Taxol-based combination chemotherapy and other in vivo preclinical antitumor studies

Abstract

Taxol, dissolved in cremophor/ethanol (50/50), followed by further dilution with saline, was successfully administered intravenously (IV) to mice bearing subcutaneously (SC) implanted murine Madison 109 lung carcinoma (M109), M5076 sarcoma, or seven different human tumor xenografts, including A431 vulva; A2780 ovarian; LX-1, H2981, and L2987 lung; and RCA and HCT-116 colon carcinomas. Taxol was active in all these distal site tumor models except the M5076 sarcoma. Schedule dependency and dose-response evaluations involving Taxol were studied in the SC M109 model. Taxol was given IV, and all treatments were of 7 days' duration. Each schedule was evaluated using several dose levels designed to incorporate the likely optimal (and maximum tolerated) dose(s). On the best schedule, daily injections for 7 days, Taxol exhibited a flat dose response; that is, good activity was obtained at Taxol dose levels that were only a fraction of its maximum tolerated dose. This profile provided an advantageous opportunity to evaluate Taxol-based combination chemotherapy. In a format in which Taxol was given every day on days 1 through 5, IV, and other drugs were given on days 1 and 5 (IV or intraperitoneally, IP) versus SC M109, dose titrations of each agent were evaluated singularly and in various Taxol-based combinations. The combination of Taxol plus cisplatin yielded a delay in tumor growth (17.8 days) that was minimally superior (P < .05) to the best delays caused by either drug alone (e.g., 13.5 days for Taxol); there was no enhancement of lifespan beyond that obtained using Taxol alone.(ABSTRACT TRUNCATED AT 250 WORDS)