Budman Daniel R, Calabro Anthony, Kreis Willi
Don Monti Division of Oncology, North Shore University Hospital, New York University School of Medicine, Manhasset, NY 11030, USA.
Anticancer Drugs. 2002 Nov;13(10):1011-6. doi: 10.1097/00001813-200211000-00005.
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.
多西他赛等微管蛋白结合剂在激素难治性前列腺癌的治疗中具有显著的临床前和临床活性。我们之前曾使用中位效应分析来确定协同和拮抗药物组合，这些组合可能对人类疾病的治疗有价值。这些研究扩展了我们在特定前列腺癌细胞系中的发现。使用了半自动微量培养系统。多西他赛与其他18种药物联合，与DU 145、LnCaP或PC 3前列腺癌细胞系孵育72小时，然后将细胞与MTT孵育以确定细胞毒性作用。对双联和三联组合均进行了检测。对每种组合测定通过组合指数衡量的协同和拮抗作用。应用非互斥标准。在所有三种细胞系中，多西他赛与维甲酸、环孢素A和长春瑞滨显示出细胞毒性相加作用或协同作用。多西他赛与表柔比星或阿霉素联合在激素难治性DU 145和PC 3细胞系中显示出细胞毒性协同作用。相比之下，临床上用于治疗激素难治性前列腺癌的药物，即顺铂、卡铂或依托泊苷，与多西他赛联合时具有拮抗作用。我们得出结论，多西他赛与维甲酸或长春瑞滨联合在激素难治性前列腺癌的治疗中可能提供增强的细胞毒性作用，需要对其治疗效果进行评估。多西他赛与蒽环类药物联合在两种激素难治性细胞系DU 145和PC3中也具有协同作用，因此提示在内分泌衰竭后的晚期疾病中可能发挥潜在作用。多西他赛与铂或依托泊苷联合在治疗中可能导致次相加作用。
