMID: 11012121] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 11012121 OWN - NLM STAT- MEDLINE DA - 20010110 DCOM- 20010301 LR - 20041117 PUBM- Print IS - 0891-6640 VI - 14 IP - 5 DP - 2000 Sep-Oct TI - Demonstration of thiopurine methyltransferase activity in the erythrocytes of cats. PG - 552-4 AB - Azathioprine is a purine analogue used as an immunosuppressive and immunomodulator agent in various mammals, including cats. Several adverse reactions have been reported and have limited the use of the drug in the cat. Adverse reactions to azathioprine in humans have been correlated with reduced activity of thiopurine methyltransferase (TPMT) in erythrocytes. The purpose of this preliminary study was to determine if cats have TPMT activity in their erythrocytes and to compare the values obtained with the normal range for humans and the normal range for dogs in a preliminary report. Activity of the enzyme was measured in blood samples drawn from 41 cats. Blood also was taken from 5 dogs. The mean erythrocyte TPMT activity in the cats was 2.4 +/- 0.4 nmol (range, 1.2-3.9 nmol) per hour per milliliter of red blood cells (U/mL RBC) or 2-8 nmol per hour per gram of hemoglobin (U/g Hb). This range was far lower than the normal human range (8-15 U/mL RBC; 16-33 U/g Hb) and was of monopolar distribution. This observation apparently precludes any diagnostic purpose in assaying erythrocyte TPMT in this species. Erythrocyte TPMT activity in the 5 dogs ranged from 5.5 to 13.1 U/mL RBC (11-27 U/g Hb), which was comparable with normal and carrier ranges for humans, but proof of TPMT genetic polymorphism in either species will require genotyping studies. AD - Department of Clinical Veterinary Science, University of Bristol, Langford, North Somerset, UK. a.p.foster@bris.ac.uk FAU - Foster, A P AU - Foster AP FAU - Shaw, S E AU - Shaw SE FAU - Duley, J A AU - Duley JA FAU - Shobowale-Bakre, E M AU - Shobowale-Bakre EM FAU - Harbour, D A AU - Harbour DA LA - eng PT - Journal Article PL - UNITED STATES TA - J Vet Intern Med JID - 8708660 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Animals MH - Azathioprine/adverse effects/therapeutic use MH - Cats/blood/*physiology MH - Comparative Study MH - Dogs MH - Erythrocytes/*enzymology MH - Female MH - Humans MH - Immunosuppressive Agents/adverse effects/therapeutic use MH - Male MH - Methyltransferases/*blood MH - Reference Values MH - Scintillation Counting/veterinary EDAT- 2000/09/30 11:00 MHDA- 2001/03/07 10:01 PST - ppublish SO - J Vet Intern Med 2000 Sep-Oct;14(5):552-4. NR -------------------------------------------------------------------------------- 61: Coulthard SA et al. A comparison of molecular and...[PMID: 10997970] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10997970 OWN - NLM STAT- MEDLINE DA - 20001010 DCOM- 20001010 LR - 20041117 PUBM- Print IS - 0007-1048 VI - 110 IP - 3 DP - 2000 Sep TI - A comparison of molecular and enzyme-based assays for the detection of thiopurine methyltransferase mutations. PG - 599-604 AB - S-Methylation by thiopurine methyltransferase (TPMT) is an important route of metabolism for the thiopurine drugs. About one in 300 individuals are homozygous for a TPMT mutation associated with very low enzyme activity and severe myelosuppression if treated with standard doses of drug. To validate the use of molecular genetic techniques for the detection of TPMT deficiency, we have determined red blood cell TPMT activity in 240 adult blood donors and 55 normal children. Genotype was determined by restriction fragment length analysis of polymerase chain reaction products in a cohort of 79 of the blood donors and five cases of azathioprine-induced myelosupression, and this confirmed a close relationship between genotype and phenotype. In 17 of the 24 cases in which mutations were found, DNA was also available from remission bone marrow. In one of these cases, DNA from the remission marrow sample indicated the presence of a non-mutated allele that had not been seen in the blast DNA sample obtained at presentation. These results indicate that polymerase chain reaction-based assays give reliable and robust results for the detection of TPMT deficiency, but that caution should be exercised in relying exclusively on DNA obtained from lymphoblasts in childhood leukaemia. AD - The LRF Molecular Pharmacology Specialist Programme, Medical School, Newcastle Upon Tyne, UK. FAU - Coulthard, S A AU - Coulthard SA FAU - Rabello, C AU - Rabello C FAU - Robson, J AU - Robson J FAU - Howell, C AU - Howell C FAU - Minto, L AU - Minto L FAU - Middleton, P G AU - Middleton PG FAU - Gandhi, M K AU - Gandhi MK FAU - Jackson, G AU - Jackson G FAU - McLelland, J AU - McLelland J FAU - O'Brien, H AU - O'Brien H FAU - Smith, S AU - Smith S FAU - Reid, M M AU - Reid MM FAU - Pearson, A D AU - Pearson AD FAU - Hall, A G AU - Hall AG LA - eng PT - Journal Article PL - ENGLAND TA - Br J Haematol JID - 0372544 RN - 0 (Immunosuppressive Agents) RN - 154-42-7 (Thioguanine) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/chemistry/pharmacology MH - Adolescent MH - Adult MH - Azathioprine/chemistry/pharmacology/therapeutic use MH - Blood Donors MH - Child MH - Child, Preschool MH - Comparative Study MH - DNA Mutational Analysis/*methods MH - Female MH - Genotype MH - Humans MH - Immunosuppressive Agents/chemistry/pharmacology/therapeutic use MH - Infant MH - Leukemia, Lymphocytic, Acute, L1/drug therapy/enzymology/*genetics MH - Male MH - Methyltransferases/blood/*deficiency/*genetics MH - Middle Aged MH - Polymerase Chain Reaction/methods MH - Polymorphism, Restriction Fragment Length MH - Reference Values MH - Research Support, Non-U.S. Gov't MH - Sensitivity and Specificity MH - Thioguanine/chemistry/pharmacology EDAT- 2000/09/21 11:00 MHDA- 2000/10/14 11:01 AID - bjh2218 [pii] PST - ppublish SO - Br J Haematol 2000 Sep;110(3):599-604. NR -------------------------------------------------------------------------------- 62: Krynetski EY et al. Genetic polymorphism of thiop...[PMID: 10971199] Related Articles, Cited in PMC, Books, LinkOut PMID- 10971199 OWN - NLM STAT- MEDLINE DA - 20001107 DCOM- 20001107 LR - 20041117 PUBM- Print IS - 0031-7012 VI - 61 IP - 3 DP - 2000 Sep TI - Genetic polymorphism of thiopurine S-methyltransferase: molecular mechanisms and clinical importance. PG - 136-46 AB - The activity of thiopurine S-methyltransferase (TPMT) is inherited as an autosomal co-dominant trait. In most large world populations studied to date, approximately 10% of the population have intermediate activity due to heterozygosity at the TPMT locus, and about 0.33% is TPMT deficient. TPMT is now one of the most well characterized genetic polymorphisms of drug metabolism, with the genetic basis having been well defined in most populations, providing molecular strategies for studying this genetic polymorphism in human and experimental models. Three mutant alleles, TPMT(*)2, TPMT(*)3A and TPMT(*)3C, account for the great majority of mutant alleles in all human populations studied to date. Significant ethnic differences occur in the frequencies of these mutant alleles. Progress in DNA analysis has made it practical to use genotyping techniques for the molecular diagnosis of TPMT deficiency and heterozygosity, thereby avoiding adverse effects that are more prevalent in TPMT-deficient and heterozygous patients prescribed thiopurine medications. CI - Copyright 2000 S. Karger AG, Basel AD - University of Tennessee and St. Jude Children's Research Hospital, Memphis, TN, USA. FAU - Krynetski, E Y AU - Krynetski EY FAU - Evans, W E AU - Evans WE LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - SWITZERLAND TA - Pharmacology JID - 0152016 RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Animals MH - Evolution MH - Humans MH - Methyltransferases/*genetics/metabolism MH - Polymorphism, Genetic/*genetics MH - Species Specificity RF - 118 EDAT- 2000/09/06 11:00 MHDA- 2001/02/28 10:01 AID - pha61136 [pii] PST - ppublish SO - Pharmacology 2000 Sep;61(3):136-46. DR -------------------------------------------------------------------------------- 63: Liang A et al. [Advances of research on the ...[PMID: 10921112] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10921112 OWN - NLM STAT- MEDLINE DA - 20000811 DCOM- 20000811 LR - 20041117 PUBM- Print IS - 0253-2727 VI - 19 IP - 2 DP - 1998 Feb TI - [Advances of research on the action of purinergic drugs and hereditary polymorphism of thiopurine methyltransferase] PG - 110-2 FAU - Liang, A AU - Liang A FAU - Guo, L AU - Guo L LA - chi PT - Journal Article PT - Review PT - Review, Tutorial PL - CHINA TA - Zhonghua Xue Ye Xue Za Zhi JID - 8212398 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*metabolism MH - Antimetabolites, Antineoplastic/*metabolism MH - Humans MH - Leukemia/drug therapy MH - Methyltransferases/*genetics MH - *Polymorphism, Genetic RF - 23 EDAT- 2000/08/02 11:00 MHDA- 2000/08/19 11:00 PST - ppublish SO - Zhonghua Xue Ye Xue Za Zhi 1998 Feb;19(2):110-2. DR -------------------------------------------------------------------------------- 64: Sebbag L et al. Thiopurine S-methyltransferas...[PMID: 10798786] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10798786 OWN - NLM STAT- MEDLINE DA - 20000525 DCOM- 20000525 LR - 20041117 PUBM- Print IS - 0041-1337 VI - 69 IP - 7 DP - 2000 Apr 15 TI - Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients. PG - 1524-7 AB - Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-methyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with four prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G460A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transplant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation-specific polymerase chain reaction-based methods) was observed in four patients (A719G: n = 2; A719G plus G460: n = 2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutation A719G and there was a 40% drop in neutrophils in the two other patients. Discontinuation of AZA in the four mutant patients corrected for the drop. Presence of TPMT mutations is associated with a greater likelihood of agranulocytosis. Determination of these mutations could reduce the risk for hematological side-effects. AD - Hopital Cardiologique, Lyon, France. FAU - Sebbag, L AU - Sebbag L FAU - Boucher, P AU - Boucher P FAU - Davelu, P AU - Davelu P FAU - Boissonnat, P AU - Boissonnat P FAU - Champsaur, G AU - Champsaur G FAU - Ninet, J AU - Ninet J FAU - Dureau, G AU - Dureau G FAU - Obadia, J F AU - Obadia JF FAU - Vallon, J J AU - Vallon JJ FAU - Delaye, J AU - Delaye J LA - eng PT - Journal Article PL - UNITED STATES TA - Transplantation JID - 0132144 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adult MH - Agranulocytosis/chemically induced MH - Azathioprine/*therapeutic use MH - Bone Marrow/*drug effects/pathology MH - Female MH - Forecasting MH - Genetic Predisposition to Disease MH - Genotype MH - *Heart Transplantation MH - Humans MH - Immunosuppressive Agents/*therapeutic use MH - Male MH - Methyltransferases/*genetics MH - Middle Aged MH - *Polymorphism, Genetic MH - Retrospective Studies EDAT- 2000/05/08 09:00 MHDA- 2000/06/08 09:00 PST - ppublish SO - Transplantation 2000 Apr 15;69(7):1524-7. DR -------------------------------------------------------------------------------- 65: McLeod HL et al. Genetic polymorphism of thiop...