Effects of priming dose schedules in methotrexate treatment of mouse leukemia L1210.

days after leukemic inoculation (i.p.), the animals were treated with MTX (i.p.) on a series of dose schedules. In each experiment, a number of geometrically spaced doses of MTX were used at the first treatment, and each was followed by various geometrically spaced levels of regularly scheduled MTX. For each of the schedules used, the optimal treatment consisted of a relatively high priming dose approximating the optimal single dose of MTX, followed by reduced regular doses. For the 5 schedules studied, the longest surviving group had a median survival time 2.5 to 6.0 days longer than that of the optimal group on a constant dose schedule. The results of experiments in which mice received log dilutions of LI 210 and were treated with a course of MTX, and in which treatment with MTX was terminated at varying intervals, suggest that MTX has a greater percentage of tumor cell kill at lower tumor cell populations. A cell cycle stage-specific agent such as MTX may kill a small percentage of tumor cells as the number of cells increases if there is either a corresponding decrease in growth fraction or an increase in mean generation time. In either case, a priming dose of MTX then may lower the tumor cell population sufficiently for subsequent low doses of MTX to kill more effectively.