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Molecular Pharmacology, Vol 15, 357-366, Copyright © 1979 by the American Society for Pharmacology and Experimental Therapeutics

Metabolism of 5-Fluorouracil in Cultured Cells. Protection from 5-Fluorouracil Cytotoxicity by Purines

BUDDY ULLMAN 1 and JAN KIRSCH 1

1 Division of Medical Genetics, Department of Medicine and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94143

The metabolic reactions leading to cytotoxicity of 5-fluorouracil (FUra) were examined in cultured mouse T-cell lymphoma cells. FUra is phosphoribosylated by orotic acid phosphoribosyl transferase, the second to last enzyme in de novo pyrimidine biosynthesis. Mutants with altered capacities to phosphoribosylate orotic acid in vitro have similarly altered capacities to phosphoribosylate FUra in vivo and in vitro. The sensitivity of these mutant lymphoma cell lines to FUra is momotonically related to their capacity to phosphoribosylate FUra. This phosphoribosylation requires pyrophosphoribosyl phosphate, an intracellular metabolite whose concentration can be regulated in vivo. Purines, which lower the concentration of pyrophosphoribosyl phosphate in cultures of wild type cells, can protect these cells from FUra toxicity. Conversely, purines that do not affect intracellular pyrophosphoribosyl phosphate content do not affect FUra mediated growth inhibition and cytotoxicity. This protection from FUra toxicity by purines requires the presence of the appropriate purine salvage enzymes. Analogous observations with purines on FUra cytotoxicity were made in other cell lines from rat, mouse, and marmoset, indicating that the metabolic activation of FUra by phosphoribosylation may be prevalent.

Note:
ACKNOWLEDGMENTS We thank Ms. Barbara Levinson, Dr. Lorraine J. Gudas, Dr. David W. Martin, Jr., Dr. Daniel V. Santi, Dr. Hibbard E. Williams and Dr. Wendy Washtien for helpful suggestions and discussions during this work.

Submitted on July 20, 1978
Accepted on October 16, 1978




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[Abstract] [Full Text]


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