[PMID: 10764140] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10764140 OWN - NLM STAT- MEDLINE DA - 20000504 DCOM- 20000504 LR - 20041117 PUBM- Print IS - 0887-6924 VI - 14 IP - 4 DP - 2000 Apr TI - Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. PG - 567-72 AB - Thiopurine methyltransferase (TPMT) catalyses the S-methylation of thiopurines, including 6-mercaptopurine and 6-thioguanine. TPMT activity exhibits genetic polymorphism, with about 1/300 inheriting TPMT deficiency as an autosomal recessive trait. If treated with standard doses of thiopurines, TPMTdeficient patients accumulate excessive thioguanine nucleotides in hematopoietic tissues, leading to severe hematological toxicity that can be fatal. However, TPMT-deficient patients can be successfully treated with a 10- to 15-fold lower dosage of these medications. The molecular basis for altered TPMT activity has been defined, with rapid and inexpensive assays available for the three signature mutations which account for the majority of mutant alleles. TPMT genotype correlates well with in vivo enzyme activity within erythrocytes and leukemic blast cells and is clearly associated with risk of toxicity. The impact of 6-mercaptopurine dose intensity is also being clarified as an important determinate of event-free survival in childhood leukemia. In addition, there are emerging data that TPMT genotype may influence the risk of secondary malignancies, including brain tumors and acute myelogenous leukemia. Ongoing studies aim to clarify the influence of TPMT on thiopurine efficacy, acute toxicity, and risk for delayed toxicity. Together, these advances hold the promise of improving the safety and efficacy of thiopurine therapy. AD - Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, UK. FAU - McLeod, H L AU - McLeod HL FAU - Krynetski, E Y AU - Krynetski EY FAU - Relling, M V AU - Relling MV FAU - Evans, W E AU - Evans WE LA - eng GR - CAZ1765/CA/NCI GR - R01 CA51001/CA/NCI GR - R37 CA 36401/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - Leukemia JID - 8704895 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Codon) RN - 0 (Neoplasm Proteins) RN - 0 (Recombinant Fusion Proteins) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/adverse effects/*pharmacokinetics MH - African Continental Ancestry Group/genetics MH - Antimetabolites, Antineoplastic/adverse effects/*pharmacokinetics MH - Asia MH - Child MH - Child, Preschool MH - Codon/genetics MH - Disease-Free Survival MH - Drug Resistance, Neoplasm/genetics MH - England MH - Ethnic Groups/genetics MH - European Continental Ancestry Group/genetics MH - France MH - Gene Frequency MH - Genotype MH - Humans MH - India MH - Infant MH - Leukemia, Lymphocytic, Acute, L1/drug therapy/enzymology/*genetics MH - Metabolic Detoxication, Drug/*genetics MH - Methyltransferases/*genetics MH - Neoplasm Proteins/*genetics MH - Neoplasms, Second Primary/chemically induced MH - Point Mutation MH - *Polymorphism, Genetic MH - Recombinant Fusion Proteins/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Risk MH - Safety MH - Treatment Outcome RF - 34 EDAT- 2000/04/14 09:00 MHDA- 2000/05/08 09:00 PST - ppublish SO - Leukemia 2000 Apr;14(4):567-72. DR -------------------------------------------------------------------------------- 66: Tavadia SM et al. Screening for azathioprine to...[PMID: 10727309] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10727309 OWN - NLM STAT- MEDLINE DA - 20000502 DCOM- 20000502 LR - 20041117 PUBM- Print IS - 0190-9622 VI - 42 IP - 4 DP - 2000 Apr TI - Screening for azathioprine toxicity: a pharmacoeconomic analysis based on a target case. PG - 628-32 AB - The risk of azathioprine-induced myelosuppression can be predicted by detecting patients with intermediate or low thiopurine methyltransferase (TPMT) activity. Population studies have shown that 89% of whites have high TPMT activity, 11% have intermediate TPMT activity, and 0.3% have low TPMT activity. Three specific mutations in the TPMT gene that cause decreased TPMT activity have recently been identified. Patients homozygous for the TPMT mutations have low TPMT activity, and patients heterozygous for TPMT mutations have intermediate TPMT activity. This has led to the development of a technique for TPMT genotype analysis that will identify patients at risk of azathioprine-induced myelosuppression. We report a case of a patient with bullous pemphigoid who experienced azathioprine-induced myelosuppression and who was later found to be homozygous for TPMT mutant alleles. Using the cost of treatment required for this patient and the estimated population prevalence of TPMT mutations, we examined the cost impact of screening for TPMT mutations in all patients being considered for azathioprine therapy. We calculated that screening is cost-neutral assuming patients homozygous for TPMT mutations experience myelosuppression, and that it is cost-beneficial assuming patients heterozygous for TPMT mutations also experience myelosuppression while receiving azathioprine. Screening patients for TPMT mutations will reduce the risk of azathioprine-induced myelosuppression, and our study suggests that it may also be a cost-attractive strategy. AD - Dermatology Research, Division of Dermatology, Sunnybrook and Women's College Health Science Centre, Toronto, Canada. FAU - Tavadia, S M AU - Tavadia SM FAU - Mydlarski, P R AU - Mydlarski PR FAU - Reis, M D AU - Reis MD FAU - Mittmann, N AU - Mittmann N FAU - Pinkerton, P H AU - Pinkerton PH FAU - Shear, N AU - Shear N FAU - Sauder, D N AU - Sauder DN LA - eng PT - Case Reports PT - Journal Article PL - UNITED STATES TA - J Am Acad Dermatol JID - 7907132 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Adult MH - Azathioprine/*adverse effects/economics MH - Costs and Cost Analysis MH - Female MH - Genetic Screening/*economics MH - Homozygote MH - Humans MH - Immunosuppressive Agents/*adverse effects/economics MH - Methyltransferases/*genetics/metabolism MH - Mutation MH - Myeloproliferative Disorders/*chemically induced MH - Pemphigoid, Bullous/drug therapy EDAT- 2000/03/22 09:00 MHDA- 2000/05/08 09:00 AID - S0190962200577767 [pii] PST - ppublish SO - J Am Acad Dermatol 2000 Apr;42(4):628-32. PR -------------------------------------------------------------------------------- 67: Lowhagen GB et al. [Bone marrow depression after...[PMID: 10707497] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10707497 OWN - NLM STAT- MEDLINE DA - 20000317 DCOM- 20000317 LR - 20041117 PUBM- Print IS - 0023-7205 VI - 97 IP - 5 DP - 2000 Feb 2 TI - [Bone marrow depression after azathioprine. New discoveries on an old drug] PG - 458-62 AB - Azathioprine, a cytostatic and immunosuppressive drug in use for some 30 years, can give rise to life-threatening neutropenia and thrombocytopenia. This may be caused by unexpectedly high concentrations of cytotoxic metabolites due to abnormally slow inactivation of 6-mercaptopurine (6-MP) by thiopurine S-methyltransferase (TPMT) and/or xanthine oxidase. Low TPMT activity may be due to genetic polymorphism or interaction with drugs such as salicylic acid derivatives, while xanthine oxidase may be inhibited by allopurinol. High TPMT activity, on the other hand, may hamper cytostatic treatment. Safer and more effective treatment with azathioprine and its metabolite 6-MP becomes possible with new laboratory methods for pharmacotherapy monitoring. AD - Institutionen for dermatologi och venereologi, Sahlgrenska Universitetssjukhuset, Goteborg. FAU - Lowhagen, G B AU - Lowhagen GB FAU - Lindstedt, G AU - Lindstedt G LA - swe PT - Case Reports PT - Journal Article TT - Benmargshamning efter azatioprin. Nya ron om ett gammalt lakemedel. PL - SWEDEN TA - Lakartidningen JID - 0027707 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) SB - IM CIN - Lakartidningen. 2000 Apr 19;97(16):1999-2000. PMID: 10826362 MH - 6-Mercaptopurine/adverse effects/metabolism MH - Aged MH - Antimetabolites, Antineoplastic/*adverse effects/metabolism MH - Azathioprine/*adverse effects/metabolism MH - Bone Marrow Cells/*drug effects MH - English Abstract MH - Female MH - Genotype MH - Hematologic Diseases/*chemically induced MH - Humans MH - Immunosuppressive Agents/*adverse effects/metabolism MH - Methyltransferases/genetics/metabolism MH - Neutropenia/chemically induced MH - Pancytopenia/chemically induced MH - Risk Factors EDAT- 2000/03/09 09:00 MHDA- 2000/03/25 09:00 PST - ppublish SO - Lakartidningen 2000 Feb 2;97(5):458-62. PR -------------------------------------------------------------------------------- 68: Linder MW et al. Pharmacogenetics in the pract...