Affiliations of authors: X. Wu, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, and School of Public Health, The University of Texas Health Science Center, Houston; H. Yu, Section of Cancer Prevention and Control, Feist-Weiller Cancer Center, Louisiana State University Medical Center, Shreveport; C. I. Amos, M. R. Spitz (Department of Epidemiology), W. K. Hong (Department of Thoracic/Head and Neck Medical Oncology), The University of Texas M. D. Anderson Cancer Center.
Correspondence to: Xifeng Wu, M.D., Ph.D., Department of Epidemiology, Box 189, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: xwu{at} notes.mdacc.tmc.edu).
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
It has been hypothesized that the capacity to repair DNA varies within the general population (16). Mutagen sensitivity assays have been used as an indirect measure of DNA repair to estimate an individual's susceptibility to cancer (17,18). In vitro mutagens tested that reflect different DNA repair pathways are bleomycin (a radiomimetic agent) and benzo[a]pyrene diol epoxide (BPDE) (a tobacco mutagen) (19,20). We have shown that the mutagen-sensitive phenotype is associated with impaired DNA repair capacity and that individuals who are mutagen sensitive are at heightened risk for cancer (17,1929).
We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic sensitivity to carcinogens and on humoral factors, such as IGFs that enhance proliferation, resistance of damaged cells to apoptosis, and clonal outgrowth of genetically damaged populations. We propose further that there might be a synergistic effect of latent genetic instability and higher proliferation potential in lung cancer risk. To test these hypotheses, we assessed the joint effects of mutagen sensitivity and IGF levels on the risk of lung cancer in a casecontrol study.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Data collection. The study was approved by the Institutional Review Board at The University of Texas M. D. Anderson Cancer Center, and written informed consent was obtained for each participant. The epidemiologic data were assembled from personal interviews. After the interview was completed, blood was drawn into heparinized tubes to be used in cytogenetic and molecular genetic analyses.
Measurement of IGFs. Blood was centrifuged at 3000g for 10 minutes at room temperature to separate the plasma. Collected plasma was stored at -80°C. In a previous study (13) in which IGF-I and IGFBP-3 levels in stored plasma and fresh samples were compared, no difference was seen. The levels of IGF-I, IGF-II, and IGFBP-3 were determined by an enzyme-linked immunosorbent assay (DSL, Webster, TX). For the IGF-I assay, the ranges for the intra-assay and interassay precision for the coefficient of variation were 4.5%8.6% and 3.3%6.8%, respectively. For IGF-II, the ranges were 3.4%6.7% and 5.9%7.9%, respectively. For IGFBP-3, the ranges were 7.3%9.6% and 8.2%11.4%, respectively. The impact of freezethaw cycles on the levels of IGF-I, IGF-II, and IGFBP-3 was determined in 10 individual heparinized plasma specimens. We measured these compounds once per cycle through five freezethaw cycles and found that all of the compounds remained constant.
Mutagen sensitivity assays. Mutagen sensitivity was measured in vitro in lymphocytes by counting chromatid breaks induced by bleomycin and BPDE as previously described (17). Briefly, blood cultures were incubated for 3 days and then exposed to bleomycin (0.03 U/mL) for 5 hours. Cells were harvested, and chromatid breaks were counted in 50 metaphases per sample and recorded as the mean number of breaks per cell. We modified the procedure for the BPDE assay by substituting BPDE at 2 µM for 24 hours (19,20). Laboratory personnel read the slides without knowledge of the individual's cancer status.
Statistical analysis.
