INCREASED SCHEDULE-DEPENDENT SYNERGISM OF VINDESINE VERSUS VINCRISTINE IN COMBINATION WITH METHOTREXATE AGAINST L1210 LEUKEMIA

Abstract

BD2F1 mice were inoculated i.p. with 106 [mouse] L1210 leukemia cells and treated with vincristine or vindesine alone or in combination with methotrexate. Drug administration was begun on Day 1 and was continued every 4 days until a total of 5 doses were given or death occurred. Methotrexate (48 or 72 mg/kg i.p.) produced a 199% and 222% increase in lifespan, respectively, as compared with untreated animals (6.9 .+-. 0.5 days). When given as single agents, vincristine (0.5-1.0 mg/kg i.p.) or vindesine (0.5-1.5 mg/kg i.p.) produced between a 27% and an 88% increase in lifespan. The therapeutic benefit observed when either vinca alkaloid was used with methotrexate was schedule-dependent. With the exception of vindesine plus 72 mg/kg of methotrexate, the increase in lifespan produced by the simultaneous administration of methotrexate and either vinca alkaloid was additive. When vindesine was administered with 72 mg/kg of methotrexate, the increase in lifespan was greater than expected from an additive effect of the 2 agents. However, none of the trials employing single-agent therapy or simultaneous combination therapy produced long-term survivors (.gtoreq. 90 days after therapy). When either vinca alkaloid was given 24 h after the folate analog, the increase in lifespan was almost 100% greater than that observed when the agents were given simultaneously; moreover, long-term survivors were produced. Vindesine in combination with 48 mg/kg of methotrexate produced 10%-25% long-term survivors, as compared to 5%-7% long-term survivors obtained with vincristine. In combination with 72 mg/kg of methotrexate, vindesine produced 27%-60% long-term survivors, as compared to 10%-20% long-term survivors obtained with vincristine. When either vinca alkaloid was administered 72 h after methotrexate, the regimen was still synergistic, but the overall effect was less than with a 24 h delay. When 2 doses of either vinca alkaloid were injected at 24 and at 72 h after the folate analog, the result was either highly therapeutic or very toxic. Two doses of 0.5 mg/kg of vindesine or vincristine with 48 mg/kg of methotrexate produced 35% and 20% long-term survivors, respectively. All other regimens were toxic.