[PMID: 10671647] Related Articles, Substance via MeSH, Books, LinkOut PMID- 10671647 OWN - NLM STAT- MEDLINE DA - 20000317 DCOM- 20000317 LR - 20041117 PUBM- Print IS - 1084-8592 VI - 4 IP - 4 DP - 1999 Dec TI - Pharmacogenetics in the practice of laboratory medicine. PG - 365-79 AB - BACKGROUND: The clinical laboratory forms an essential bridge between fundamental discoveries in biological sciences and their transition into effective medical practice. The genetic basis for individuality in drug metabolism and response is the result of a finite number of inherited sequence variants (alleles) of genes encoding drug-metabolizing enzymes and drug receptors. Pharmacogenetics (PG) links differences in gene structure with pharmacological differences in pharmacokinetics and pharmacodynamics. The next step in the process of applying PG (or pharmacogenomic) information to individualized therapeutic management is dissemination of this information to practicing physicians by clinical laboratorians. Transitioning PG analysis into clinical practice will require professionals in laboratory medicine to identify relevant polymorphisms, develop sensitive and specific testing strategies, and, in conjunction with physicians and pharmacologists, communicate interpretive guidelines regarding appropriate indications for testing and rational dose adjustment. We review these concepts and provide examples of how PG can be applied to support therapeutic decision making. AD - Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA. mwlind01@gwise.louisville.edu FAU - Linder, M W AU - Linder MW FAU - Valdes, R Jr AU - Valdes R Jr LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Mol Diagn JID - 9614965 RN - 0 (Pharmaceutical Preparations) RN - 0 (Receptors, Adrenergic, beta-2) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1.5 (Arylamine N-Acetyltransferase) SB - IM MH - Arylamine N-Acetyltransferase/genetics MH - Clinical Protocols MH - Cytochrome P-450 Enzyme System/genetics MH - Humans MH - *Laboratory Techniques and Procedures MH - Methyltransferases/genetics MH - Pharmaceutical Preparations/metabolism MH - *Pharmacogenetics MH - Polymorphism, Genetic MH - Receptors, Adrenergic, beta-2/genetics RF - 92 EDAT- 2000/02/15 09:00 MHDA- 2000/03/25 09:00 AID - 10.154/MODI00400365 [doi] AID - 00400365 [pii] PST - ppublish SO - Mol Diagn 1999 Dec;4(4):365-79. NR -------------------------------------------------------------------------------- 69: Iyer L. Inherited variations in drug-...[PMID: 10671643] Related Articles, Books, LinkOut PMID- 10671643 OWN - NLM STAT- MEDLINE DA - 20000317 DCOM- 20000317 LR - 20041117 PUBM- Print IS - 1084-8592 VI - 4 IP - 4 DP - 1999 Dec TI - Inherited variations in drug-metabolizing enzymes: significance in clinical oncology. PG - 327-33 AB - Pharmacogenetics has emerged as a novel and challenging area of interest in oncology. Cancer chemotherapy is characterized by major intersubject variability in tumor responses and host toxicity. This variation may be caused by genetic differences in the enzymes involved in the metabolism of anticancer agents. Anticancer agents, such as 6-mercaptopurine, 5-fluorouracil, and irinotecan, have a narrow therapeutic index that can sometimes result in severe life-threatening toxicities. The impact of polymorphisms in metabolizing enzymes (thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, and uridine diphosphate glucuronosyltransferase) that participate significantly in the disposition of these anticancer agents is discussed. AD - Department of Medicine and Committee on Clinical Pharmacology, The University of Chicago, Chicago, Illinois 60637, USA. liyer@mcis.bsd.uchicago.edu FAU - Iyer, L AU - Iyer L LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Mol Diagn JID - 9614965 RN - 0 (Antineoplastic Agents) RN - EC 1. (Oxidoreductases) RN - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP)) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.4.1.17 (Glucuronosyltransferase) SB - IM MH - Alleles MH - Antineoplastic Agents/*metabolism MH - Dihydrouracil Dehydrogenase (NADP) MH - Genotype MH - Glucuronosyltransferase/*genetics MH - Humans MH - Methyltransferases/*genetics MH - Oxidoreductases/*genetics MH - Phenotype MH - Polymorphism, Genetic MH - *Variation (Genetics) RF - 75 EDAT- 2000/02/15 09:00 MHDA- 2000/03/25 09:00 AID - 10.154/MODI00400327 [doi] AID - 00400327 [pii] PST - ppublish SO - Mol Diagn 1999 Dec;4(4):327-33. DR -------------------------------------------------------------------------------- 70: Ishioka S et al. Thiopurine methyltransferase ...[PMID: 10628931] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10628931 OWN - NLM STAT- MEDLINE DA - 20000127 DCOM- 20000127 LR - 20041117 PUBM- Print IS - 0918-2918 VI - 38 IP - 12 DP - 1999 Dec TI - Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. PG - 944-7 AB - OBJECTIVE: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds, including Azathioprine (AZA). It has been reported that the level of AZA toxicity is dependent on the TPMT genotypes in Caucasian individuals; we thus investigated this relationship in Japanese. METHODS: The TPMT genotype was determined using peripheral blood cell DNA obtained from 36 Japanese patients with rheumatic diseases who were treated with AZA, by polymerase chain reaction (PCR) technique. Duration of AZA administration, white blood cell counts before and after AZA administration, and side effects were investigated in each subject, and were compared between the patients with or without TPMT mutation. RESULTS: The TPMT allelotype was TPMT*1/TPMT*1 in 33 (91.7%) and TPMT*1/TPMT*3C in 3 (8.3%) individuals. All 3 patients (100%) with the mutant TPMT allele (TPMT*3C) discontinued AZA treatment due to leucopenia while only 4 patients (12%) without mutant TPMT alleles showed leucopenia (p=0.0049, Fisher's exact test). However, leucopenia developed relatively late in patients with mutant TPMT. CONCLUSION: The TPMT mutant allele, TPMT*3C, also exists in Japanese individuals, and the bone marrow toxicity of AZA is likely stronger in patients with this mutant allele. AD - Second Department of Internal Medicine, Hiroshima University School of Medicine, Kasumi. FAU - Ishioka, S AU - Ishioka S FAU - Hiyama, K AU - Hiyama K FAU - Sato, H AU - Sato H FAU - Yamanishi, Y AU - Yamanishi Y FAU - McLeod, H L AU - McLeod HL FAU - Kumagai, K AU - Kumagai K FAU - Maeda, H AU - Maeda H FAU - Yamakido, M AU - Yamakido M LA - eng PT - Journal Article PL - JAPAN TA - Intern Med JID - 9204241 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM CIN - Intern Med. 2000 Jul;39(7):523-4. PMID: 10888203 MH - Azathioprine/*adverse effects MH - Genotype MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Japan MH - Methyltransferases/*genetics MH - Mutation MH - Research Support, Non-U.S. Gov't MH - Rheumatic Diseases/*drug therapy/*enzymology/genetics EDAT- 2000/01/11 MHDA- 2000/01/11 00:01 PST - ppublish SO - Intern Med 1999 Dec;38(12):944-7. DR -------------------------------------------------------------------------------- 71: Relling MV et al. Mercaptopurine therapy intole...[PMID: 10580024] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10580024 OWN - NLM STAT- MEDLINE DA - 19991221 DCOM- 19991221 LR - 20041117 PUBM- Print IS - 0027-8874 VI - 91 IP - 23 DP - 1999 Dec 1 TI - Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. PG - 2001-8 AB - BACKGROUND: Patients with acute lymphoblastic leukemia are often treated with 6-mercaptopurine, and those with homozygous deficiency in thiopurine S-methyltransferase (TPMT) enzyme activity have an extreme sensitivity to this drug as a result of the accumulation of higher cellular concentrations of thioguanine nucleotides. We studied the metabolism, dose requirements, and tolerance of 6-mercaptopurine among patients with different TPMT phenotypes. METHODS: We compared, by use of statistical modeling, 6-mercaptopurine pharmacology and tolerance in 180 patients who achieved remission on St. Jude Children's Research Hospital Protocol Total XII composed of weekly methotrexate (40 mg/m(2)) and daily oral 6-mercaptopurine (75 mg/m(2)) given for 2.5 years, interrupted every 6 weeks during the first year for treatment with either high-dose methotrexate or teniposide plus cytarabine. Statistical tests were two-sided. RESULTS: Erythrocyte concentrations of thioguanine nucleotides (pmol/8 x 10(8) erythrocytes) were inversely related to TPMT enzyme activity (P<.01), with averages (+/- standard deviations) of 417 (+/-179), 963 (+/-752), and 3565 (+/-1282) in TPMT homozygous wild-type (n = 161), heterozygous (n = 17), and homozygous-deficient (n = 2) patients, respectively. There was complete concordance between TPMT genotype and phenotype in a subset of 28 patients for whom TPMT genotype was determined. There were no sex differences in thioguanine nucleotide concentrations (P =.24), TPMT enzyme activity (P =.22), or average weekly prescribed dose of 6-mercaptopurine (P=.49). The cumulative incidence of 6-mercaptopurine dose reductions due to toxicity was highest among patients homozygous for mutant TPMT (100%), intermediate among heterozygous patients (35%), and lowest among wild-type patients (7%) (P<.001), with average (+/- standard deviation) final weekly 6-mercaptopurine doses of 72 (+/-60), 449 (+/-160), and 528 (+/-90) mg/m(2), respectively. Lowering doses of 6-mercaptopurine in TPMT heterozygotes and in deficient patients allowed administration of full protocol doses of other chemotherapy while maintaining high thioguanine nucleotide concentrations. CONCLUSION: We conclude that genetic polymorphism in TPMT is an important determinant of mercaptopurine toxicity, even among patients who are heterozygous for this trait. AD - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. mary.relling@stjude.org FAU - Relling, M V AU - Relling MV FAU - Hancock, M L AU - Hancock ML FAU - Rivera, G K AU - Rivera GK FAU - Sandlund, J T AU - Sandlund JT FAU - Ribeiro, R C AU - Ribeiro RC FAU - Krynetski, E Y AU - Krynetski EY FAU - Pui, C H AU - Pui CH FAU - Evans, W E AU - Evans WE LA - eng GR - CA20180/CA/NCI GR - CA36401/CA/NCI GR - CA51001/CA/NCI GR - etc. PT - Clinical Trial PT - Journal Article PT - Randomized Controlled Trial PL - UNITED STATES TA - J Natl Cancer Inst JID - 7503089 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Combined Chemotherapy Protocols) RN - 0 (Guanine Nucleotides) RN - 0 (Prodrugs) RN - 0 (Thionucleotides) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM CIN - J Natl Cancer Inst. 1999 Dec 1;91(23):1983-5. PMID: 10580012 MH - 6-Mercaptopurine/*administration & dosage/adverse effects/*pharmacokinetics MH - Antimetabolites, Antineoplastic/*administration & dosage/adverse effects/*pharmacokinetics MH - Antineoplastic Combined Chemotherapy Protocols/*therapeutic use MH - Area Under Curve MH - Child MH - Erythrocytes/metabolism MH - Female MH - Guanine Nucleotides/metabolism MH - Heterozygote MH - Humans MH - Leukemia, Lymphocytic, Acute, L1/*drug therapy/genetics MH - Male MH - Methylation MH - Methyltransferases/*genetics/metabolism MH - Phenotype MH - Polymorphism, Genetic MH - Prodrugs/*administration & dosage/adverse effects/*pharmacokinetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Thionucleotides/metabolism EDAT- 1999/12/02 MHDA- 1999/12/02 00:01 PST - ppublish SO - J Natl Cancer Inst 1999 Dec 1;91(23):2001-8. DR -------------------------------------------------------------------------------- 72: Bo J et al. Possible carcinogenic effect ...