Flavopiridol, a novel cyclin-dependent kinase inhibitor, in clinical development.

OBJECTIVE: To review preclinical and clinical information on flavopiridol, an inhibitor of cyclin-dependent kinases (CDKs), tested as an antitumor agent. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1990-June 2001). Abstracts from recent meetings were also used as source materials. DATA EXTRACTION: Flavopiridol was reviewed with regard to its mechanisms, preclinical and clinical results, pharmacokinetics, and metabolism. DATA SYNTHESIS: Flavopiridol is an inhibitor of several CDKs and displays unique anticancer properties. In addition to direct CDK inhibition, flavopiridol also exhibited other features such as inducing apoptosis in many cancer cell lines, decreasing cyclin D1 concentration, and inhibiting angiogenesis. Preclinical xenograft models showed significant antitumor activity for flavopiridol. The regimen using 72-hour continuous infusion every 2 weeks has been most extensively applied in clinical trials, with a 1-hour infusion currently being explored to achieve higher peak concentrations. Several Phase I and II trials have been reported, with some evidence of antitumor activity noted. Further Phase I and II trials using flavopiridol as a single agent and in combination with standard chemotherapeutic regimens and various tumor types are ongoing.
CONCLUSIONS: Flavopiridol is the first CDK inhibitor to enter clinical trials. Several Phase I and Phase II clinical trials with different regimens (72-h or 1-h infusion) have been completed. Initial clinical trials have been intriguing, but many questions remain: What is the best regimen (< or =72-h infusion)? Does optimal future development of this drug depend on the combination with other chemotherapy? What is the best combination of flavopiridol with other chemotherapy?