Schedule-dependent synergism of methotrexate and vincristine against murine L1210 leukemia

BD2F1 mice were inoculated with 10(6) L1210 murine lymphocytic leukemia cells and treated simultaneously with methotrexate and vincristine or with methotrexate followed by vincristine greater than or equal to 24 hours later. Four to six doses of methotrexate, 48 mg/kg ip, administered every 4 days beginning on Day 1 resulted in a 168%-228% increase in lifespan, while vincristine, at 0.5 mg/kg ip, given on the same schedule until death (two or three doses) gave only a 37% increase in lifespan. Simultaneous administration of both agents resulted in a therapeutic effect which was approximately additive. When vincristine was given 24 hours or 24 and 72 hours after the methotrexate, a further increase (70%-100%) in lifespan over that expected from an additive effect and long-term survivors (greater than 90 days) were obtained. Synergism between the two agents and long-term survivors were also seen with higher methotrexate concentrations (72 or 96 mg/kg) given in four or five courses. If therapy was initiated on Day 2 when the peritoneal tumor burden was approximately 2 x 10(7) cells, the combination of methotrexate with delayed vincristine still resulted in an increased therapeutic effect over that obtained with either drug alone, or that expected on an additive basis.