Various biochemical studies have been carried out in vitro with Ehrlich ascites carcinoma cells susceptible and resistant to fluorinated pyrimidines. There is no major difference between the two cell lines with respect to the utilization of formate or thymidine for DNA thymine biosynthesis, nor the incorporation of uracil or orotic acid into RNA uracil. The incorporation of formate-C14 into DNA thymine is inhibited by fluorinated pyrimidines to a considerably greater extent in the susceptible than in the resistant cells. Although in the resistant cells there is a decreased conversion of 5-fluorouracil into 5-fluorouridylic acid and incorporation into RNA, the amount of 5-fluoro-2′-deoxyuridine-5′-monophosphate (FUDRP) produced was equivalent in the two types of cells. In a cell-free system it was shown that thymidylate synthetase obtained from the susceptible cells was inhibited by FUDRP, whereas the enzyme obtained from the resistant cells was not inhibited by FUDRP. Thus, the mechanism of resistance to fluoropyrimidines in this line of the Ehrlich ascites carcinoma appears to involve the alteration of the enzyme, thymidylate synthetase, in such manner that FUDRP is not inhibitory in the resistant cells.

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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 account of part of this work appeared in Fed. Proc., 18:244, 1959. Paper X in this series is in Cancer Research, 20:897–902, 1960.

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