[PMID: 10491537] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 10491537 OWN - NLM STAT- MEDLINE DA - 19991005 DCOM- 19991005 LR - 20041117 PUBM- Print IS - 0008-543X VI - 86 IP - 6 DP - 1999 Sep 15 TI - Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. PG - 1080-6 AB - BACKGROUND: 6-Mercaptopurine (6MP) has been regarded as nonleukemogenic, even though the cytotoxicity of 6MP depends on the incorporation of 6-thioguanine nucleotides (6TGN) into DNA. In hematopoietic cells this pathway competes with S-methylation catalyzed by thiopurine methyltransferase (TPMT). However, methylated 6MP metabolites inhibit purine de novo synthesis and thus may enhance incorporation of 6TGN into DNA. Approximately 10% of white individuals have low TPMT activity as a result of polymorphisms in the TPMT gene. The authors attempted to test the hypothesis that the degree of DNA damage during 6MP therapy might reflect variations in 6MP metabolism and pharmacokinetics. METHODS: The authors measured TPMT activity as well as erythrocyte levels of 6TGN (E-6TGN) and methylated 6MP metabolites (E-MeMP) during 6MP therapy in 439 children with acute lymphoblastic leukemia, 5 of whom later developed secondary myelodysplasia or acute myeloid leukemia (sMDS/AML). RESULTS: The patients who developed sMDS/AML had significantly lower TPMT activity compared with the remaining patients (P = 0.03). The 55 patients with TPMT activity <14 U/mL red blood cells (RBC) (antimode of the bimodal distribution) had a 5-year risk of sMDS/AML of 9 +/- 6% versus 1 +/- 1% for the remaining patients (P = 0.002). Cox regression analysis identified TPMT activity and E-MeMP level as the strongest predictors of risk for sMDS/AML (global P value = 0.02). Patients with low TPMT activity and high E-MeMP levels had the highest risk. All 5 patients with sMDS/AML had E-6TGN and/or E-MeMP levels > the 90% percentiles or had TPMT activity < 14 U/mL RBC. CONCLUSIONS: These data demonstrate an increased leukemogenic risk when 6MP is administered with other cytotoxic agents in patients with low TPMT activity, and indicate that not only high 6TGN levels but also high levels of methylated metabolites may lead to DNA damage. CI - Copyright 1999 American Cancer Society. AD - The Laboratory for Pediatric Oncology, The Pediatric Clinic II, The National University Hospital, Copenhagen, Denmark. FAU - Bo, J AU - Bo J FAU - Schroder, H AU - Schroder H FAU - Kristinsson, J AU - Kristinsson J FAU - Madsen, B AU - Madsen B FAU - Szumlanski, C AU - Szumlanski C FAU - Weinshilboum, R AU - Weinshilboum R FAU - Andersen, J B AU - Andersen JB FAU - Schmiegelow, K AU - Schmiegelow K LA - eng GR - RO1-GM28157/GM/NIGMS GR - RO1-GM35720/GM/NIGMS PT - Clinical Trial PT - Journal Article PL - UNITED STATES TA - Cancer JID - 0374236 RN - 0 (Antineoplastic Combined Chemotherapy Protocols) RN - 0 (Guanine Nucleotides) RN - 0 (Thionucleotides) RN - 15867-02-4 (6-thioguanylic acid) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM MH - 6-Mercaptopurine/administration & dosage/*adverse effects MH - Adolescent MH - Antineoplastic Combined Chemotherapy Protocols/*adverse effects MH - Bone Marrow Cells/*drug effects/metabolism MH - Child MH - Child, Preschool MH - Comparative Study MH - DNA Damage MH - Guanine Nucleotides/metabolism MH - Humans MH - Immunophenotyping MH - Infant MH - Leukemia, Lymphocytic, Acute/*drug therapy MH - Methyltransferases/genetics/metabolism MH - Myelodysplastic Syndromes/*chemically induced MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Risk MH - Thionucleotides/metabolism EDAT- 1999/09/24 MHDA- 1999/09/24 00:01 AID - 10.1002/(SICI)1097-0142(19990915)86:6<1080::AID-CNCR26>3.0.CO;2-5 [pii] PST - ppublish SO - Cancer 1999 Sep 15;86(6):1080-6. NR -------------------------------------------------------------------------------- 73: Naughton MA et al. Identification of thiopurine ...[PMID: 10461478] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 10461478 OWN - NLM STAT- MEDLINE DA - 19990908 DCOM- 19990908 LR - 20041117 PUBM- Print IS - 1462-0324 VI - 38 IP - 7 DP - 1999 Jul TI - Identification of thiopurine methyltransferase (TPMT) polymorphisms cannot predict myelosuppression in systemic lupus erythematosus patients taking azathioprine. PG - 640-4 AB - OBJECTIVE: To determine whether the presence of polymorphisms associated with reduced or absent activity of thiopurine methyltransferase (TPMT), an enzyme involved in azathioprine metabolism, can predict side-effects, particularly myelosuppression, in patients taking this drug. METHODS: The TPMT genotype was determined in 120 patients with systemic lupus erythematosus (SLE) together with 15 patients with inflammatory bowel disease (IBD) and correlated with the effects of clinical exposure to azathioprine. RESULTS: TPMT polymorphisms were detected in eight patients. Severe marrow toxicity occurred in the single homozygote identified. Azathioprine was generally well tolerated, but 11 drug-associated neutropenias were detected. In only one of the 11 cases was a TPMT polymorphism identified. CONCLUSION: Homozygous TPMT deficiency was associated with severe marrow suppression. In the majority of cases, however, TPMT genotyping prior to azathioprine therapy would not have predicted myelosuppressive events and may augment, but not replace, regular blood monitoring. AD - Imperial College of Science and Medicine, Rheumatology Section, London, UK. FAU - Naughton, M A AU - Naughton MA FAU - Battaglia, E AU - Battaglia E FAU - O'Brien, S AU - O'Brien S FAU - Walport, M J AU - Walport MJ FAU - Botto, M AU - Botto M LA - eng PT - Journal Article PL - ENGLAND TA - Rheumatology (Oxford) JID - 100883501 RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM MH - Azathioprine/*adverse effects MH - Genotype MH - Humans MH - Immunosuppressive Agents/*adverse effects MH - Inflammatory Bowel Diseases MH - Lupus Erythematosus, Systemic/*drug therapy/enzymology MH - Methyltransferases/*genetics/metabolism MH - Neutropenia/chemically induced MH - *Polymorphism, Genetic MH - Predictive Value of Tests EDAT- 1999/08/26 MHDA- 1999/08/26 00:01 PST - ppublish SO - Rheumatology (Oxford) 1999 Jul;38(7):640-4. DR -------------------------------------------------------------------------------- 74: Alves S et al. Thiopurine methyltransferase ...[PMID: 10376773] Related Articles, OMIM, Books, LinkOut PMID- 10376773 OWN - NLM STAT- MEDLINE DA - 19990716 DCOM- 19990716 LR - 20041117 PUBM- Print IS - 0960-314X VI - 9 IP - 2 DP - 1999 Apr TI - Thiopurine methyltransferase pharmacogenetics: alternative molecular diagnosis and preliminary data from Northern Portugal. PG - 257-61 AB - The thiopurine methyltransferase (TPMT) genetic polymorphism has been shown to have a highly significant clinical impact, namely in the therapeutic efficiency of thiopurine drugs used in the treatment of a wide range of diseases. Available diagnostic methods, although reproducible and sensitive, are relatively laborious. Thus population studies are still very scarce. In this work we describe a new polymerase chain reaction-single strand confirmational analysis based protocol for TPMT specific detection which introduces a substantial technical simplification avoiding the use of restriction enzyme treatment after polymerase chain reaction amplification. Additionally, the use of this protocol allows the simultaneous detection of a T474 to C substitution, a frequent silent mutation in the North Portuguese population (TPMT*1S = 0.215). In a sample of 310 unrelated Northern Portuguese individuals, 15 were found to be heterozygous for the TPMT*3A allele (defined by the presence of two transitions, G460 to A and A719 to G) which is associated with TPMT enzymatic deficiency; the corresponding gene frequency estimate was 0.024. We also attempted to evaluate the relationship between the molecular TPMT genotype and the reaction to treatments involving thiopurine drugs by analysing a sample of 24 children submitted to curative therapy of acute lymphoblastic leukaemia. Four of them were shown to be heterozygous for the TPMT*3A allele. An examination of their clinical histories showed that all four patients exhibited signs of severe hepatic toxicity during treatment. AD - IPATIMUP, Faculdade de Ciencias da Universidade do Porto, Portugal. FAU - Alves, S AU - Alves S FAU - Prata, M J AU - Prata MJ FAU - Ferreira, F AU - Ferreira F FAU - Amorim, A AU - Amorim A LA - eng PT - Journal Article PL - ENGLAND TA - Pharmacogenetics JID - 9211735 RN - 0 (Antineoplastic Agents) RN - 0 (DNA Primers) RN - 0 (Purines) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Antineoplastic Agents/adverse effects/metabolism/therapeutic use MH - Base Sequence MH - Child MH - DNA Primers MH - Heterozygote MH - Humans MH - Leukemia, Lymphocytic, Acute, L1/drug therapy/enzymology MH - Methyltransferases/*genetics MH - *Pharmacogenetics MH - Polymorphism, Restriction Fragment Length MH - Portugal MH - Purines/adverse effects/*metabolism/therapeutic use MH - Research Support, Non-U.S. Gov't EDAT- 1999/06/22 MHDA- 1999/06/22 00:01 PST - ppublish SO - Pharmacogenetics 1999 Apr;9(2):257-61. DR -------------------------------------------------------------------------------- 75: McLeod HL et al. Analysis of thiopurine methyl...