In this study therapeutic synergism was observed in combination chemotherapy of leukemia L5178Y with L-asparaginase (A-Ase) plus methotrexate (MTX) over a variety of treatment schedules. Therapeutic synergism occurred when a single dose of A-Ase was followed at varying times (immediately or up to 6 hr later) by daily treatment with MTX. It was also observed when daily treatment with MTX was initiated just prior to or up to 6 hr before a single treatment with A-Ase. Similarly, increases in survival time were observed in leukemic mice when daily treatment with MTX was initiated 4 days prior to a single dose of A-Ase on Day 7. In one instance, the occurrence of therapeutic synergism was dependent upon the sequence of drug administration. Whereas therapeutic synergism was observed when mice bearing L5178Y leukemia were given 5 daily treatments of MTX followed 3 days later by 5 daily treatments of A-Ase; it did not occur when A-Ase preceded MTX on the same schedule. Treatment with MTX was found to be equally effective against leukemia L5178Y and its A-Ase-resistant line.

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These studies supported in part by Contract NO1-CM-33728 with Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Md. 20014.

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