Plasma levels of IGF-I, IGF-II, and IGFBP-3 as well as bleomycin sensitivity and BPDE sensitivity were analyzed as continuous and categorical variables. We report results from two-sided tests. As continuous variables, the differences between case patients and control subjects were calculated with a two-sample Student's t test for demographic variables and mutagen sensitivity and a Wilcoxon rank sum test for IGFs (which are not normally distributed). As categorical variables, high levels of IGFs and mutagen sensitivity have been associated with increased lung cancer risk. Consequently, the 75th percentile values in the control subjects of IGF-I level (178 ng/mL), IGF-II level (
682 ng/mL), bleomycin sensitivity (
0.70 breaks per cell), and BPDE sensitivity (
0.60 breaks per cell) were used as cutoff points for risk assessment. Because low levels of IGFBP-3 were associated with increased lung cancer risk, for control subjects, the 25th percentile value of IGFBP-3 levels (
3133 ng/mL) was selected as the cutoff point. Individuals with levels less than or equal to the control subjects' 25th percentile were coded as at risk. All cutoff points were selected before we began the stratified and logistic regression analyses. Unconditional logistic regression analysis was used to evaluate the association between lung cancer risk and the risk factors by calculating the odds ratio (OR) and its corresponding 95% confidence interval (CI). Both univariate and multivariate regression analyses were performed, including sex, age, ethnicity, smoking status, body mass index (i.e., weight in g/[height in m]2), and family history of cancer (either "yes" or "no" in first-degree relatives). Joint effects were estimated by stratified analysis in which we formed joint strata of IGFs and mutagen sensitivity risk factors (see Tables 24
). The joint relationships between IGFs and mutagen sensitivity were also modeled in the logistic regression model by including an interaction term between the variables that tests a multiplicative model. The interaction terms were coded as 1 if the individuals had high levels of IGF-I and exhibited the sensitive phenotype. The interaction terms were coded as 0 for all other individuals. Because IGFBP-3 regulates the action of IGF-I and IGF-II and because plasma levels of IGFBP-3 are associated with IGF-I and IGF-II (15), we evaluated the association of IGF-I, IGF-II, and disease risk, with adjustment for IGFBP-3 levels. We also investigated the effect of the IGF-I/IGFBP-3 molar ratio.
|
|
|
|
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We next calculated the ORs with logistic regression analysis (Table 1). Higher levels of plasma IGF-I carried a statistically significantly elevated risk for lung cancer (adjusted OR = 2.13; 95% CI = 1.203.78); higher IGFBP-3 plasma levels were associated with a reduced risk (adjusted OR = 0.59; 95% CI = 0.331.05). A higher IGF-I/IGFBP-3 molar ratio was also statistically significantly associated with increased lung cancer risk (OR = 1.79; 95% CI = 1.053.06).
The number of mutagen-induced breaks per cell was statistically significantly higher in case patients than in control subjects for both assays usedbleomycin sensitivity (adjusted OR = 2.50; 95% CI = 1.494.20) and BPDE sensitivity (adjusted OR = 2.95; 95% CI = 1.725.06) (data not shown).
The joint effects of bleomycin sensitivity and IGF-I, IGF-II, IGFBP-3, or IGF-I/IGFBP-3 molar ratio on the risk of lung cancer were next assessed in stratified analyses (Table 2). Using nonsensitive individuals with lower levels of IGF-I as the referent category, we found that a higher level of IGF-I alone was associated with an adjusted OR of 1.96 (95% CI = 1.073.60). The risk was also increased in individuals who were only bleomycin sensitive (adjusted OR = 2.86; 95% CI = 1.674.88). There was an 8.88-fold (adjusted OR = 8.88; 95% CI = 3.6721.50) increased risk for those who were both bleomycin sensitive and had higher levels of IGF-I. We observed similar effects for bleomycin-sensitive individuals with higher levels of IGF-II (adjusted OR = 5.88; 95% CI = 2.4514.13).
We performed similar analyses for the IGF-I/IGFBP-3 molar ratio and noted an 11.08-fold (95% CI = 4.5626.92) increased risk for those who were both bleomycin sensitive and had a higher molar ratio. The joint effects of bleomycin sensitivity and IGF-I, IGF-II, or IGF-I/IGFBP-3 molar ratio on lung cancer risk appeared to be greater than multiplicative.
We then determined the relationships between the IGFs and mutagen sensitivity in the logistic regression model with the multiplicative model interaction term of the variables. The interaction term between the molar ratio and bleomycin sensitivity was associated with an OR of 3.10 (95% CI = 1.128.57), but other interaction terms were not statistically significant.
