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Potentiation of Taxol Efficacy by Discodermolide in Ovarian Carcinoma Xenograft-Bearing Mice

Authors' Affiliations: ¹ Department of Molecular Pharmacology, Albert Einstein College of Medicine; ² Department of Obstetrics, Gynecology, and Women's Health, Division of Gynecologic Oncology; ³ Department of Medicine, Division of Medical Oncology, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, New York; and ⁴ Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania

Requests for reprints: Susan Band Horwitz, Department of Molecular Pharmacology, Albert Einstein College of Medicine, Golding 201, 1300 Morris Park Avenue, Bronx, NY 10461. Phone: 718-430-2163; Fax: 718-430-8959; E-mail: shorwitz{at}aecom.yu.edu.

Purpose: To evaluate the drug combination of discodermolide and Taxol in human ovarian cancer cells and in an in vivo model of ovarian carcinoma.

Experimental Design: The combination index method was used to evaluate the interaction of Taxol and discodermolide in human ovarian SKOV-3 carcinoma cells. Data were correlated with alterations in cell cycle distribution and caspase activation. In addition, SKOV-3 xenograft-bearing mice were treated with either Taxol, discodermolide, or a combination of both drugs given concurrently to evaluate the antitumor efficacy and toxicity of this combination. The Matrigel plug assay and CD31 immunohistochemistry were done to assess antiangiogenic effects.

Results: Taxol and discodermolide interact synergistically over a range of concentrations and molar ratios that cause drug-induced aneuploidy in ovarian carcinoma cells. In SKOV-3 xenograft-bearing mice, the combination is significantly superior to either single agent, and induces tumor regressions without notable toxicities. Immunohistochemical analysis of CD31 and Matrigel plug analysis show decreased vessel formation in mice treated with the combination relative to either drug alone.

Conclusions: The synergistic activity of Taxol and discodermolide in cells is most potent at drug concentrations that result in drug-induced aneuploidy rather than mitotic arrest. Moreover, in an animal model of ovarian carcinoma, this is a well-tolerated combination that induces tumor regressions and suppresses angiogenesis. These data confirm the potency of this combination and support the use of concurrent low doses of Taxol and discodermolide for potential use in cancer therapeutics.

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				T. H. Davis Profile of Susan Band Horwitz PNAS, July 5, 2006; 103(27): 10163 - 10165. [Full Text] [PDF]