Increased schedule-dependent synergism of vindesine versus vincristine in combination with methotrexate against L1210 leukemia.

BD2F1 mice were inoculated ip with 10(6) 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 five doses were given or death occurred. Methotrexate (48 or 72 mg/kg ip) produced a 199% and a 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 ip) or vindesine (0.5-1.5 mg/kg ip) 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 two agents. However, none of the trials employing single-agent therapy or simultaneous combination therapy produced long-term survivors (greater than or equal to 90 days after therapy). When either vinca alkaloid was given 24 hours 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 hours after methotrexate, the regimen was still synergistic, but the overall effect was less than with a 24-hour delay. When two doses of either vinca alkaloid were injected at 24 and 72 hours 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.