[PMID: 10354134] Related Articles, Compound via MeSH, Substance via MeSH, Cited in Books, Books, LinkOut PMID- 10354134 OWN - NLM STAT- MEDLINE DA - 19990721 DCOM- 19990721 LR - 20041117 PUBM- Print IS - 0007-1048 VI - 105 IP - 3 DP - 1999 Jun TI - Analysis of thiopurine methyltransferase variant alleles in childhood acute lymphoblastic leukaemia. PG - 696-700 AB - The role of 6-mercaptopurine (6MP) in the treatment of childhood acute lymphoblastic leukaemia (ALL) is well established. However, the efficacy of 6MP is significantly influenced by inactivation by the polymorphic enzyme thiopurine methyltransferase (TPMT). In the general population 89-94% have high TPMT activity, 6-11% have intermediate activity, and approximately 0.3% have low activity. Individuals with low-activity experience severe or fatal toxicity with standard 6MP doses. Prospective identification of this group of patients might prevent this problem. Recent identification of the molecular basis for low TPMT activity enabled rapid assessment of altered 6MP metabolism by PCR methods. This study evaluated the frequency of mutant TPMT alleles in 147 children with ALL. One patient was homozygous mutant (0.7%), and 16 patients were heterozygous for variant TPMT alleles (10.9%). The majority of mutant alleles were TPMT*3A. Both the allele frequency and the pattern of TPMT mutations were similar to that observed in an adult British population. The number of weeks when 6MP therapy was administered at full dose was determined in patients on MRC UKALL X and XI. The 94 patients spent a median 11% of the maintenance period receiving no therapy as a result of haematological toxicity. There was no significant difference in the number of weeks when no therapy could be administered among patients with a wild-type or heterozygous genotype. However, the one patient with a homozygous mutant genotype had severe haematological toxicity and no therapy could be administered for 53% of the maintenance period. This study demonstrates that 11.6% of the children had variant TPMT alleles. Prospective identification of TPMT genotype may be a promising tool for decreasing excessive haematological toxicity in individuals with low activity. AD - Department of Medicine and Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen. h.l.mcleod@abdn.ac.uk FAU - McLeod, H L AU - McLeod HL FAU - Coulthard, S AU - Coulthard S FAU - Thomas, A E AU - Thomas AE FAU - Pritchard, S C AU - Pritchard SC FAU - King, D J AU - King DJ FAU - Richards, S M AU - Richards SM FAU - Eden, O B AU - Eden OB FAU - Hall, A G AU - Hall AG FAU - Gibson, B E AU - Gibson BE LA - eng PT - Journal Article PL - ENGLAND TA - Br J Haematol JID - 0372544 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/therapeutic use MH - Adult MH - Antimetabolites, Antineoplastic/therapeutic use MH - Child MH - Gene Frequency MH - Humans MH - Leukemia, Lymphocytic, Acute, L1/drug therapy/*enzymology/genetics MH - Methyltransferases/genetics/*metabolism MH - Mutation/genetics MH - Research Support, Non-U.S. Gov't EDAT- 1999/06/03 MHDA- 1999/06/03 00:01 AID - bjh1416 [pii] PST - ppublish SO - Br J Haematol 1999 Jun;105(3):696-700. DR -------------------------------------------------------------------------------- 76: Weinshilboum RM et al. Methylation pharmacogenetics:...[PMID: 10331075] Related Articles, Protein, Structure, 3D Domains, Cited in PMC, Books, LinkOut PMID- 10331075 OWN - NLM STAT- MEDLINE DA - 19990709 DCOM- 19990709 LR - 20041117 PUBM- Print IS - 0362-1642 VI - 39 DP - 1999 TI - Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. PG - 19-52 AB - Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity. AD - Department of Pharmacology, Mayo Medical School/Mayo Clinic/Mayo Foundation, Rochester, Minnesota 55905, USA. weinshilboum.richard@mayo.edu FAU - Weinshilboum, R M AU - Weinshilboum RM FAU - Otterness, D M AU - Otterness DM FAU - Szumlanski, C L AU - Szumlanski CL LA - eng GR - RO1 GM28157/GM/NIGMS GR - RO1 GM35720/GM/NIGMS PT - Journal Article PT - Review PL - UNITED STATES TA - Annu Rev Pharmacol Toxicol JID - 7607088 RN - 0 (Pharmaceutical Preparations) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.6 (Catechol O-Methyltransferase) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.1.1.8 (Histamine N-Methyltransferase) SB - IM MH - Animals MH - Catechol O-Methyltransferase/genetics/*metabolism MH - Histamine N-Methyltransferase/genetics/*metabolism MH - Humans MH - Methylation MH - Methyltransferases/genetics/*metabolism MH - Pharmaceutical Preparations/metabolism MH - Research Support, U.S. Gov't, P.H.S. RF - 157 EDAT- 1999/05/20 MHDA- 1999/05/20 00:01 AID - 10.1146/annurev.pharmtox.39.1.19 [doi] PST - ppublish SO - Annu Rev Pharmacol Toxicol 1999;39:19-52. PR -------------------------------------------------------------------------------- 77: Krynetski EY et al. Pharmacogenetics as a molecul...[PMID: 10213363] Related Articles, Compound via MeSH, Substance via MeSH, Cited in Books, Books, LinkOut PMID- 10213363 OWN - NLM STAT- MEDLINE DA - 19990625 DCOM- 19990625 LR - 20041117 PUBM- Print IS - 0724-8741 VI - 16 IP - 3 DP - 1999 Mar TI - Pharmacogenetics as a molecular basis for individualized drug therapy: the thiopurine S-methyltransferase paradigm. PG - 342-9 AB - Genetic polymorphism of drug metabolizing enzymes can be the major determinant of inter-individual differences in drug disposition and effects. In this mini-review, the evolution of pharmacogenetic studies, from the recognition of phenotypic polymorphisms to the discovery of genetic mutations responsible for these inherited traits, is illustrated by the genetic polymorphism of thiopurine S-methyltransferase (TPMT). TPMT, which exhibits autosomal co-dominant polymorphism, plays an important role in metabolism of the antileukemic and immunosuppressive medications, mercaptopurine, thioguanine, and azathioprine. The genetic polymorphism of TPMT activity in humans was first reported in 1980, and in the last five years the genetic basis for this polymorphism has been elucidated. Isolation and cloning of mutant alleles from humans with TPMT deficiency has identified the major mutant alleles, established the basis for loss of TPMT activity and permitted development of PCR-based genotyping assays to make a molecular diagnosis of TPMT-deficiency and heterozygosity. These studies illustrate the potential clinical benefits of elucidating the molecular basis of inherited differences in drug metabolism and disposition, and future automation of molecular diagnostics will make it feasible to more precisely select the optimal drug and dosage for individual patients. AD - St. Jude Children's Research Hospital, Memphis, Tennessee 38101, USA. FAU - Krynetski, E Y AU - Krynetski EY FAU - Evans, W E AU - Evans WE LA - eng GR - CA21765/CA/NCI GR - R01 CA78224/CA/NCI GR - R37 CA36401/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Pharm Res JID - 8406521 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*metabolism/toxicity MH - Amino Acid Sequence MH - Antimetabolites, Antineoplastic/metabolism/toxicity MH - Humans MH - Methyltransferases/deficiency/*genetics/metabolism MH - Molecular Sequence Data MH - Mutation MH - *Pharmacogenetics MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Sequence Homology, Amino Acid RF - 56 EDAT- 1999/04/23 MHDA- 1999/04/23 00:01 PST - ppublish SO - Pharm Res 1999 Mar;16(3):342-9. DR -------------------------------------------------------------------------------- 78: Collie-Duguid ES et al. The frequency and distributio...[PMID: 10208641] Related Articles, OMIM, Books, LinkOut PMID- 10208641 OWN - NLM STAT- MEDLINE DA - 19990528 DCOM- 19990528 LR - 20041117 PUBM- Print IS - 0960-314X VI - 9 IP - 1 DP - 1999 Feb TI - The frequency and distribution of thiopurine methyltransferase alleles in Caucasian and Asian populations. PG - 37-42 AB - Thiopurine methyltransferase metabolizes 6-mercaptopurine, thioguanine and azathioprine, thereby regulating cytotoxicity and clinical response to these thiopurine drugs. In healthy Caucasian populations, 89-94% of individuals have high thiopurine methyltransferase activity, 6-11% intermediate and 0.3% low, resulting from genetic polymorphism. Four variant thiopurine methyltransferase alleles were detected in over 80% of individuals with low or intermediate thiopurine methyltransferase activity. The wild-type allele is defined as TPMT*1 and the mutant alleles are TPMT*2 (G238C), TPMT*3A (G460A and A719G), TPMT*3B (G460A) and TPMT*3B (A719G). The frequency of these alleles in different ethnic groups is not well defined. In this study, DNA from 199 British Caucasian, 99 British South West Asian and 192 Chinese individuals was analysed for the presence of these variant alleles using polymerase chain reaction-restriction fragment length polymorphism and allele-specific polymerase chain reaction based assays. The frequency of individuals with a variant thiopurine methyltransferase genotype was: Caucasians 10.1% (20/199), South West Asians 2.0% (2/99) and Chinese 4.7% (9/192). Two TPMT*2 heterozygotes were identified in the Caucasian population, but this allele was not found in the two Asian populations. TPMT*3A was the only mutant allele found in the South West Asians (two heterozygotes). This was also the most common mutant allele in the Caucasians (16 heterozygotes and one homozygote) but was not found in the Chinese. All mutant alleles identified in the Chinese population were TPMT*3C (nine heterozygotes). This allele was found at a low frequency in the Caucasians (one heterozygote). This suggests that A719G is the oldest mutation, with G460A being acquired later to form the TPMT*3A allele in the Caucasian and South West Asian populations. TPMT*2 appears to be a more recent allele, which has only been detected in Caucasians to date. These ethnic differences may be important in the clinical use of thiopurine drugs. AD - The University of Aberdeen, Department of Medicine and Therapeutics, Institute of Medical Sciences, Foresterhill, UK. e-collie-duguid@abdn.ac.uk FAU - Collie-Duguid, E S AU - Collie-Duguid ES FAU - Pritchard, S C AU - Pritchard SC FAU - Powrie, R H AU - Powrie RH FAU - Sludden, J AU - Sludden J FAU - Collier, D A AU - Collier DA FAU - Li, T AU - Li T FAU - McLeod, H L AU - McLeod HL LA - eng PT - Journal Article PL - ENGLAND TA - Pharmacogenetics JID - 9211735 RN - 0 (DNA Primers) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - *Alleles MH - Asian Continental Ancestry Group/*genetics MH - Base Sequence MH - DNA Primers MH - European Continental Ancestry Group/*genetics MH - *Gene Frequency MH - Humans MH - Methyltransferases/*genetics MH - Polymerase Chain Reaction MH - Research Support, Non-U.S. Gov't EDAT- 1999/04/20 MHDA- 1999/04/20 00:01 PST - ppublish SO - Pharmacogenetics 1999 Feb;9(1):37-42. PR -------------------------------------------------------------------------------- 79: Iyer L et al. Pharmacogenetics and cancer c...