Immunosuppressive and antitumor activity of periodate oxidation product of beta-D-ribosyl-6-methylthiopurine.

Abstract

The periodate oxidation product of β-d-ribosyl-6-methylthiopurine (6MeMPR-OP) was prepared and tested for immune suppressive and antileukemic activity. The results showed that 6MeMPR-OP had significant activity, both in suppressing the rejection of skin grafts in mice and in prolonging the life of mice bearing an L1210 line resistant to 6-mercaptopurine (L1210/MP). On a comparative basis, 6MeMPR-OP was found to be less toxic than 6MeMPR toward the AKR mice used in the skin graft studies. 6MeMPR-OP had little or no effect on the production of hemagglutinin titers in AKR mice, whereas 6MeMPR depressed hemagglutinin titers. In vitro experiments with spleen cell preparations revealed that the utilization of glycine for protein synthesis was the more sensitive area of inhibition by 6MeMPR-OP. In vivo studies with L1210/MP ascites tumor cells showed that 6MeMPR-OP not only inhibited the utilization of glycine, 4-amino-5-imidazole carboxamide (AIC), and adenine for RNA and DNA synthesis but also inhibited the utilization of glycine, lysine, and glutamic acid for protein synthesis, an effect not found with 6MeMPR. In vitro experiments with L1210/MP cells showed that 6MeMPR was a strong “feedback” inhibitor of de novo purine synthesis; this correlated with the observed lack of inhibition of the in vivo utilization of AIC and adenine but complete inhibition of glycine utilization. “Feedback” studies with 6MeMPR-OP were compromised by an as yet undefined interaction with the glycine-2-14C used as the tracer.