The effects of 5-fluorouracil and 5-fluoroorotic acid on nucleic acid biosynthesis in livers, spleens, and Ehrlich ascites carcinoma cells have been studied in vivo in mice
These drugs inhibited the conversion of uracil-2-C14 and orotic-6-C14 acid into DNA thymine, RNA uracil, and, to a lesser extent, into nucleic acid cytosine. The inhibition was usually greater in spleen and ascites tumor cells than in liver.
The conversion of formate-C14 into the methyl group of DNA thymine in spleen and tumor was completely inhibited by 5-fluorouracil and 5-fluoroorotic acid. In vivo dose-response curves in this reaction indicated that there was some selective action of fluorinated pyrimidines on the tumor cells. 5-fluorouridine and 5-fluoro-2′-deoxyuridine were more potent inhibitors of this reaction than the free fluorinated pyrimidine bases.
The incorporation of phosphate-P32 into DNA was inhibited by 5-fluorouracil and 5-fluoroorotic acid. However, these compounds were ineffective in blocking the conversion of labeled thymidine into DNA thymine. This is further evidence that the drugs block the reaction involving the formation of the methyl group of DNA thymine.
This work was supported in part by a grant-in-aid of the Wisconsin Division of the American Cancer Society; a grant, C-2832, from the National Cancer Institute, National Institutes of Health, U.S. Public Health Service; and by a grant-in-aid from Hoffmann-Laroche, Inc. Preliminary reports of part of this work appeared in Fed. Proc., 16, 194, 1957, and Abstr. Am. Chem. Soc. Meeting, Sept. 8–13, p. 20C, 1957.