[PMID: 9893619] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Cited in Books, Books, LinkOut PMID- 9893619 OWN - NLM STAT- MEDLINE DA - 19990125 DCOM- 19990125 LR - 20041117 PUBM- Print IS - 0959-8049 VI - 34 IP - 10 DP - 1998 Sep TI - Pharmacogenetics and cancer chemotherapy. PG - 1493-9 AB - Cancer chemotherapy is limited by significant inter-individual variations in responses and toxicities. Such variations are often due to genetic alterations in drug metabolising enzymes (pharmacokinetic polymorphisms) or receptor expression (pharmacodynamic polymorphisms). Pharmacogenetic screening prior to anticancer drug administration may lead to identification of specific populations predisposed to drug toxicity or poor drug responses. The role of polymorphisms in specific enzymes, such as thiopurine S-methyltransferases (TPMT), dihydropyrimidine dehydrogenase (DPD), aldehyde dehydrogenases (ALDH), glutathione S-transferases (GST), uridine diphosphate glucuronosyl-transferases (UGTs) and cytochrome P450 (CYP 450) enzymes in cancer therapy are discussed in this review. AD - Committee on Clinical Pharmacology, University of Chicago, Illinois 60637, USA. FAU - Iyer, L AU - Iyer L FAU - Ratain, M J AU - Ratain MJ LA - eng GR - T32-GM07019/GM/NIGMS PT - Journal Article PT - Review PT - Review, Tutorial PL - ENGLAND TA - Eur J Cancer JID - 9005373 RN - 0 (Antineoplastic Agents) RN - 0 (Enzymes) RN - 58-98-0 (Uridine Diphosphate) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1. (Oxidoreductases) RN - EC 1.2.1.3 (Aldehyde Dehydrogenase) RN - EC 1.3.1.2 (Dihydrouracil Dehydrogenase (NADP)) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1. (Acetyltransferases) RN - EC 2.5.1.18 (Glutathione Transferase) SB - IM MH - Acetyltransferases/metabolism MH - Aldehyde Dehydrogenase/metabolism MH - Antineoplastic Agents/metabolism/*therapeutic use MH - Cytochrome P-450 Enzyme System/metabolism MH - Dihydrouracil Dehydrogenase (NADP) MH - Enzymes/genetics/*metabolism MH - Glutathione Transferase/metabolism MH - Humans MH - Methyltransferases/metabolism MH - Neoplasms/*drug therapy/*enzymology/genetics MH - Oxidoreductases/metabolism MH - Research Support, U.S. Gov't, P.H.S. MH - Uridine Diphosphate/analogs & derivatives/metabolism RF - 156 EDAT- 1999/01/20 MHDA- 1999/01/20 00:01 AID - S0959804998002305 [pii] PST - ppublish SO - Eur J Cancer 1998 Sep;34(10):1493-9. DR -------------------------------------------------------------------------------- 80: Coulthard SA et al. The relationship between thio...[PMID: 9763570] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9763570 OWN - NLM STAT- MEDLINE DA - 19981109 DCOM- 19981109 LR - 20041117 PUBM- Print IS - 0006-4971 VI - 92 IP - 8 DP - 1998 Oct 15 TI - The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia. PG - 2856-62 AB - The level of expression of the enzyme thiopurine methyltransferase (TPMT) is an important determinant of the metabolism of thiopurines used in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Studies in red blood cells (RBC) have shown that TPMT expression displays genetic polymorphism with 11% of individuals having intermediate and one in 300 undetectable levels. The genetic basis for this polymorphism has now been elucidated and polymerase chain reaction (PCR)-based assays described for the most common mutations accounting for reduced activity. In previous studies, genotype has been correlated with red blood cell activity. In this report, we describe the relationship between genotype and TPMT activity measured directly in the target of drug action, the leukemic cell. We have demonstrated that the TPMT activity in lymphoblasts from 38 children and adults found by PCR to be homozygotes (*1/*1) was significantly higher than that in the five heterozygotes (*1/*3) detected (median, 0.25 v 0.08, P < .002, Mann-Whitney U). Similar results were obtained when results from children were analyzed separately. However, comparison of activity in blasts from AML and ALL showed a higher level in the former (0.35 v 0.22 nU/mg, P < .002, n = 17, 35), suggesting that factors other than genotype may also influence expression. CI - Copyright 1998 by The American Society of Hematology. AD - LRF Molecular Pharmacology Specialist Programme, Cancer Research Unit, Medical School, University of Newcastle, Newcastle, UK. FAU - Coulthard, S A AU - Coulthard SA FAU - Howell, C AU - Howell C FAU - Robson, J AU - Robson J FAU - Hall, A G AU - Hall AG LA - eng PT - Journal Article PL - UNITED STATES TA - Blood JID - 7603509 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Neoplasm Proteins) RN - 0 (Prodrugs) RN - 50-44-2 (6-Mercaptopurine) RN - EC 1.1.3.22 (Xanthine Oxidase) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.4.2.8 (Hypoxanthine Phosphoribosyltransferase) SB - AIM SB - IM MH - 6-Mercaptopurine/*pharmacokinetics MH - Acute Disease MH - Adolescent MH - Adult MH - Aged MH - Antimetabolites, Antineoplastic/*pharmacokinetics MH - Child MH - Child, Preschool MH - Comparative Study MH - Drug Resistance, Neoplasm/*genetics MH - Enzyme Induction MH - Female MH - Genotype MH - Humans MH - Hypoxanthine Phosphoribosyltransferase/metabolism MH - Infant MH - Leukemia/drug therapy/*enzymology/genetics MH - Male MH - Methyltransferases/*metabolism MH - Middle Aged MH - Neoplasm Proteins/*metabolism MH - Polymorphism, Genetic MH - Prodrugs/pharmacokinetics MH - Research Support, Non-U.S. Gov't MH - Xanthine Oxidase/metabolism EDAT- 1998/10/09 MHDA- 1998/10/09 00:01 PST - ppublish SO - Blood 1998 Oct 15;92(8):2856-62. PR -------------------------------------------------------------------------------- 81: Krynetski EY et al. Pharmacogenetics of cancer th...[PMID: 9634537] Related Articles, Books, LinkOut PMID- 9634537 OWN - NLM STAT- MEDLINE DA - 19980813 DCOM- 19980813 LR - 20041117 PUBM- Print IS - 0002-9297 VI - 63 IP - 1 DP - 1998 Jul TI - Pharmacogenetics of cancer therapy: getting personal. PG - 11-6 AD - St. Jude Children's Research Hospital, Memphis, TN 38105, USA. FAU - Krynetski, E Y AU - Krynetski EY FAU - Evans, W E AU - Evans WE LA - eng GR - CA20180/CA/NCI GR - CA21765/CA/NCI GR - R37 CA36401/CA/NCI PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Am J Hum Genet JID - 0370475 RN - 0 (Antineoplastic Agents) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Antineoplastic Agents/metabolism/toxicity MH - Erythrocytes/enzymology MH - Humans MH - Methyltransferases/genetics/metabolism MH - Neoplasms/*drug therapy MH - *Pharmacogenetics MH - Polymorphism, Genetic/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. RF - 37 EDAT- 1998/06/23 02:01 MHDA- 2000/03/21 09:00 AID - AJHG980379 [pii] PST - ppublish SO - Am J Hum Genet 1998 Jul;63(1):11-6. PR -------------------------------------------------------------------------------- 82: De Abreu RA et al. Thiopurine treatment in child...[PMID: 9598153] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9598153 OWN - NLM STAT- MEDLINE DA - 19980723 DCOM- 19980723 LR - 20041117 PUBM- Print IS - 0065-2598 VI - 431 DP - 1998 TI - Thiopurine treatment in childhood leukemia. Metabolic aspects and sensitivity. PG - 687-92 AD - Department of Pediatrics, University Hospital Nijmegen, The Netherlands. FAU - De Abreu, R A AU - De Abreu RA FAU - Bokkerink, J P AU - Bokkerink JP FAU - Keuzenkamp-Jansen, C W AU - Keuzenkamp-Jansen CW FAU - Stet, E H AU - Stet EH FAU - Trijbels, J F AU - Trijbels JF LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - Adv Exp Med Biol JID - 0121103 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Antineoplastic Combined Chemotherapy Protocols) RN - 154-42-7 (Thioguanine) RN - 50-44-2 (6-Mercaptopurine) RN - 59-05-2 (Methotrexate) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/administration & dosage/pharmacokinetics/*therapeutic use MH - Antimetabolites, Antineoplastic/pharmacokinetics/*therapeutic use MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Child MH - Chromosomes, Human, Pair 6 MH - Humans MH - Leukemia/*drug therapy/metabolism MH - Methotrexate/administration & dosage MH - Methyltransferases/deficiency/genetics/*metabolism MH - Polymorphism, Genetic MH - Thioguanine/pharmacokinetics/*therapeutic use RF - 38 EDAT- 1998/05/23 MHDA- 1998/05/23 00:01 PST - ppublish SO - Adv Exp Med Biol 1998;431:687-92. PR -------------------------------------------------------------------------------- 83: Yamamoto I et al. [Individualization of drug th...[PMID: 9549339] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 9549339 OWN - NLM STAT- MEDLINE DA - 19980622 DCOM- 19980622 LR - 20041117 PUBM- Print IS - 0047-1852 VI - 56 IP - 3 DP - 1998 Mar TI - [Individualization of drug therapy and pharmacogenetics] PG - 579-83 AB - This brief review discusses the relationship between genetic polymorphism of drug metabolizing enzyme and drug's safety and efficacy. When elimination occurs via a single metabolic pathway, individual differences in metabolic rates can lead to large differences in drug and metabolite concentrations in the blood. Genetic polymorphism leads to subpopulation of patients with decreased, absent or even increased activities of certain reactions (e.g., CYP2C19, CYP2D6, CYP2C9, N-acetyltransferase, thiopurine methyltransferase polymorphism). The consequences of a genetic polymorphism include not only altered kinetics of specific drug substrate but idiosyncratic adverse drug reactions. Having these information will aid in determining dosage of certain medications to the patients with an inherited abnormality of drug metabolizing enzyme. Pharmacogenetics already has influenced therapeutics. AD - Department of Clinical Evaluation of Medicines and Therapeutics, Faculty of Pharmaceutical Sciences, Osaka University. FAU - Yamamoto, I AU - Yamamoto I FAU - Azuma, J AU - Azuma J LA - jpn PT - Journal Article PT - Review PT - Review, Tutorial PL - JAPAN TA - Nippon Rinsho JID - 0420546 RN - 0 (Anticoagulants) RN - 0 (Immunosuppressive Agents) RN - 446-86-6 (Azathioprine) RN - 73590-58-6 (Omeprazole) RN - 81-81-2 (Warfarin) RN - 9035-51-2 (Cytochrome P-450 Enzyme System) RN - EC 1.- (Mixed Function Oxygenases) RN - EC 1.14.- (Steroid Hydroxylases) RN - EC 1.14.14.1 (Aryl Hydrocarbon Hydroxylases) RN - EC 1.14.14.1 (Cytochrome P-450 CYP2D6) RN - EC 1.14.14.1 (Steroid 16-alpha-Hydroxylase) RN - EC 1.14.14.1 (testosterone 16-alpha-hydroxylase, mouse) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) RN - EC 2.3.1.5 (Arylamine N-Acetyltransferase) RN - NM_000769 (CYP2C19 protein, human) SB - IM MH - Anticoagulants/pharmacokinetics MH - *Aryl Hydrocarbon Hydroxylases MH - Arylamine N-Acetyltransferase/*genetics MH - Azathioprine/adverse effects/pharmacokinetics MH - Cytochrome P-450 CYP2D6/genetics/physiology MH - Cytochrome P-450 Enzyme System/antagonists & inhibitors/*genetics/physiology MH - English Abstract MH - Humans MH - Immunosuppressive Agents/adverse effects/pharmacokinetics MH - Methyltransferases/*genetics MH - Mixed Function Oxygenases/antagonists & inhibitors/*genetics/physiology MH - Mutation MH - Omeprazole/pharmacology MH - *Polymorphism, Genetic MH - *Steroid 16-alpha-Hydroxylase MH - Steroid Hydroxylases/genetics/physiology MH - Variation (Genetics) MH - Warfarin/pharmacokinetics RF - 19 EDAT- 1998/04/29 MHDA- 1998/04/29 00:01 PST - ppublish SO - Nippon Rinsho 1998 Mar;56(3):579-83. PR -------------------------------------------------------------------------------- 84: Aarbakke J et al. Thiopurine biology and pharma...