The use of cyclin-dependent kinase inhibitors alone or in combination with established cytotoxic drugs in cancer chemotherapy

Cyclin-dependent kinase (CDK) inhibitors are small molecule inhibitors of the kinases required for the orderly progression of cells, both normal and neoplastic, through the cell cycle. Because cell cycle dysregulation is such a common occurrence in neoplasia, the search for agents that might block cell cycle traverse has been the focus of intense interest. These efforts have led to the identification of a broad array of compounds that interfere directly with the function of CDKs. Two of these agents (flavopiridol and UCN-01) have now entered the clinical arena, and others are scheduled to do so in the near future. In preclinical studies, CDK inhibitors have shown the ability not only to block neoplastic cell proliferation, but also to induce, through a variety of mechanisms, programmed cell death. The latter capacity may stem from the diverse effects that CDK inhibitors exert on multiple kinases and apoptotic regulatory molecules. In addition, there is abundant preclinical evidence that CDK inhibitors can potentiate, generally in a dose- and sequence-dependent manner, the anti-tumor effects of many established cytotoxic agents. In clinical studies in humans, flavopiridol and UCN-01 have been shown to be tolerable, although clear evidence of single agent activity or enhancement of the efficacy of established agents has not yet emerged. This may reflect a failure to optimize drug schedules/pharmacokinetics, or to identify the critical molecular targets of these agents. Finally, in recent years, a rationale has emerged for combining CDK inhibitors with other molecularly targeted agents (i.e. differentiation-inducers and signal transduction modulators). Current research has basically two goals: (a) to identify CDK inhibitor concentrations and schedules that inhibit the growth of and induce apoptosis in specific tumor cell types; and (b) to establish a rational basis for combining CDK inhibitors with more conventional cytotoxic agents to enhance antitumor efficacy. This review gives a brief summary of such efforts, with an emphasis on agents and combinations that are in or near clinical development.