Schedule-dependent synergy and antagonism between high-dose 1-beta-D-arabinofuranosylcytosine and asparaginase in the L5178Y murine leukemia.
The effect of schedule of 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 either ara-C (10(-6) M) or asparaginase (0.5 IU/ml) for 8 hr resulted in 45 and 24% viability, respectively; simultaneous exposure to both drugs resulted in 25% viability, a subadditive effect. Sequential 8-hr 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 hr. Treatment of leukemic mice with asparaginase, ara-C, or both drugs simultaneously 3 days after inoculation of 10(6) cells resulted in mean survival times of 16, 21, and 18 days, respectively (control mean survival time, 10 days). With a 120-hr interval between the two drugs, treatment with ara-C followed by asparaginase resulted in 20 of 24 sixty-day survivors. In contrast, 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 probable components of antileukemic combinations, understanding of such drug-drug interactions would optimize clinical therapy.
D000818:Animals; D001215:Asparaginase / Q000008:administration & dosage* / Q000627:therapeutic use; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003561:Cytarabine / Q000008:administration & dosage* / Q000378:metabolism / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004336:Drug Antagonism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D007700:Kinetics; D007940:Leukemia L5178 / Q000188:drug therapy*; D007942:Leukemia, Experimental / Q000188:drug therapy*; D051379:Mice; D008940:Mitotic Index / Q000187:drug effects
D003561:Cytarabine; D001215:Asparaginase