[PMID: 9114722] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 9114722 OWN - NLM STAT- MEDLINE DA - 19970519 DCOM- 19970519 LR - 20041117 PUBM- Print IS - 0165-6147 VI - 18 IP - 1 DP - 1997 Jan TI - Thiopurine biology and pharmacology. PG - 3-7 AD - Department of Pharmacology, Institute of Medical Biology, University of Tromso, Norway. FAU - Aarbakke, J AU - Aarbakke J FAU - Janka-Schaub, G AU - Janka-Schaub G FAU - Elion, G B AU - Elion GB LA - eng PT - Congresses PL - ENGLAND TA - Trends Pharmacol Sci JID - 7906158 RN - 0 (Antimetabolites, Antineoplastic) RN - 0 (Immunosuppressive Agents) RN - 0 (Purines) RN - 154-42-7 (Thioguanine) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/metabolism/pharmacology/therapeutic use MH - Animals MH - Antimetabolites, Antineoplastic/metabolism/pharmacology/therapeutic use MH - Azathioprine/chemistry/metabolism/pharmacology MH - Cloning, Molecular MH - Genotype MH - Humans MH - Immunosuppressive Agents/chemistry/metabolism/pharmacology MH - Leukemia, Lymphocytic, Acute/drug therapy/genetics/metabolism MH - Methyltransferases/deficiency/*genetics/metabolism MH - Mice MH - Polymorphism, Genetic/genetics MH - Purines/chemistry/*metabolism MH - Structure-Activity Relationship MH - Thioguanine/metabolism/pharmacology/therapeutic use EDAT- 1997/01/01 MHDA- 1997/01/01 00:01 AID - S0165614796010073 [pii] PST - ppublish SO - Trends Pharmacol Sci 1997 Jan;18(1):3-7. PR -------------------------------------------------------------------------------- 85: Lennard L et al. Individualizing therapy with ...[PMID: 8857546] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8857546 OWN - NLM STAT- MEDLINE DA - 19970108 DCOM- 19970108 LR - 20041117 PUBM- Print IS - 0163-4356 VI - 18 IP - 4 DP - 1996 Aug TI - Individualizing therapy with 6-mercaptopurine and 6-thioguanine related to the thiopurine methyltransferase genetic polymorphism. PG - 328-34 AB - The formation of intracellular thionucleotides are a prerequisite for mercaptopurine (MP) cytotoxicity, and interindividual variations in the inherited level of thiopurine methyltransferase (TPMT) activity regulate their formation. Measurement of pretreatment TPMT activities can identify the TPMT "deficient" patient and, conversely, the individual with very high enzyme activities. The former are at higher risk of acute toxicity and potentially fatal bone marrow failure and the latter of suboptimal treatment. Leukaemic children taking MP therapy who form inadequate amounts of thioguanine nucleotides (TGNs) do not experience drug toxicity and are at an increased risk of disease relapse. When low TGNs are due to very high TPMT activities, thioguanine may be a more appropriate thiopurine. Another cause of inadequate TGN concentrations is partial or noncompliance with oral chemotherapy. Compliance problems can be identified by the measurement of both TGNs and methylated drug metabolites. AD - Department of Medicine and Pharmacology, Royal Hallamshire Hospital, Sheffield, U.K. FAU - Lennard, L AU - Lennard L FAU - Lilleyman, J S AU - Lilleyman JS LA - eng PT - Journal Article PL - UNITED STATES TA - Ther Drug Monit JID - 7909660 RN - 0 (Antimetabolites, Antineoplastic) RN - 154-42-7 (Thioguanine) RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/*metabolism/pharmacology MH - Antimetabolites, Antineoplastic/*metabolism/pharmacology MH - Azathioprine/*metabolism MH - Humans MH - Leukemia/*drug therapy/metabolism MH - Methyltransferases/*genetics MH - Patient Compliance MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Thioguanine/*metabolism/pharmacology EDAT- 1996/08/01 MHDA- 1996/08/01 00:01 PST - ppublish SO - Ther Drug Monit 1996 Aug;18(4):328-34. NR -------------------------------------------------------------------------------- 86: Keuzenkamp-Jansen CW et al. Thiopurine methyltransferase:...[PMID: 8861653] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 8861653 OWN - NLM STAT- MEDLINE DA - 19970528 DCOM- 19970528 LR - 20041117 PUBM- Print IS - 0378-4347 VI - 678 IP - 1 DP - 1996 Mar 29 TI - Thiopurine methyltransferase: a review and a clinical pilot study. PG - 15-22 AB - Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of 6-mercaptopurine (6MP), which is used in the treatment of acute lymphoblastic leukemia (ALL). TPMT catalyzes the formation of methylthioinosine monophosphate (MetIMP), which is cytotoxic for cultured cell lines, and it plays a role in detoxification of 6MP. Population studies show a genetic polymorphism for TPMT with both high and low activity alleles. About 1 of 300 subjects is homozygous for the low activity. The function TPMT plays in detoxification or therapeutic efficacy of 6MP in vivo is not clear. In this article the genetic polymorphism of TPMT is reviewed and the contribution of TPMT to the cytotoxic action, or detoxification, of 6MP in children with ALL is discussed. Induction of TPMT activity has been described during the treatment for ALL. We performed a pilot study on the influence of high-dose 6MP infusions (1300 mg/m2 in 24 h) on TPMT activity of peripheral blood mononuclear cells (pMNC) of eleven patients with ALL. The TPMT activities were in, or, above the normal range. There was no statistically significant difference between the TPMT activities before and after the 6MP infusions. MetIMP levels in pMNC increased during successive courses. This might be explained by TPMT induction, but other explanations are plausible as well. Twenty five percent of the TPMT assays failed, because less than the necessary 5.10(6) pMNC could be isolated from the blood of leukopenic patients. Red blood cells can not be used for TPMT measurements, since transfusions are frequently required during the treatment with 6MP infusions. Therefore, the influence of high-dose 6MP infusions on TPMT activity can only be investigated further when a TPMT assay which requires less pMNC has been developed. AD - Center for Pediatric Oncology SE Netherlands, St Radboud University Hospital, Nijmegen, Netherlands. FAU - Keuzenkamp-Jansen, C W AU - Keuzenkamp-Jansen CW FAU - Leegwater, P A AU - Leegwater PA FAU - De Abreu, R A AU - De Abreu RA FAU - Lambooy, M A AU - Lambooy MA FAU - Bokkerink, J P AU - Bokkerink JP FAU - Trijbels, J M AU - Trijbels JM LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - NETHERLANDS TA - J Chromatogr B Biomed Appl JID - 9421796 RN - 0 (Antimetabolites, Antineoplastic) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/metabolism/pharmacokinetics/therapeutic use MH - Antimetabolites, Antineoplastic/metabolism/pharmacokinetics/therapeutic use MH - Humans MH - Leukemia, Lymphocytic, Acute, L1/drug therapy/metabolism MH - Metabolic Detoxication, Drug MH - Methyltransferases/genetics/*metabolism MH - Pilot Projects MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't RF - 53 EDAT- 1996/03/29 MHDA- 1996/03/29 00:01 AID - 0378434795004327 [pii] PST - ppublish SO - J Chromatogr B Biomed Appl 1996 Mar 29;678(1):15-22. NR -------------------------------------------------------------------------------- 87: McLeod HL et al. Polymorphic thiopurine methyl...[PMID: 7703493] Related Articles, Compound via MeSH, Substance via MeSH, Cited in PMC, Books, LinkOut PMID- 7703493 OWN - NLM STAT- MEDLINE DA - 19950509 DCOM- 19950509 LR - 20041117 PUBM- Print IS - 0006-4971 VI - 85 IP - 7 DP - 1995 Apr 1 TI - Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. PG - 1897-902 AB - The activity of thiopurine methyltransferase (TPMT) exhibits genetic polymorphism, with approximately 1 in 300 individuals inheriting TPMT deficiency as an autosomal recessive trait, and about 11% having intermediate activity (ie, heterozygotes). Patients with TPMT deficiency accumulate excessive concentrations of 6-thioguanine nucleotides (TGNs) and develop severe toxicity when treated with standard dosages of mercaptopurine. High TPMT activity has been associated with lower concentrations of TGNs, yielding a higher risk of treatment failure in children with acute lymphoblastic leukemia (ALL). As the biochemical basis of these pharmacodynamic relationships has not been fully elucidated, we investigated the variability and relationship of TPMT activity in erythrocytes and lymphoblasts from children with ALL. A 58-fold range of erythrocyte TPMT activity was found among 119 patients receiving ALL chemotherapy (0.6 to 34.9 U/mL packed erythrocytes), but relatively low intrapatient variability (coefficient of variation, 13.5%) was observed over 1 year. A 27-fold range in TPMT activity was observed in leukemic blasts obtained from 42 patients at initial diagnosis (3.3 to 88.9 U/1 x 10(9) cells). TPMT activity in leukemic blasts at diagnosis was significantly correlated with TPMT in erythrocytes before therapy (rs = .75, P < .0001, N = 13). These data document extensive interpatient variability of TPMT activity in ALL blasts and establish its linkage to polymorphic TPMT activity in erythrocytes, providing a new mechanism by which erythrocytes serve as prognostic markers of mercaptopurine metabolism and TPMT activity in children with ALL. AD - Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. FAU - McLeod, H L AU - McLeod HL FAU - Relling, M V AU - Relling MV FAU - Liu, Q AU - Liu Q FAU - Pui, C H AU - Pui CH FAU - Evans, W E AU - Evans WE LA - eng GR - CA 20180/CA/NCI GR - CA 21765/CA/NCI GR - R37 CA 36401/CA/NCI PT - Journal Article PL - UNITED STATES TA - Blood JID - 7603509 RN - 0 (Antineoplastic Combined Chemotherapy Protocols) RN - 0 (Neoplasm Proteins) RN - 0 (TOTAL-XII protocol) RN - 0 (Tumor Markers, Biological) RN - 147-94-4 (Cytarabine) RN - 29767-20-2 (Teniposide) RN - 50-44-2 (6-Mercaptopurine) RN - 59-05-2 (Methotrexate) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM MH - 6-Mercaptopurine/administration & dosage/adverse effects/pharmacokinetics MH - Adolescent MH - Aneuploidy MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Bone Marrow/*enzymology/pathology MH - Child MH - Child, Preschool MH - Cytarabine/administration & dosage MH - Erythrocytes/*enzymology MH - Female MH - Humans MH - Leukemia, Lymphocytic, Acute/drug therapy/*enzymology/pathology MH - Lymphocytes/*enzymology MH - Male MH - Methotrexate/administration & dosage MH - Methyltransferases/*analysis MH - Neoplasm Proteins/*analysis MH - Polymorphism, Genetic MH - Prognosis MH - Remission Induction MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Teniposide/administration & dosage MH - Treatment Failure MH - Tumor Markers, Biological/*analysis MH - Tumor Stem Cells/*enzymology EDAT- 1995/04/01 MHDA- 1995/04/01 00:01 PST - ppublish SO - Blood 1995 Apr 1;85(7):1897-902. NR -------------------------------------------------------------------------------- 88: Lee D et al. Thiopurine methyltransferase ...