The biochemical activity of 6-azauridine: interference with pyrimidine metabolism in transplantable mouse tumors.

Previous work has shown that the asymmetric triazine analogue of uridine, 6-azauracil riboside (azauridine), is a much more potent inhibitor of the growth of transplantable mouse tumors than is 6-azauracil (1,2). Presumably this difference in activity reflects the limited extent of the conversion of azauracil to azauridine in mammalian systems (3). On the other hand, formation of the 5’-phosphate ester from the ribonucleoside is rapid in neoplastic and normal tissues (4, 5). No polyphosphates of azauridine have been detected in such systems. Two areas of pyrimidine metabolism have been postulated as the primary sites of action of azauridine or its metabolites. Elion et al. (6) have considered azauracil or its ribonucleoside to be antagonists of uracil anabolism, presumably at some stage between uracil and UTP. In support of this hypothesis, gkoda and Sorm (7) have demonstrated that azauridine competes to some extent with uridine as a substrate for the uridine kinase of Escherichia coli B. The nature of the other site of action is based on the observed accumulation of orotidine in certain tumors of animals which have received azauridine (8). This would indicate an interference with the metabolism of erotic acid, rather than of uracil. Furthermore, incorporation of erotic acid into the nucleic acids of L-5178-Y lymphoma and adenocarcinoma-755 in mice was depressed by azauridine; uridine incorporation was unaffected. When a particle-free supernatant fraction of tumor was incubated with erotic acid in the presence of azauridine, orotidine 5’-phosphate (orotidylic acid) accumulated, whereas the metabolism of neither uracil nor uridine was altered by azauridine or azauracil (5). Consistent with an interference in erotic acid metabolism was the isolation of erotic acid and orotidine from the urine of animals treated with azauracil or its ribonucleoside by Habermann and 8orm (4). The present paper details the nature of the biochemical effects observed and previously reported in preliminary notes