Effect of the interval between exposures to cytarabine on its cytotoxic action on HL-60 myeloid leukemic cells.

As an in vitro model for the chemotherapy of acute myeloid leukemia with cytarabine (ARA-C), the cytotoxicity of this drug was investigated using a human promyelocytic cell line (HL-60) and different drug schedules. The continuous exposure to ARA-C was shown to be more cytotoxic than the intermittent exposures at identical concentrations or under conditions where the concentrations multiplied by time of exposure were the same. In a comparison of exposures, as the intervals between drug exposures were reduced, the cytotoxicity of ARA-C increased. Flow microfluorometric analysis of DNA content showed that a 3-hour exposure to ARA-C every 6 hours produced a greater accumulation of cells in S phase than the same exposure repeated every 12 hours. After a 3-hour exposure to 20 micrograms/ml of ARA-C, the cells recovered 38% and 85% of their capacity to synthesize DNA within 4 and 8 hours, respectively. These findings can be explained in part by the short half-life of the intracellular nucleotide pool of ARA-CTP in these cells (about 60 minutes). These data indicate that when there is a prolongation of the interval between exposures to ARA-C, a greater fraction of cells recover from the inhibitory effects of this drug and escape its cytotoxic action. These observations may be important with respect to the design of more optimal schedules of high-dose ARA-C therapy for the treatment of patients with acute leukemia.