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Schedule-dependent Synergy and Antagonism between High-Dose 1-ß-D-Arabinofuranosylcytosine and Asparaginase in the L5178Y Murine Leukemia¹

North Carolina Memorial Hospital and Department of Medicine and Pharmacology, University of North Carolina School of Medicine, Chapel Hill, North Carolina 27514

The effect of schedule of drug administration on the biochemical and therapeutic effects of the combination of 1-ß-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 10⁶ 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.

¹ This work was supported by Grant CH-35C from the American Cancer Society. Presented in part at the 68th Annual Meeting of the American Association for Cancer Research, Inc. (34).

² To whom requests for reprints should be addressed, at Division of Hematology/Oncology, University of North Carolina School of Medicine, Chapel Hill, N.C. 27514.

Received 8/10/81. Accepted 3/ 9/82.