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Flavopiridol Sensitivity of Cancer Cells Isolated from Ascites and Pleural Fluids

Authors' Affiliations:¹ Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada and ² Sanofi Aventis, Bridgewater, New Jersey

Requests for reprints: Thunder Bay Regional Health Sciences Centre, 980 Oliver Road, Thunder Bay, Ontario, Canada P7B 6V4. Phone: 807-684-7245; Fax: 807-684-5803; E-mail: thngj{at}tbh.net; jpht{at}yahoo.ca.

Purpose: We examined the efficacy of flavopiridol, a cyclin-dependent kinase inhibitor that is undergoing clinical trials, on primary cancer cells isolated from the ascites or pleural fluids of patients with metastatic cancers.

Experimental Design: Metastasized cancer cells were isolated from the pleural fluids (n = 20) or ascites (n = 15) of patients, most of whom were refractory to chemotherapy. These primary cancer cells were used within 2 weeks of isolation without selecting for proliferative capacities. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide viability assay was used to characterize the response of these cancer cells to commonly used chemotherapeutic agents, and their response to flavopiridol was compared with rapidly dividing cultured cell lines.

Results: The primary cancer cells displayed phenotypes that were different from established cell lines; they had very low replication rates, dividing every 1 to 2 weeks, and underwent replicative senescence within five passages. These primary tumor cells retained their resistance to chemotherapeutic drugs exhibited by the respective patients but did not show cross-resistance to other agents. However, these cancer cells showed sensitivity to flavopiridol with an average LD₅₀ of 50 nmol/L (range, 21.5-69 nmol/L), similar to the LD₅₀ in established cell lines. Because senescent cells also showed similar sensitivity to flavopiridol, it suggests that the mechanism of action is not dependent on the activity of cyclin-dependent kinases that regulate the progression of the cell cycle.

Conclusion: Using cancer cells isolated from the ascites or pleural fluids, this study shows the potential of flavopiridol against cancer cells that have developed resistance to conventional chemotherapeutic agents.

Key Words: cyclin dependent • chemotherapy • cdk • chemoresistance • ascites • cell cycle mechanisms of anticancer drug action • cellular responses to anticancer drugs • CDKs and CDK inhibitors • drug resistance • novel assay technology