Efficacy of microtubule-active drugs followed by ketoconazole in human metastatic prostate cancer cell lines

Purpose: Once a relapse occurs following primary endocrine treatment, metas tatic prostate cancer is one of the most therapy-resistant human neoplasms. Ketoconazole is used for complete androgen deprivation, and recent data su ggest it has direct activity against prostate cancer cells. Materials and Methods: LNCaP, DU145, and PC3 cells, human prostate cancer c ell lines, and HL60, a human leukemia cell line, were lysed and soluble pro teins were harvested. Cells were plated in 96-well flat bottom plates and t hen exposed to the pharmacological agents, ketoconazole, vinblastine and pa clitaxel. DNA synthesis was monitored by H-3-thymidine incorporation. Results: We demonstrate that ketoconazole exerts a cytostatic effect on a p anel of human prostate cancer cell lines, with IC50 of 4 to 5 mu g./ml., 12 mu g./ml., and 25 mu g./ml. for LNCaP, PC3/PC3M, and DU145 cells, respecti vely. On the other hand, using microtubule-active drugs, vinblastine and pa clitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree o f Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a be neficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse tr eatment with vinblastine. Conclusion: Pulse-administration of vinblastine followed by continuous admi nistration of ketoconazole warrants investigation in the treatment of hormo ne-independent metastatic prostate cancer.