Metabolic effects of 6-thioguanine. II. Biosynthesis of nucleic acid purines in vivo and in vitro.

6-Thioguanine (3) has been shown to inhibit a wide spectrum of neoplasms. Its anti-tumor prop erties are markedly potentiated when combined with azaserine, an inhibitor of the synthesis de novo of purines (10, 13). One of these reports also indicated that, for maximum effect, the antimetabolites had to be administered simultaneous ly. These results suggest that thioguanine inter feres with some phase of nucleic acid purine metabolism. To investigate this possibility, a study of purine biosynthesis in the presence of 6thioguanine was made with the Ehrlich ascites carcinoma. Experiments were also carried out with the thioguanine-resistant subline of this tu mor to determine whether the resistant population differed in any phase of purine metabolism. In a preliminary report (11), thioguanine was found to inhibit the utilization of guanine-8-C14 for nucleic acid synthesis. The degree of inhibition was much greater in the sensitive ascites cells. Brown and Mandel (l) reported that thio guanine decreased the rate of uptake of formateC14into cells of the L1210 leukemia in vitro. The experiments presented here suggest that 6thioguanine produces at least three different meta bolic blocks in the area of purine biosynthesis. In hibition of the various pathways occurs to a lesser degree in the resistant tumor; this is correlated with the relatively small quantity of thioguanine in the resistant ascites cells (12).