Studies on the Suppression of the Homograft Response With Folic Acid Antagonists

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Abstract
Leukemia L1210 and antifolic-resistant variants M46R, M66-3R, and C82R were transplanted into incompatible strains of mice. In each foreign strain the tumor usually grew and regressed in typical homograft response. Surviving mice were resistant to challenge with the sensitive or resistant variant. The homograft response evidenced with the resistant tumors could be suppressed by administration of antifolics. In such case, treatment resulted in progressive tumor growth and death. The extent of suppression of homograft response appeared to be related to drug dosage. However, the antifolics did not interfere as readily with the induction of host immunity. Also, once immunity was established, it was not readily suppressed by antifolics. Antifolic treatment, which abrogated the homograft response to resistant leukemia, failed to interfere with the ability of an inoculum of sensitive L1210 or spleen to make the mice immune to reinoculation. Survivors of resistant as well as sensitive L1210 were obtained with delayed administration of antagonist and were immune to reinoculation. Doses of antifolic too low to overcome the homograft response with resistant variants failed to interfere with the development of immunity. Sufficiently extensive treatment with antifolics may interfere to some extent with the ability of normal or sensitive leukemic spleen to immunize incompatible strains of mice. It may even interfere somewhat with already established immunity. Suppression of the homograft response may not occur if a more effective folic acid antagonist is used. Instead, inhibition of tumor growth may result. The results are discussed with reference to therapy with antifolics.