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Factors Influencing the Therapeutic Activity of L-Asparaginase (NSC 109229) in Leukemic (L5178Y) Mice¹

Microbiological Associates, Inc., Bethesda, Maryland 20014 [S. V., M. P., and V. S. W.], and Chemotherapy, National Cancer Institute, Bethesda, Maryland 20014 [A. G.]

Studies were conducted with L-asparaginase (NSC 109229), a high-molecular-weight protein, to determine factors pertaining to the host and tumor which may influence its therapeutic effectiveness in the treatment of leukemia L5178Y. Single and multiple treatment schedules with L-asparaginase were effective in increasing the survival time of mice with leukemia L5178Y. There was considerable retention of chemotherapeutic effect when the drug was administered against advanced disease. Multiple treatment schedules were not more effective than single treatments in increasing the survival time of the animals. The development of leukemic cell resistance and the immunological response of the host against the antigens of the enzyme preparation would both appear to be severely limiting factors in the treatment of the L5178Y leukemia with L-asparaginase. Leukemic cell resistance occurred following single dose administration of L-asparaginase and may account for the failure of multiple treatment schedules to elicit a greater therapeutic response than single treatment. The formation of antibody to L-asparaginase was observed in nonleukemic mice following a series of treatments. Further, L-asparaginase was rendered therapeutically ineffective in the treatment of L5178Y when the animals had received a series of pretreatment with the enzyme. In addition, treatment of leukemia L5178Y with L-asparaginase did not result in resistance of the leukemic cells in animals that had been pretreated with L-asparaginase. Although the origin of leukemic cell resistance and of host immunity to the enzyme preparation appeared to be independent phenomena, the experiments suggest that they must both be effectively controlled in order to maximize the therapeutic response to this drug.

¹ This study was supported in part by Contract PH-43-68-1283 from Chemotherapy, National Cancer Institute, NIH.

Received 11/10/69. Accepted 1/20/70.