The joint effects of IGF-I and BPDE sensitivity were similar to those seen with bleomycin sensitivity (Table 3). The risk for individuals with the sensitive phenotype and elevated IGF-I levels (adjusted OR = 13.53; 95% CI = 4.4840.89) was substantially higher than the risk for individuals with either a higher level of IGF-I (OR = 2.04; 95% CI = 1.044.01) or BPDE sensitivity (OR = 2.89; 95% CI = 1.595.25). Similarly, the joint effects of IGF-II and BPDE sensitivity or the IGF-I/IGFBP-3 molar ratio and BPDE sensitivity were also greater than single factors alone.
When all three variables were considered together, the joint effects of IGFs, bleomycin sensitivity, and BPDE sensitivity are clearly observed (Table 4). With the use of individuals who had lower levels of IGF-I and were not sensitive to either bleomycin or BPDE as a referent group, one risk factor alone (high IGF-I levels, bleomycin sensitivity, or BPDE sensitivity) increased the risk of lung cancer by 1.6-fold to 2.5-fold. Two risk factors (high IGF-I levels plus bleomycin sensitivity, high IGF-I levels plus BPDE sensitivity, or bleomycin sensitivity plus BPDE sensitivity) elevated the risk 5.3-fold to 13-fold above the reference. When all three risk factors (IGF-I, bleomycin sensitive, and BPDE sensitive) were present, the risk was 17 times higher than that of the reference group (OR = 17.09; 95% CI = 4.1670.27). In contrast, levels of IGF-II did not change lung cancer risk. The IGF-I/IGFBP-3 molar ratio was associated with the highest risk estimates. In the presence of all three risk phenotypes, the OR was 21.10 (95% CI = 5.2385.24).
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
This study also demonstrated joint effects between elevated IGF-I levels (higher proliferative potential) and the mutagen sensitivity phenotype (genetic instability) in the risk of lung cancer. If all three of the risk factors (higher levels of IGF-I, bleomycin sensitivity, and BPDE sensitivity) were considered together, the estimated relative risk reached as high as 17.09-fold. On the other hand, as reported previously (15), high levels of IGFBP-3 were associated with reduced lung cancer risk (OR = 0.59; 95% CI = 0.331.05). Furthermore, in the regression model for lung cancer risk, there was a statistically significant multiplicative interaction between the IGF-I/IGFBP-3 molar ratio and bleomycin sensitivity.
Biologically, IGF-I and mutagen sensitivity reflect two distinct cellular activities (i.e., cell proliferation and DNA repair). Cells with uncontrolled proliferation and with impaired or inactive DNA repair will contribute to a substantial increase in the population of damaged cells. As indicated in this study, accumulation of these abnormalities seems to have a profound impact on the risk of lung cancer.
Many in vitro studies have shown that IGF-I is a potent mitogen for a variety of normal and cancerous cells and that high levels of IGF-I in circulation appear to enhance cell proliferation (30). We would expect to find an association between a systemic increase in mitogens and an elevated risk for cancer. Indeed, several epidemiologic studies found that high levels of IGF-I in circulation were associated with increased risks for lung cancer (15), breast cancer (14), prostate cancer (13), and colorectal cancer (31). However, Lee et al. (32) have recently reported serum levels of IGF-I to be lower in lung cancer patients than in control subjects. A weakness of that study is that only 40 case subjects were included and the source of the control subjects was not defined.
We have shown that IGFBP-3 has an inverse impact on the risk of lung cancer. Physiologically, IGFBP-3 binds IGFs with an affinity that is stronger than that of the specific IGF-I receptor on the cell membrane. IGF-I that is bound to IGFBP-3 cannot interact with its receptor; thus, the mitogenic and antiapoptotic actions of IGF-I are blocked. In this study, the effects of IGF-I and IGFBP-3 on lung cancer risk were consistent with their biologic functions described in cell culture and animal experiments. Experimental findings suggest that IGF-II has similar mitogenic activity on various cancer cells, but no relationship with cancer risk has been demonstrated in epidemiologic studies.
