Combined effect of cytosine arabinoside and thiopurines

Dose and time survival for leukemic colony-forming units (LCFU) and normal hematopoietic colony-forming units (NCFU) were obtained after the administration of either 6-mercaptopurine (6-MP) or 6-thioguanine (TG). Survival decreased to a plateau level with increasing doses as expected with phase-specific agents. Time survival curves demonstrated increased killing of LCFU after administration of 2 mg of 6-MP/mouse or 0.1 mg of TG/mouse reaching a minimum by 3-8 hours with repopulation therafter. Cytosine arabinoside (Ara-C) (1 mg/mouse) was combined with each agent, and the effects of sequence and interval were examined in terms of LCFU and NCFU survival. When Ara-C and either thiopurine were administered together, fractional survival was less than additive. However, as the interval was increased for either sequence and for both combinations, survival decreased to synergistic levels. Variation in dose of Ara-C and TG showed an inhibitory effect to be dependent upon the Ara-C dose. A correlation between results from the colony assay for for LCFU and survival of treated tumor-bearing mice was demonstrated for Ara-C plus TG. The results of these experiments are interpreted in terms of the proliferation kinetics of L1210 and the cellular effects of the agents; their clinical implications are discussed.