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Sequence-dependent Synergistic Cytotoxicity of Ecteinascidin-743 and Paclitaxel in Human Breast Cancer Cell Lines in Vitro and in Vivo¹

Program of Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [N. T., W. L., D. B., Y. G., Y. W-T., T-C. C., K. W. S., J. R. B.]; Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [N. T., M. F. B.]; and Department of Surgery, The Jikei University School of Medicine, Minato-ku, Tokyo 105-8461, Japan [N. T.]

Ecteinascidin 743 (ET-743) is a potent antitumor agent from the Caribbean tunicate Ecteinascidia turbinata and is presently in clinical trials for human cancers. The aim of this study was to assess the nature of the interaction between ET-743 and other antineoplastic agents using the combination index method of Chou and Talalay to better understand how ET-743 might be used clinically. We examined the cytotoxic effect of ET-743 combined with six other antineoplastic agents on human breast cancer cell lines, MX-1, MCF7, and P-glycoprotein overexpressing MCF7/DXR to different schedules. Pretreatment with paclitaxel for 24 h before ET-743 was the most effective combination regimen in all three breast cancer cell lines. Furthermore, sequential treatment with paclitaxel followed by ET-743 increased the antitumor effects in nude mice bearing MX-1 mammary carcinoma xenografts without increasing toxicity. These results suggest that the combination of ET-743 and paclitaxel should be assessed in clinical trials for the treatment of breast cancer.

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