Hsu (16) hypothesized that the general population has a variety of DNA repair capacities (3338) and that latent genetic instability could be unmasked by in vitro mutagen challenge. Environmentally induced genetic damage would accumulate more quickly in people with DNA repair defects than in similarly exposed people without such defects; therefore, those with DNA repair defects might be at higher risk for cancer. A series of studies (17,2129) has indicated that mutagen sensitivity holds promise as a predictor of cancer risk. Bleomycin causes oxidative damage along with single- and double-stranded DNA breaks that require base-excision repair and recombinational DNA repair (39,40). Thus, the bleomycin assay is relevant to tobacco carcinogenesis because there are numerous compounds in cigarettes that can cause oxidative damage. BPDE is the metabolic product of benzo[a]pyrene, a tobacco carcinogen. BPDEs form covalent DNA adducts that can be repaired through the nucleotide excision pathway (41,42). We (19,20) have reported previously that there are synergistic interactions between bleomycin sensitivity and BPDE sensitivity for cancer risk.
To analyze the combined effect of IGF and mutagen sensitivity, we chose dichotomous variables for all three markers. Values at the 75th percentile distribution in the control group were used as a cutoff. Because the cutoff values were objective and a doseresponse relationship with lung cancer risk was seen for all three markers in our previous studies (15,19), the selection of the cutoff should not affect the results of our study. The case patients and control subjects in the study were matched on age, sex, race, and smoking habits. The results of the analysis were not altered after these variables were adjusted. Despite lower values for the body mass index in case patients than in control subjects, the ORs did not show substantial changes when we adjusted the analysis for the body mass index. There was no statistically significant association between IGF-I levels and the body mass index. As stated previously, we also found that, although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. However, Mazzocolli et al. (43) observed a steady decrease in IGF-I serum levels in lung cancer patients in relation to advancing stage. Therefore, the relationship between serum levels of IGF-I and the disease progression needs further study.
Because our findings were derived from a casecontrol study, we cannot rule out the impact of disease status. However, findings of the cohort studies resembled those of casecontrol studies (31,44,45). Because the associations of IGF-I and IGFBP-3 with these cancers and lung cancer were similar, it would be reasonable to assume that IGF-I also may be elevated before the development of lung cancer.
In summary, the combination of high levels of IGF-I and mutagen sensitivity was associated with a higher risk for lung cancer than any one of the markers alone. Because IGF-I stimulates cell proliferation and mutagen sensitivity indicates impaired DNA repair, the finding that these markers have a joint impact on lung cancer risk advances our capacity to identify individuals who are at greater risk for lung cancer.
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Macaulay VM. Insulin-like growth factors and cancer. Br J Cancer 1992;65:31120.[Medline]
2 Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:334.[Medline]
3 Ankrapp DP, Bevan DR. Insulin-like growth factor-I and human lung fibroblast-derived insulin-like growth factor-I stimulate the proliferation of human lung carcinoma cells in vitro. Cancer Res 1993;53:3399404.[Abstract]
4 Favoni RE, de Cupis A, Ravera F, Cantoni C, Pirani P, Ardizzoni A, et al. Expression and function of the insulin-like growth factor I system in human non-small-cell lung cancer and normal lung cell lines. Int J Cancer 1994;56:85866.[Medline]
5 Reeve JG, Brinkman A, Hughes S, Mitchell J, Schwander J, Bleehen NM. Expression of insulinlike growth factor (IGF) and IGF-binding protein genes in human lung tumor cell lines. J Natl Cancer Inst 1992;84:62834.[Abstract]
6 Wegmann BR, Schoneberger HJ, Kiefer PE, Jaques G, Brandscheid D, Havemann K. Molecular cloning of IGFBP-5 from SCLC cell lines and expression of IGFBP-4, IGFBP-5 and IGFBP-6 in lung cancer cell lines and primary tumours. Eur J Cancer 1993;29A:157884.
7 Noll K, Wegmann BR, Havemann K, Jaques G. Insulin-like growth factors stimulate the release of insulin-like growth factor-binding protein-3 (IGFBP-3) and degradation of IGFBP-4 in nonsmall cell lung cancer cell lines. J Clin Endocrinol Metab 1996;81:265362.[Abstract]
8
Quinn KA, Treston AM, Unsworth EJ, Miller MJ, Vos M, Grimley C, et al. Insulin-like growth factor expression in human cancer cell lines. J Biol Chem 1996;271:1147783.
