Studies on fluorinated pyrimidines. XI. In vitro studies on tumor resistance.

Various biochemical studies have been carried out in vitro with Ehrlich ascites car cinoma 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 thy midine for DNA thymine biosynthesis, nor the incorporation of uracil or orotic acid into RNA uracil. The incorporation of formate-C'4 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 5fluorouracil into 5-fluorouridylic acid and incorporation into RNA, the amount of 5-fluoro-@'-deoxyuridine-5'-monophosphate (FUDRP) produced was equivalent in the two types of cells. In a cell-free system it was shown that thymidylate synthetase oh tamed from the susceptible cells was inhibited by FUDRP, whereas the enzyme ob tamed 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 FUDRPisnot inhibitoryin the resistantcells.