Synergistic and antagonistic combinations of drugs in human prostate cancer cell lines in vitro

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Abstract
Microtubulin binding agents such as docetaxel have significant preclinical and clinical activity in the treatment of hormone-refractory prostate cancer. We have previously used median-effect analysis to define both synergistic and antagonistic drug combinations which may be of value in management of human disease. These studies extend our findings in defined prostate cancer cell lines. A semi-automated microtiter culture system was used. Docetaxel was combined with 18 other agents, incubated with DU 145, LnCaP or PC 3 prostate cancer cell lines for 72 h and the cells then incubated with MTT to determine cytotoxic effect. Both doublet and triplet combinations were examined. Synergy and antagonism as measured by the combination index were determined for each combination. The non-mutually exclusive criterion was applied. Docetaxel demonstrated cytotoxic additive effects or synergy with -retinoic acid, cyclosporin A and vinorelbine in all three cell lines. Docetaxel combined with either epirubicin or doxorubicin displayed cytotoxic synergistic effects in hormone-refractory DU 145 and PC 3 cell lines. In contrast, drugs which have been combined clinically to treat hormone-refractory prostate cancer, i.e. cisplatin, carboplatin or etoposide, were antagonistic when combined with docetaxel. We conclude that combinations of docetaxel with either -retinoic acid or vinorelbine may offer an enhanced cytotoxic effect in the management of hormone-refractory prostate cancer and need to be evaluated for therapeutic effect. The combination of docetaxel with an anthracycline was also synergistic in the two hormone-refractory cell lines, DU 145 and PC3, thus suggesting a potential role in advanced disease after endocrine failure. Combinations of docetaxel with platinum or etoposide may lead to subadditive effects in treatment.

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