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Intracavitary Therapy of Murine Ovarian Cancer with cis-Diamminedichloroplatinum(II) and 10-Ethyl-10-deazaaminopterin Incorporating Systemic Leucovorin Protection¹

Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [F. M. S., F. A. S.], and SRI International, Menlo Park, California 94025 [J. I. D.]

Administration i.p. of 10-ethyl-10-deazaaminopterin(10EDAM) with cis-diamminedichloroplatinum(II) (cis-Pt) had significant antitumor activity against the murine ovarian tumor. This tumor is a teratoma originating in the ovary with pathogenesis and metastatic properties similar to those of human ovarian cancer. Drug was given on a schedule of once every 3 days for 3 doses 1 or 2 days after i.p. implant of 10⁷ tumor cells. Despite the 2-fold attenuation of dosage required, antitumor activity of the combination (increased life span, 161%) was approximately twice that obtained with maximum tolerated doses of either agent alone and tumor-free, long-term survivors were obtained. Incorporation of s.c. calcium leucovorin administration 16 h after each dose of 10EDAM and cis-Pt allowed a 4-fold increase in dosage of 10-EDAM without an increase in toxicity, increased median survival by an additional 120%, and quadrupled the number of tumor-free, long-term survivors to 40% of treated animals. By comparison, methotrexate was only modestly active against this tumor model either as a single agent, with cis-Pt, or with delayed s.c. calcium leucovorin administration. These results appear to suggest that 10EDAM with cis-Pt may have considerable potential for intracavitary therapy of human cancer, including ovarian carcinoma, particularly when incorporating delayed systemic calcium leucovorin administration.

¹ Supported in part by Grants CA 08748, CA 18856, CA 22764, and CA 28783 from the National Cancer Institute and the Elsa U. Pardee Foundation.

² To whom requests for reprints should be addressed, at Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021.

Received 8/15/88. Revised 2/15/89. Accepted 3/ 6/89.

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