1. A study of the effects of fluorinated pyrimidines on nucleic acid biosynthesis has been carried out in suspensions of Ehrlich ascites cells incubated anaerobically with various labeled substrates. The drugs did not inhibit glycolysis.

  2. The conversion of formate-C14 into DNA thymine was inhibited in increasing order of potency by 5-fluoroorotic acid, 5-fluorouracil, 5-fluorouridine, and 5-fluoro-2′-deoxyuridine. This inhibition by 5-fluorouracil and 5-fluoroorotic acid was reversed by deoxyuridine. However, formate incorporation into nucleic acid adenine was not inhibited.

  3. In studies of permeability it was found that 5-fluorouracil was taken up by the ascites cells to a greater extent than were uracil, orotic acid, and fluoroorotic acid. 5-Fluorouridine caused an increased cellular uptake of uracil and orotic acid.

  4. The fluorinated pyrimidines did not affect the conversion of thymidine-6-H3 into DNA thymine, nor the incorporation of phosphate-P32 into DNA or RNA in these cell suspensions.

  5. The fluorinated pyrimidines inhibited the metabolic conversion of uracil-2-C14 and orotic-6-C14 acid into DNA thymine and, with the exception of 5-fluoro-2′-deoxyuridine, inhibited the incorporation of the same precursors into RNA uracil. The metabolic transformation of uracil and orotic acid into nucleic acid cytosine was not greatly affected by the drugs.

  6. 5-Fluorouracil-2-C14 was converted into 5-fluoro-2′-deoxyuridine monophosphate and was also incorporated as such into RNA in these cell suspensions.

  7. It is concluded that these fluorinated pyrimidines inhibit the metabolic methylation of deoxyuridine monophosphate to thymidine monophosphate. With the exception of 5-fluoro-2′-deoxyuridine, the compounds inhibit the conversion of pyrimidines into RNA uracil. The exact metabolic locus of this block has not yet been determined. These biochemical observations have been discussed in the light of the tumor-inhibitory properties of these drugs.

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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. A preliminary report of part of this work appeared in Fed. Proc., 16, 194, 1957, and in Abstr. Am. Chem. Soc. Meeting, p. 20C, Sept. 8–13, 1957.

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