Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in vivo.

In conjunction with the studies on the metabo lism and incorporation of labeled 5-fluorouracil and 5-fluoroorotic acid into RNA (2), investigations have been carried out to determine the effects of various fluorinated pyrimidine derivatives as in hibitors of nucleic acid biosynthesis. Because the fluorine atom in the pyrimidine molecule is at tached to the same carbon that bears the methyl group of thymine, it was early surmised that these compounds would block the methylation reactions leading to the metabolic formation of DNA thy mine. Preliminary evidence that this is so was presented in a report from this laboratory (12). Although there has been abundant work on the effects of antifolics, alkylating agents, azaserine, N-methylformamide, etc., on the processes of nu cleic acid biosynthesis, cf. Skipper (22), only scanty effort has been devoted to studios of the effects of purine or pyrimidine analogs on the incorporation of normal precursors into nucleic acids, such as those carried out here. In the bio chemical screening of a large series of compounds, Davidson and Freeman have demonstrated the inhibition of P32 incorporation into DNA of the 755 tumor by 6-mercaptopurine and 8-azaguanine (44); LePage and Greenlees have found that in in vitro Ehrlich ascites cells the incorporation of glycine-2-C14 into nucleic acid purines was inhib ited by 6-mercaptopurine, but not significantly by 8-azaguanine (17); Heidelberger and Keller re ported that, in slices of Flexner-Jobling carcinoma, the incorporation of formate into nucleic acid pu rines was inhibited by 6-mercaptopurine, 8-aza guanine, and 2,6-diaminopurine (15). Eidinoff has found that 5-aminouridine inhibits the incorpora-