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


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.


CONCLUSIONS
Pulse-administration of vinblastine followed by continuous administration of ketoconazole warrants investigation in the treatment of hormone-independent metastatic prostate cancer.
Blagosklonny
M V
MV
Medicine Branch, Division of Clinical Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Dixon
S C
SC
Figg
W D
WD
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007654:Ketoconazole / Q000627:therapeutic use*; D008297:Male; D008870:Microtubules / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D014747:Vinblastine; D017239:Paclitaxel; D007654:Ketoconazole