9 LeRoith D, Werner H, Beitner-Johnson D, Roberts CT Jr. Molecular and cellular aspects of the insulin-like growth factor I receptor. Endocr Rev 1995;16:14363.[Medline]
10
Parrizas M, LeRoith D. Insulin-like growth factor-1 inhibition of apoptosis is associated with increased expression of the bcl-xL gene product. Endocrinology 1997;138:13558.
11
Wang L, Ma W, Markovich R, Lee WL, Wang PH. Insulin-like growth factor I modulates induction of apoptotic signaling in H9C2 cardiac muscle cells. Endocrinology 1998;139:135460.
12 Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev 1995;16:334.[Medline]
13
Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:5636.
14 Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet 1998;351:13936.[Medline]
15
Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a casecontrol analysis. J Natl Cancer Inst 1999;91:1516.
16 Hsu TC. Genetic instability in the human population: a working hypothesis. Hereditas 1983;98:19.[Medline]
17 Hsu TC, Johnston DA, Cherry LM, Ramkissoon D, Schantz SP, Jessup JM, et al. Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis. Int J Cancer 1989;43:4039.[Medline]
18 Hsu TC, Spitz MR, Schantz SP. Mutagen sensitivity: a biologic marker of cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1991;1:839.[Abstract]
19 Wu X, Gu J, Amos CI, Jiang H, Hong WK, Spitz MR. A parallel study of in vitro sensitivity to benzo[a]pyrene diol epoxide and bleomycin in lung cancer cases and controls. Cancer 1998;111827.
20
Wu X, Gu J, Hong WK, Lee JJ, Amos CI, Jiang H, et al. Benzo[a]pyrene diol epoxide and bleomycin sensitivity and susceptibility to cancer of upper aerodigestive tract. J Natl Cancer Inst 1998;90:13939.
21 Spitz MR, Fueger JJ, Beddingfield NA, Annegers JF, Hsu TC, Newell GR, et al. Chromosome sensitivity to bleomycin-induced mutagenesis, an independent risk factor for upper aerodigestive tract cancers. Cancer Res 1989;49:46268.[Abstract]
22 Schantz SP, Hsu TC, Ainslie N, Moser RP. Young adults with head and neck cancer express increased susceptibility to mutagen-induced chromosome damage. JAMA 1989;262:33135.[Abstract]
23 Spitz MR, Fueger JJ, Halabi S, Schantz SP, Sample D, Hsu TC. Mutagen sensitivity in upper aerodigestive tract cancer: a casecontrol analysis. Cancer Epidemiol Biomarkers Prev 1993;2:32933.[Abstract]
24
Cloos J, Spitz MR, Schantz SP, Hsu TC, Zhang ZF, Tobi H, et al. Genetic susceptibility to head and neck squamous cell carcinoma. J Natl Cancer Inst 1996;88:5305.
25 Spitz MR, Hsu TC, Wu X, Fueger JJ, Amos CI, Roth JA. Mutagen sensitivity as a biological marker of lung cancer risk in African Americans. Cancer Epidemiol Biomarkers Prev 1995;4:99103.[Abstract]
26 Strom SS, Wu X, Sigurdson AJ, Hsu TC, Fueger JJ, Lopez J, et al. Lung cancer, smoking patterns, and mutagen sensitivity in Mexican-Americans. J Natl Cancer Inst Monogr 1995;18:2933.[Medline]
27 Wu X, Delclos GL, Annegers FJ, Bondy ML, Honn SE, Henry B, et al. A casecontrol study of wood dust exposure, mutagen sensitivity, and lung cancer risk. Cancer Epidemiol Biomarkers Prev 1995;4:5838.[Abstract]
28
Spitz MR, Lippman SM, Jiang H, Lee JJ, Khuri F, Hsu TC, et al. Mutagen sensitivity as a predictor of tumor recurrence in patients with cancer of the upper aerodigestive tract. J Natl Cancer Inst 1998;90:2435.
