Molecular Pharmacology, Vol 5, 481-486, Copyright © 1969 by the American Society for Pharmacology and Experimental Therapeutics

Metabolism of Uracil and 5-Fluorouracil in P388 Murine Leukemia Cells

¹ Department of Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14620, and Laboratories of Pharmacology, Children's Cancer Research Foundations, Boston, Massachusetts 02115

The drug 5-fluorouracil shows a high degree of antitumor activity against both the P388 murine leukemia and the P388/38280 subline. Although previous studies had shown that the capacity of cell lines to convert 5-fluorouracil to its nucleotides in vitro was a major determinant of drug responsiveness, the P388/38280 cell line had a very low capacity for this conversion. Moreover, conversion of uracil to nucleotides could not be detected in P388/38280 cells. Enzymatic studies showed that P388/38280 cells have a very low level of uridine phosphorylase (EC 2.4.2.3) activity. In both P388 and P388/38280 cells, however, pyrimidine 5'-phosphoribosyltransferase activity could be demonstrated. The latter enzyme catalyzes the formation of 5-fluorouridylic acid from 5-fluorouracil and 5-phosphoribosyl 1-pyrophosphate. Uracil was a very poor substrate for the transferase. These data suggest that the total capacity of tumor cells for 5-fluorouracil nucleotide formation is not necessarily the major determinant of drug responsiveness.