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Effect of Alkylating Agents on Meningeal Leukemia L1210 Arising in Methotrexate-treated Mice¹

Drug Evaluation Branch, Cancer Chemotherapy National Service Center, National Cancer Institute, Bethesda, Maryland

The current studies show that by extending the survival time of leukemia L1210-inoculated mice by methotrexate (MTX) therapy, the animals develop and succumb with meningeal leukemia. Continuous therapy with MTX retarded the disease in blood and spleen but did not retard the infiltration and progressive growth occurring in the brain.

Enhanced therapeutic response was achieved by combining MTX therapy with either of 2 alkylating agents, Cytoxan and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Combined MTX and Cytoxan therapy was capable of managing the leukemia of blood and spleen but was ineffective in eradicating or decreasing the leukemia that became established in the brain.

Combined MTX and BCNU therapy suppressed the leukemia of blood, spleen, and brain, resulting in greater increases in survival time and a significant number of survivors. The better therapeutic response achieved with BCNU treatment is attributable to its capacity to penetrate the blood-brain barrier.

The experimental results achieved with this model system provide evidence to explain the apparent increase during the last 15 years of the meningeal leukemia syndrome that has occurred in humans with acute leukemia and who have been treated with chemotherapeutic agents.

¹ Presented in part at the 65th Annual Meeting, American Association for Cancer Research, Chicago, Illinois, April, 1964.

Received 1/28/66.