Synergistic cytotoxicity of different alkylating agents for epithelial ovarian cancer

Alkylating agents have been used individually and in combination to treat epithelial ovarian carcinoma. In this study, the cytotoxicity of 7 alkylating agents has been measured using a serial dilution clonogenic assay. When individual agents were evaluated, markedly different activity was observed against several ovarian cancer cell lines. Among 4 cell lines tested, OVCA 432 was the most sensitive to cisplatin, thiotepa and melphalan. When alkylating agents were used in combination against OVCA 432, synergistic activity was observed with cisplatin and each of several other alkylating agents including thiotepa, melphalan, 4-hydroperoxycyclophosphamide (4HC) and carboplatin. The combination of cisplatin and thiotepa also exerted synergistic activity against the OVCA 420, 429 and 433 cell lines, but had only additive or subadditive activity against the NIH:OVCAR-3 cell line. Sequential treatment of tumor cell lines with the different alkylating agents was as effective as simultaneous treatment. Synergistic anti-tumor activity in cell culture is consistent with clinical observations that alkylating agents in combination appear more effective than single agents for treatment of advanced epithelial ovarian cancer. In addition, our study suggests that cisplatin in combination with thiotepa, 4HC or melphalan might prove useful for high-dose therapy with autologous bone-marrow support.