[PMID: 7628307] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, GEO Profiles, Books, LinkOut PMID- 7628307 OWN - NLM STAT- MEDLINE DA - 19950907 DCOM- 19950907 LR - 20041117 PUBM- Print IS - 0090-9556 VI - 23 IP - 3 DP - 1995 Mar TI - Thiopurine methyltransferase pharmacogenetics. Cloning of human liver cDNA and a processed pseudogene on human chromosome 18q21.1. PG - 398-405 AB - Thiopurine methyltransferase (TPMT) is a genetically polymorphic enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. This genetic polymorphism is an important factor responsible for individual variation in thiopurine drug response. A cDNA for TPMT has been cloned from T84 human colon carcinoma cells. Northern blot analysis of multiple human tissues was performed with the T84 human colon carcinoma TPMT cDNA open reading frame (ORF) as a probe as one step toward understanding the molecular basis for the TPMT genetic polymorphism. Three mRNA species (approximately 1.4, 2.0, and 3.6 kb in length) were present in all tissues studied, including liver. However, none of these mRNAs matched the length of the 2.7 kb T84 TPMT cDNA. Therefore, it was important to clone a TPMT cDNA from a human drug-metabolizing organ such as the liver to determine whether its sequence matched that of the cDNA cloned from the T84 cell line. A human liver cDNA library was screened with the T84 TPMT cDNA ORF as a probe, and a 1.8 kb cDNA was isolated with a coding region sequence identical to that of the T84 TPMT cDNA. The TPMT cDNA ORF was then used to screen a human lymphocytes genomic DNA library in an attempt to clone the TPMT gene(s) in humans. Three intronless clones were isolated with identical ORF sequences that were 96% identical to that of the TPMT cDNA, but which contained multiple nucleotide substitutions and one deletion. The 3'- and 5'-flanking regions of one of the genomic DNA clones were sequenced.(ABSTRACT TRUNCATED AT 250 WORDS) AD - Department of Pharmacology, Mayo Medical School, Rochester, MN 55905-0001, USA. FAU - Lee, D AU - Lee D FAU - Szumlanski, C AU - Szumlanski C FAU - Houtman, J AU - Houtman J FAU - Honchel, R AU - Honchel R FAU - Rojas, K AU - Rojas K FAU - Overhauser, J AU - Overhauser J FAU - Wieben, E D AU - Wieben ED FAU - Weinshilboum, R M AU - Weinshilboum RM LA - eng SI - GENBANK/U11424 SI - GENBANK/U12387 GR - GM 28157/GM/NIGMS GR - GM 35720/GM/NIGMS PT - Journal Article PL - UNITED STATES TA - Drug Metab Dispos JID - 9421550 RN - 0 (DNA, Complementary) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - Base Sequence MH - Blotting, Northern MH - Chromosome Mapping MH - *Chromosomes, Human, Pair 18 MH - Cloning, Molecular MH - DNA, Complementary/*genetics MH - Humans MH - Liver/*metabolism MH - Methyltransferases/*genetics MH - Molecular Sequence Data MH - *Polymorphism, Genetic MH - *Pseudogenes MH - Research Support, U.S. Gov't, P.H.S. MH - Tumor Cells, Cultured EDAT- 1995/03/01 MHDA- 1995/03/01 00:01 PST - ppublish SO - Drug Metab Dispos 1995 Mar;23(3):398-405. NR -------------------------------------------------------------------------------- 89: Krynetski EY et al. A single point mutation leadi...[PMID: 7862671] Related Articles, Gene, Compound via MeSH, Substance via MeSH, UniGene, Nucleotide, Protein, OMIM, GEO Profiles, Free in PMC, Cited in PMC, Books, LinkOut PMID- 7862671 OWN - NLM STAT- MEDLINE DA - 19950320 DCOM- 19950320 LR - 20041117 PUBM- Print IS - 0027-8424 VI - 92 IP - 4 DP - 1995 Feb 14 TI - A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. PG - 949-53 AB - Thiopurine S-methyltransferase (TPMT; S-adenosyl-L-methionine:thiopurine S-methyltransferase, EC 2.1.1.67) activity exhibits genetic polymorphism, with approximately 0.33% of Caucasians and African-Americans inheriting TPMT deficiency as an autosomal recessive trait. To determine the molecular genetic basis for this polymorphism, we cloned the TPMT cDNA from a TPMT-deficient patient who had developed severe hematopoietic toxicity during mercaptopurine therapy. Northern blot analysis of RNA isolated from leukocytes of the deficient patient demonstrated the presence of TPMT mRNAs of comparable size to that in subjects with high TPMT activity. Sequencing of the mutant TPMT cDNA revealed a single point mutation (G238-->C), leading to an amino acid substitution at codon 80 (Ala80-->Pro). When assessed in a yeast heterologous expression system, this mutation led to a 100-fold reduction in TPMT catalytic activity relative to the wild-type cDNA, despite a comparable level of mRNA expression. A mutation-specific PCR amplification method was developed and used to detect the G238-->C mutation in genomic DNA of the propositus and her mother. This inactivating mutation in the human TPMT gene provides insights into the genetic basis for this inherited polymorphism in drug metabolism. AD - Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, TN 38105. FAU - Krynetski, E Y AU - Krynetski EY FAU - Schuetz, J D AU - Schuetz JD FAU - Galpin, A J AU - Galpin AJ FAU - Pui, C H AU - Pui CH FAU - Relling, M V AU - Relling MV FAU - Evans, W E AU - Evans WE LA - eng SI - GENBANK/J01353 SI - GENBANK/M11167 GR - CA20180/CA/NCI GR - CA21765/CA/NCI GR - R37 CA36401/CA/NCI PT - Journal Article PL - UNITED STATES TA - Proc Natl Acad Sci U S A JID - 7505876 RN - 0 (DNA, Complementary) RN - 0 (RNA, Messenger) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM GS - TPMT MH - Alleles MH - Base Sequence MH - Catalysis MH - Child MH - Cloning, Molecular MH - DNA, Complementary MH - Female MH - Genotype MH - Humans MH - Methyltransferases/genetics/*metabolism MH - Molecular Sequence Data MH - *Point Mutation MH - Polymorphism, Restriction Fragment Length MH - RNA, Messenger/genetics MH - Research Support, Non-U.S. Gov't MH - Research Support, U.S. Gov't, P.H.S. MH - Saccharomyces cerevisiae/genetics MH - Transcription, Genetic EDAT- 1995/02/14 MHDA- 1995/02/14 00:01 PST - ppublish SO - Proc Natl Acad Sci U S A 1995 Feb 14;92(4):949-53. DR -------------------------------------------------------------------------------- 90: Snow JL et al. The role of genetic variation...[PMID: 7857117] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7857117 OWN - NLM STAT- MEDLINE DA - 19950310 DCOM- 19950310 LR - 20041117 PUBM- Print IS - 0003-987X VI - 131 IP - 2 DP - 1995 Feb TI - The role of genetic variation in thiopurine methyltransferase activity and the efficacy and/or side effects of azathioprine therapy in dermatologic patients. PG - 193-7 AB - BACKGROUND: Thiopurine methyltransferase (TPMT) is one of three major enzymes involved in the metabolism of azathioprine and its active metabolite 6-mercaptopurine. Thiopurine methyltransferase activity is determined by an allelic polymorphism for either high (TPMTH) or low (TPMTL) enzyme activity. Homozygotes for the low activity allele are known to be at risk for profound myelosuppression with azathioprine. Heterozygotes may be at risk for myelosuppression. Homozygotes for the high activity allele may be inadequately immunosuppressed with conventional, empiric doses of azathioprine. We analyzed TPMT activity in red blood cell (RBC) lysates and determined the TPMT genotypes (based on normal population screening) of 28 dermatologic patients. This information was correlated with the observed efficacy and side effects of azathioprine therapy. OBSERVATIONS: Two patients with TPMT levels of less than 12.5 U/mL RBCs (both TPMTH heterozygotes) experienced leukopenia (white blood count < 4.0 x 10(9)/L) with azathioprine doses around 1.5 mg/kg. A third patient who experienced leukopenia had a TPMT level at the lower end of the homozygous range (15.5 U/mL RBCs) but received the highest dose of azathioprine (2.6 mg/kg) of all patients in this series. Ten patients with TPMT levels of more than 18.5 U/mL RBCs (all TPMTH homozygotes) receiving less than 1.5 mg/kg of azathioprine were judged to have a poor clinical response. In comparison, seven patients with TPMT levels between 12.5 and 18.5 U/mL RBCs (six TPMTH homozygotes and one TPMTH heterozygote) receiving 0.9 to 1.8 mg/kg of azathioprine had a favorable clinical response. Adverse effects of gastrointestinal upset and liver function test abnormalities did not appear to correlate with TPMT activity. CONCLUSION: The TPMTH heterozygotes may be at increased risk for myelosuppression with standard, empiric doses of azathioprine. On the other hand, homozygotes for TPMTH, particularly those with TPMT levels at the upper end of the homozygous range, may have a poor clinical response to azathioprine due to inadequate empiric dosing. AD - Department of Dermatology, Mayo Clinic, Rochester, Minn. FAU - Snow, J L AU - Snow JL FAU - Gibson, L E AU - Gibson LE LA - eng PT - Journal Article PL - UNITED STATES TA - Arch Dermatol JID - 0372433 RN - 446-86-6 (Azathioprine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - AIM SB - IM CIN - Arch Dermatol. 1995 Sep;131(9):1087-8. PMID: 7661617 MH - Adult MH - Aged MH - Azathioprine/*therapeutic use MH - Female MH - Genotype MH - Humans MH - Male MH - Methyltransferases/*genetics/*metabolism MH - Middle Aged MH - Skin Diseases/*drug therapy/*enzymology MH - *Variation (Genetics) EDAT- 1995/02/01 MHDA- 1995/02/01 00:01 PST - ppublish SO - Arch Dermatol 1995 Feb;131(2):193-7. DR -------------------------------------------------------------------------------- 91: Snow JL et al. A pharmacogenetic basis for t...[PMID: 7822499] Related Articles, Compound via MeSH, Substance via MeSH, Books, LinkOut PMID- 7822499 OWN - NLM STAT- MEDLINE DA - 19950216 DCOM- 19950216 LR - 20041117 PUBM- Print IS - 0190-9622 VI - 32 IP - 1 DP - 1995 Jan TI - A pharmacogenetic basis for the safe and effective use of azathioprine and other thiopurine drugs in dermatologic patients. PG - 114-6 AD - Department of Dermatology, Mayo Clinic, Rochester, MN 55905. FAU - Snow, J L AU - Snow JL FAU - Gibson, L E AU - Gibson LE LA - eng PT - Journal Article PT - Review PT - Review, Tutorial PL - UNITED STATES TA - J Am Acad Dermatol JID - 7907132 RN - 446-86-6 (Azathioprine) RN - 50-44-2 (6-Mercaptopurine) RN - EC 2.1.1. (Methyltransferases) RN - EC 2.1.1.67 (thiopurine methyltransferase) SB - IM MH - 6-Mercaptopurine/metabolism/pharmacology/therapeutic use MH - Alleles MH - Azathioprine/metabolism/pharmacology/*therapeutic use MH - Erythrocytes/drug effects/enzymology MH - Heterozygote MH - Homozygote MH - Humans MH - Methyltransferases/blood/genetics/*metabolism MH - Polymorphism, Genetic MH - Research Support, Non-U.S. Gov't MH - Skin Diseases/*drug therapy/genetics/metabolism RF - 19 EDAT- 1995/01/01 MHDA- 1995/01/01 00:01 PST - ppublish SO - J Am Acad Dermatol 1995 Jan;32(1):114-6. PR