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

Abstract

PURPOSE:

Once a relapse occurs following primary endocrine treatment, metastatic prostate cancer is one of the most therapy-resistant human neoplasms. Ketoconazole is used for complete androgen deprivation, and recent data suggest it has direct activity against prostate cancer cells.

MATERIALS AND METHODS:

LNCaP, DU145, and PC3 cells, human prostate cancer cell lines, and HL60, a human leukemia cell line, were lysed and soluble proteins were harvested. Cells were plated in 96-well flat bottom plates and then exposed to the pharmacological agents, ketoconazole, vinblastine and paclitaxel. DNA synthesis was monitored by 3H-thymidine incorporation.

RESULTS:

We demonstrate that ketoconazole exerts a cytostatic effect on a panel of human prostate cancer cell lines, with IC50 of 4 to 5 microg./ml., 12 microg./ml., and 25 microg./ml. for LNCaP, PC3/PC3M, and DU145 cells, respectively. On the other hand, using microtubule-active drugs, vinblastine and paclitaxel, we found that PC3M and PC3 cells were more resistant than either DU145 or LNCaP cells. This resistance was associated with a lesser degree of Raf-1 and Bcl-2 phosphorylation following exposure to microtubule-active drugs. Combinations of microtubule-active drugs with ketoconazole were a beneficial treatment in DU145 cancer cells. Furthermore, ketoconazole blocked recovery of all the prostate cancer cell lines following 24 hours-pulse treatment with vinblastine.

CONCLUSION:

Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.

• Authors: M V Blagosklonny, S C Dixon, W D Figg
• Journal: The Journal of urology (J Urol) Vol. 163 Issue 3 Pg. 1022-6 (Mar 2000) ISSN: 0022-5347 [Print] United States
• PMID: 10688042 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Vinblastine
• Paclitaxel
• Ketoconazole

Topics

• Antineoplastic Agents (therapeutic use)
• Drug Screening Assays, Antitumor
• Humans
• Ketoconazole (therapeutic use)
• Male
• Microtubules (drug effects)
• Paclitaxel (therapeutic use)
• Phosphorylation (drug effects)
• Prostatic Neoplasms (drug therapy, secondary)
• Tumor Cells, Cultured
• Vinblastine (therapeutic use)