Intracavitary therapy of murine ovarian cancer with cis-diamminedichloroplatinum(II) and 10-ethyl-10-deazaaminopterin incorporating systemic leucovorin protection.
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 10(7) 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.
Sirotnak
F M
FM
Memorial Sloan-Kettering Cancer Center, New York, New York 10021.
Schmid
F A
FA
DeGraw
J I
JI
D000630:Aminopterin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D002945:Cisplatin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D002955:Leucovorin / Q000627:therapeutic use*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism
D005493:Folic Acid Antagonists; C040210:edatrexate; D000630:Aminopterin; D002945:Cisplatin; D002955:Leucovorin; D008727:Methotrexate