Relevance of recruitment-synchronization in the scheduling of 1-beta-D-arabinofuranosylcytosine in a slow-growing acute myeloid leukemia of the rat.

The relevance of recruitment of resting leukemic cells into cycle has been investigated in an acute myeloid leukemia of the rat (brown Norway myeloid leukemia) that, because of its slow growth rate, has been considered a good model for comparative studies. At Day 15 after transplantation, when more than 50% of the leukemic cells are nonproliferating, a single high dose of 1-ß-D-arabinofuranosylcytosine (200 mg/kg body weight) produces a block in cell proliferation followed by a synchronous recruitment of the resting population into cycle. A second dose of the drug given when most of the cells are engaged in DNA synthesis results in a very significant reduction in the tumor load. On the contrary, the reduction in the tumor load produced by an injection of 1-ß-D-arabinofuranosylcytosine when most of the recruited cells are out of S phase is not very significant. The toxicity towards the normal hemopoietic system, tested with the colony-forming units-spleen assay, is the same with the two schedules. Moreover, the mean survival time of animals treated repeatedly with the first schedule (interval, 12 hr) is prolonged to 41 days, whereas it is only 31 days with the second schedule (interval, 24 hr). If the treatment is started early in the development of the disease, when presumably no leukemic cells are in the resting state, no difference is seen between the two schedules. It is concluded that in late stages of the disease the recruitment of leukemic cells into cycle increases the antileukemic effect of 1-ß-D-arabinofuranosylcytosine without a parallel increased toxicity for the normal hemopoietic cells and that changes in kinetic parameters during the development of the disease modify the schedule dependence of the leukemic cells.