ABSTRACT
A number of cyclin-dependent kinase (CDK) inhibitors have now been evaluated in clinical trials, including flavopiridol, UCN-01 (7-hydroxystaurosporine), R-roscovitine (CYC202, seliciclib), BMS-387032, Ro31-7453, and E7070. A current focus, especially in the clinic, is on their use in combination with various cytotoxic agents. This is based on the dual facts that single-agent activity of CDK inhibitors in Phase II clinical trials has been generally disappointing, with low percentages of objective
in vitro
. Most such combination studies performed
in vitro
show that cell kill is sequence dependent, with greater kill observed when the cytotoxic is added to cells before the CDK inhibitor (rather than after or concurrently). In some, but not all cases, these
in vitro
findings have been translated successfully to clinical trials. For the most clinically advanced CDK inhibitor, flavopiridol, single-agent activity is modest but appears greater when using a 1 h bolus infusion rather than a continuous infusion over 3 d. Phase II combination studies are taking place with irinotecan in patients with hepatocellular carcinoma and with cisplatin in ovarian cancer, and more such studies are planned. UCN-01 inhibits cell cycle checkpoint kinases as well as CDKs and shows synergy against cell lines, especially when combined with DNA-damaging agents. Phase II trials are taking place with UCN-01 in combination with 5 fluorouracil (5FU) in pancreatic cancer and with topotecan in ovarian cancer. In some cases, toxicity has precluded the robust clinical evaluation of CDK inhibitors combined with cytotoxics (e.g., flavopiridol with docetaxel or carboplatin, and UCN-01 with cisplatin). Roscovitine is currently undergoing Phase II monotherapy trials by the oral route. Phase I combination studies have started with Ro31-1453 plus gemcitabine or paclitaxel. The results of all of these combination Phase II trials are awaited with great interest and will define the role of the currently available CDK inhibitors in current cancer therapy.
