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Effect of Inhibitors of the de Novo Pyrimidine Biosynthetic Pathway on Serum Uridine Levels in Mice

Laboratory of Chemical Pharmacology, National Cancer Institute, NIH, Bethesda, Maryland 20205

Since C57BL x DBAF₁ (hereafter called BDF₁ mice possess a relatively constant concentration of serum uridine [9.7 ± 1.3 (S.D.) nmol/ml], circulating uridine is available to cells with an intact pyrimidine salvage pathway and thus could influence the effectiveness of certain antitumor agents which inhibit de novo pyrimidine biosynthesis and whose cytotoxic properties are reversed by uridine. Three inhibitors of the de novo pyrimidine biosynthetic pathway were studied to determine their effects on circulating uridine concentrations in BDF₁ mice. Pyrazofurin and 6-azauridine were found to have no significant effect on serum uridine levels when administered as a single dose or on 4 consecutive days. In contrast, N-(phosphonacetyl)-L-aspartate reduced serum uridine levels by 55% when administered either as a single dose or on 4 consecutive days. This reduction could contribute to the antitumor effectiveness of N-(phosphonacetyl)-L-aspartate by limiting the rescue of cells possessing a salvage pathway.

D-Galactosamine, a stimulator of the de novo pyrimidine pathway, was also studied and found to increase total liver uridine (uridine plus uracil nucleotides and uridine diphosphate esters) by 4-fold at 8 hr, returning to normal by 24 to 48 hr. However, these large effects were not reflected in the serum.

¹ To whom requests for reprints should be addressed.

Received 4/20/81. Accepted 9/ 9/81.