Development of a cell kinetic approach to curative therapy of acute myelocytic leukemia in remission using the cell cycle-specific drug 1-beta-D-arabinofuranosylcytosine in a rat model.

The timing of sequentially administered antineoplastic drugs is one determinant of toxicity and therapeutic benefit. We have conducted a series of studies with 1-beta-D-arabinofuranosylcytosine (ara-C) in the rat model (Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia) for human acute myelocytic leukemia to examine the factors determining optimum timing of sequential administration of this cell cycle DNA synthesis phase-specific drug. Late-stage disease in this model is not curable with ara-C, but the maximum survival is achieved by rats given serial 2-day courses of ara-C 6 days apart. ara-C given in 2- or 4-day-interval sequences to rats with late-stage disease is more toxic and not more effective. However, Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia in early complete remission are curable with ara-C given in optimum timed sequence. In these experiments, groups of rats in early complete remission were given a 2-day course of ara-C in every-8-hr s.c. injections, and then a second 2-day course was given after 2-, 4-, 6-, 8-, 10-, or 12-day intervals. The best cure rate of rats surviving toxicity was achieved when sequentially administered 2-day courses of ara-C were given at 2- to 4-day intervals to rats in early complete remission. In the minimal residual disease state, as in late-stage disease, 2- and 4-day-interval sequencing was the most toxic. No significant number of cures of minimal residual disease could be obtained by even the maximum tolerated dose of ara-C given in longer than 6-day-interval sequences or by various continuous or intermittent schedules. The fact that the Lewis X brown Norway F1 hybrid rats bearing brown Norway myelocytic leukemia, while relatively refractory to ara-C, are curable with this drug when used in optimum timed sequence in early remission is encouraging for similar clinical trials in humans and suggests some principles for the design of such trials.