SCHEDULE-DEPENDENT SYNERGY AND ANTAGONISM BETWEEN HIGH-DOSE 1-BETA-D-ARABINOFURANOSYLCYTOSINE AND ASPARAGINASE IN THE L5178Y MURINE LEUKEMIA

Abstract

The effect of schedule on drug administration on the biochemical and therapeutic effects of the combination of 1-.beta.-D-arabinofuranosylcytosine (ara-C) and asparaginase was investigated in vivo and in vitro using the murine leukemia L5178Y. Treatment of cells in vitro with ara-C (10-6 M) or asparaginase (0.5 IU/ml) for 8 h resulted in 45.degree. and 24% viability, respectively; simultaneous exposure to both drugs resulted in 25% viability, a subadditive effect. Sequential 8 h in vitro treatments with asparaginase preceding ara-C or ara-C preceding asparaginase resulted in 43% and 8% viability, respectively, indicating strong schedule dependency. Recovery from drug-induced inhibition of cell growth in vivo suggested an optimal interval of 120 h. Treatment of leukemic mice with asparaginase, ara-C or both drugs simultaneously 3 days after inoculation of 106 cells resulted in mean survival times of 16, 21 and 18 days, respectively (control mean survival time, 10 days). With a 120 h interval between the 2 drugs, treatment with ara-C followed by asparaginase resulted in 20 of 24 60-day survivors. When asparaginase preceded ara-C, there was a mean survival time of only 23 days with no 60-day survivors. Maximal weight loss with either combination was only 10%. Mechanisms for the pharmacological antagonism include asparaginase-induced decreased cellular uptake and incorporation of ara-C into macromolecules. The apparent synergy is related to the timing of asparaginase treatment, the optimal therapeutic effect occurring when sequential asparaginase is administered before the cells recover from the ara-C effect. Since both drugs are probably components of antileukemic combinations, understanding of such drug-drug interactions would optimize clinical therapy.