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Selective Antagonism of 5-Fluorouracil Cytotoxicity by 4-Hydroxypyrazolopyrimidine (Allopurinol) in Vitro¹

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510

Allopurinol (HPP) antagonized the growth-inhibitory activity of 5-fluorouracil (FUra) in L5178Y cells in culture as well as in a number of other murine leukemic cell lines. HPP depressed the incorporation of FUra into fluoropyrimidine nucleotides in L5178Y cells by interfering with the conversion of FUra to 5-fluorouridine 5'-phosphate; decreased concentrations of FUra nucleoside triphosphate also reduced the incorporation of FUra into RNA. HPP prevented the inhibition of deoxyuridine incorporation into DNA via thymidylate synthetase caused by FUra alone, presumably by reduction in the formation of 5-fluorodeoxyuridine 5'-phosphate. The site of HPP action consistent with these observations is inhibition of orotidylate decarboxylase resulting in the accumulation of intracellular orotate. The increased intracellular orotate is believed to compete with FUra for conversion to nucleotide form in those cells that activate FUra via an orotate phosphoribosyltransferase pathway. Further evidence for this mechanism was the finding that uridine nullified the HPP antagonism of FUra growth inhibition in L5178Y cells and prevented the accumulation of intracellular orotate caused by HPP alone.

In contrast, HPP did not reduce FUra cytotoxicity in two other cell lines, Walker 256 and HeLa, which appear to anabolize FUra via the uridine phosphorylase and uridine kinase pathway. Furthermore, other inhibitors of orotidylate decarboxylase such as oxypurinol and pyrazofurin did not antagonize FUra cytotoxicity in Walker 256 cells as had been observed with L5178Y.

¹ Supported by Grant CH68L from the American Cancer Society, Grant CA16359 from the NIH, and Fellowship CA06219 from the NIH.

² To whom requests for reprints should be addressed.

Received 12/21/78. Accepted 4/24/79.

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