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We investigated the antitumor effect of 6-mercaptopurine (6-MP) and its analogs using the double grafted tumor technique. BALB/c mice were inoculated intradermally with MethA fibrosarcoma cells at the right inguinal region on day 0 (the primary tumor) and at the left on day 10 (the secondary tumor). Intraperitoneal or intra-lesional administration of 6-MP, 6-mercaptopurine riboside (6-MP-r) and 6-mercaptopurine riboside triacetate (6-MPRTA) from day 3 to 7 dose-dependently inhibited growth of the secondary tumor. Without the primary inoculation, 6-MP showed no effect on growth of the tumor inoculated on day 10, indicating that the antitumor effect of 6-MP could not be attributable to its direct antimetabolic or tumoricidal action only, and that the primary tumor inoculation is necessary for these compounds to inhibits growth of the challenging tumor. 6-MP did not inhibit the secondary MethA growth in the BALB/c (nu/nu) mouse. Both CD4+ and CD8+ T cells increased in the spleen of mice treated with 6-MP. Meanwhile, delayed-type hypersensitivity (DTH) reaction to the methylated bovine serum albumin (MBSA) antigen at the footpad was not augmented but inhibited by 6-MP-r and 6-MPRTA in both normal and tumor-bearing mice. Thus, the immunomodulatory activity of 6-MP could be observed in two opposite directions, augmentation of tumor immunity and inhibition of DTH to MBSA. This indicates that the immune mechanism and/or the type of effector cells induced in these two cell-mediated immune systems are different from each other.

Augmentation of Tumor Immunity by 6-Mercaptopurine (6-MP) and Its Analogs in the Double Grafted Tumor System in Mice.