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.