The effect of the sequence of administration of cytoxan and methotrexate on the life-span of L1210 leukemic mice.

were treated with one dose of MTX 2 days after tumor inoculation (Day 2) and one dose of Cyt on Day 4 or 6. For each group of mice in this study there was a corresponding group that received the same doses of the drugs but for which the order of administration was reversed; i.e., Cyt was given on Day 2 and MTX was given on Day 4 or 6. When the doses of Cyt and MTX were 80 and 30 mg/kg, respectively, significantly longer survivals were noted when Cyt was administered prior to MTX. In other experiments, MTX was administered in a series of doses at 2or 4-day intervals to L1210 mice. When a high dose of Cyt (120 mg/kg) was substituted for a regularly scheduled dose of MTX, the earlier the substitution, the longer was the survival. No effect of replacement was noted when Cyt (40 mg/kg) was substituted for MTX. When a higher dose of MTX (36 mg/kg) replaced a dose of MTX (4 mg/kg), earlier substitution appeared to increase survival. The advantage to therapy of a high priming dose may reflect a prior observation that the percentage kill of tumor cells of cell cycle stage-specific agents such as MTX is greater for smaller populations of tumor cells. Early administration of a high priming dose of Cyt or MTX apparently lowers the tumor cell population so that scheduled doses of MTX can kill tumor cells more effectively.