CORRESPONDENCE

Re: Preclinical and Clinical Development of Cyclin-Dependent Kinase Modulators

Zbigniew Darzynkiewicz

Correspondence to: Zbigniew Darzynkiewicz, M.D., Ph.D., Brander Cancer Research Institute, New York Medical Center, 19 Bradhurst Ave., Hawthorne, NY 10532 (e-mail: darzynk{at}nymc.edu).

The comprehensive and stimulating review on strategies that involve modulation of the cell cycle regulation machinery in treatment of cancer (1) did not address one approach that is potentially applicable in the clinic. As the authors of that review correctly emphasized (1), the vast majority of human cancers have abnormalities in the retinoblastoma (Rb) pathway (2). Such abnormalities make proliferation of these tumors independent of signals from mitogenic and growth factors that come from the cell environment. Proliferation of normal cells, on the other hand, depends on the presence of these factors. Therefore, inhibitors of the components of the cell cycle or the signal transduction pathways upstream of the abnormality in the Rb pathway of the tumor can arrest (in G0/1 phase) normal cells but not the cells of that tumor. When such inhibitors are administered with the cytotoxic drugs that target proliferating cells (e.g., DNA replication or mitotic poisons), they protect normal cells by sequestering them in the nonsensitive G0/1-phase compartment, but they offer no such protection to the tumor cells. Intense chemotherapy can then be administered to the cancer patient with less toxic effects. This strategy was suggested by us (3,4) and others (5) following the observation that the protein kinase inhibitor staurosporine, at low concentrations, had no effect on the cell cycle progression of tumor cells but arrested normal cells in G0/1 phase.

REFERENCES

1 Senderowicz AM, Sausville EA. Preclinical and clinical development of cyclin-dependent kinase modulators. J Natl Cancer Inst 2000;92:367–87.

2 Bartek J, Bartkova J, Lukas J. The retinoblastoma protein pathway in cell cycle control and cancer. Exp Cell Res 1997;237:1–6.[Medline]

3 Bruno S, Ardelt B, Skierski JS, Traganos F, Darzynkiewicz Z. Different effects of staurosporine, an inhibitor of protein kinases, on the cell cycle and chromatin structure of normal and leukemic lymphocytes. Cancer Res 1992;52:470–3.[Abstract]

4 Darzynkiewicz Z. Apoptosis in antitumor strategies: modulation of cell cycle or differentiation. J Cell Biochem 1995;58:151–9.[Medline]

5 Crissman HA, Gadbois DM, Tobey RA, Bradbury EM. Transformed mammalian cells are deficient in kinase-mediated control of progression through the G1 phase of the cell cycle. Proc Natl Acad Sci U S A 1991;88:7580–4.[Abstract]



             
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