Affiliations of authors: A. M. Senderowicz, Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, Bethesda, MD; E. A. Sausville, Clinical Trials Unit, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD.
Correspondence to: Adrian M. Senderoewicz, M.D., National Institutes of Health, Bldg. 30, Rm. 211, Bethesda, MD 208924340 (e-mail: sendero{at}helix.nih.gov).
Dr. Darzynkiewicz's strategy to use signal transduction and cell cycle modulators to protect normal cells from cytotoxic agents sounds very attractive, at first. Certainly, inhibitors that specifically modulate only signals important for the "Rb [retinoblastoma] pathway" may arrest normal cells in G0/1 phase. However, several caveats should be entertained. First, it is very difficult to find specific modulators that do not interfere with other cell cycle components. For instance, flavopiridol (a pan cyclin-dependent kinase [cdk] inhibitor) and olomucine and roscovitine (specific cdk1/cdk2 inhibitors) may arrest cells not only at the G1/ boundary but also at the G2/M boundary (1). As mentioned by Dr. Darzynkiewicz, several investigators demonstrated differential in vitro cell cycle effects of staurosporine, a nonspecific tyrosine and protein kinase inhibitor, in normal and tumor cells. However, stauropsorine has significant toxicity in animal models precluding its clinical development (2). Furthermore, UCN-01, a staurosporine analog actually potentiates the effect of chemotherapy in vitro and in vivo (1). Second, in the best case scenario, where such a specific molecule could be identified, many chemotherapeutic agents demonstrate cytotoxicity even in cells that are in G0/1 phase (35). Third, Dr. Darzynkiewicz has suggested that protecting normal cells from cytotoxic compounds may allow us to escalate standard chemotherapy. This suggestion is the basis for high-dose chemotherapy trials, pioneered in the last decade. Although high-dose chemotherapy has a role in hematopoietic neoplasms, more prevalent neoplasms are not usually affected by current versions of this approach (6). It is unlikely that the elusive cure for cancer will be achieved with higher doses of traditional chemotherapeutic agents. We feel that, with the understanding of the molecular basis of cancer along with the sequencing of the human genome, rational therapy targeting important proteins and/or pathways responsible for human carcinogenesis will likely improve our anticancer therapeutic field. The bottom line is that the ideal cdk modulator to affect the strategy outlined by Dr. Darzynkiewicz has not been defined, and it is not clear what the best immediate use for that strategy as a cytoprotectant approach might be.
REFERENCES
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Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000;92:37687.
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3 Brusselbach S, Nettelbeck DM, Sedlacek HH, Muller R. Cell cycle-independent induction of apoptosis by the anti-tumor drug Flavopiridol in endothelial cells. Int J Cancer 1998;77:14652.[Medline]
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Lippman ME. High-dose chemotherapy plus autologous bone marrow transplantation for metastatic breast cancer [editorial]. N Engl J Med 2000;342:111920.
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