29 Wei Q, Spitz MR, Gu J, Cheng L, Xu X, Strom SS, et al. DNA repair capacity correlates with mutagen sensitivity in lymphoblastoid cell lines. Cancer Epidemiol Biomarkers Prev 1996;5:199204.[Abstract]
30 Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res 1990;50:741521.[Abstract]
31
Ma J, Pollak MN, Giovannucci E, Chan JM, Tao Y, Hennekens CH, et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J Natl Cancer Inst 1999;91:6205.
32 Lee DY, Kim SJ, Lee YC. Serum insulin-like growth factor (IGF)-I and IGF-binding proteins in lung cancer patients. J Korean Med Sci 1999;14:4014.[Medline]
33 German J, editor. Chromosome mutation and neoplasia. New York (NY): Liss; 1983.
34 Maher VM, Ouellette LM, Curren RD, McCormick JJ. Frequency of ultraviolet light-induced mutations is higher in xeroderma pigmentosum variant cells than in normal human cells. Nature 1976;261:5935.[Medline]
35 Parrington JM, Delhanty JD, Baden HP. Unscheduled DNA synthesis, u.v.-induced chromosome aberrations and SV 40 transformation in cultured cells from xeroderma pigmentosum. Ann Hum Genet 1971;35:14960.[Medline]
36 Setlow RB, Regan JD, German J, Carrier WL. Evidence that xeroderma pigmentosum cells do not perform the first step in the repair of ultraviolet damage to their DNA. Proc Natl Acad Sci U S A 1969;64:103541.[Abstract]
37 Cleaver JE. Defective repair replications of DNA in xeroderma pigmentosum. Nature 1968;218:6526.[Medline]
38 Paterson MC, Smith PJ. Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing radiation and related DNA-damaging chemicals. Annu Rev Genet 1979;13:291318.[Medline]
39
Xu YJ, Kim EY, Demple B. Excision of C-4`-oxidized deoxyribose lesions from double-stranded DNA by human apurinic/apyrimidinic endonuclease (Ape1 protein) and DNA polymerase beta. J Biol Chem 1998;273:2883744.
40 Dar ME, Winters TA, Jorgensen TJ. Identification of defective illegitimate recombinational repair of oxidatively-induced DNA double-strand breaks in ataxia-telangiectasia cells. Mutat Res 1997;384:16979.[Medline]
41 Shou M, Harvey RG, Penning TM. Reactivity of benzo[a]pyrene-7,8-dione with DNA. Evidence for the formation of deoxyguanosine adducts. Carcinogenesis 1993;14:47582.[Abstract]
42 Tang MS, Pierce JR, Doisy RP, Nazimiec ME, MacLeod MC. Differences and similarities in the repair of two benzo[a]pyrene diol epoxide isomers induced DNA adducts by uvrA, uvrB, and uvrC gene products. Biochemistry 1992;31:842936.[Medline]
43 Mazzoccoli G, Giuliani A, Bianco G, De Cata A, Balzanelli M, Carella AM, et al. Decreased serum levels of insulin-like growth factor (IGF)-I in patients with lung cancer: temporal relationship with growth hormone (GH) levels. Anticancer Res 1999;19:13979.[Medline]
44 Bruning PF, Van Doorn J, Bonfrer JM, Van Noord PA, Korse CM, Linders TC, et al. Insulin-like growth-factor-binding protein 3 is decreased in early-stage operable pre-menopausal breast cancer. Int J Cancer 1995;62:26670.[Medline]
45
Wolk A, Mantzoros CS, Anderson SO, Bergstrom R, Signorello LB, Lagiou P, et al. Insulin-like growth factor 1 and prostate cancer risk: a population-based, casecontrol study. J Natl Cancer Inst 1998;90:9115.
Manuscript received July 19, 1999; revised January 21, 2000; accepted February 15, 2000.
This article has been cited by other articles in HighWire Press-hosted journals:
![]() |
||||
|
Oxford University Press Privacy Policy and Legal Statement |