Cyclin-dependent kinases as targets for cancer therapy.

With the overwhelming evidence that the majority of human neoplasms are the result of 'cdk hyperactivation' leading to the abrogation of the Rb pathway, novel direct and indirect cdk inhibitors are being developed. The first 2 direct cdk inhibitors tested in clinical trials, flavopiridol and UCN-01, showed promising results with some evidence of antitumor activity reaching plasma concentrations effective to inhibit cdk-related functions. Other indirect cdk inhibitors such as PS-341, perifosine are also being tested in the clinic. The best schedule of administration, combination with standard chemotherapeutic agents, determination of predictive markers (using novel technologies such as cDNA arrays) for response/toxicity and demonstration of cdk modulation from tumor samples from patients in these trials are important issues that need to be answered in order to obtain the best possible results with these agents.