Pyrazofurin (PF), a C-nucleoside which inhibits pyrimidine biosynthesis, is being tested clinically as an anticancer agent. Pyrazofurin 5′-monophosphate (PF-PO4), the active metabolite of PF, has a structural resemblance to 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranosyl 5′-monophosphate (AICAR), a nucleotide intermediate in the biosynthesis of purines. Because of this structural similarity, the effects of PF and PF-PO4 on AICAR formyltransferase and purine synthesis were studied.

PF-PO4 inhibited AICAR formyltransferase in rat liver supernatants 46, 69, and 89% at concentrations of 0.2, 0.4, and 1 mm, respectively. The K1 for AICAR formyltransferase by PF-PO4 was 3 × 10-5m. AICAR formyltransferase was inhibited 32% by 2 mm PF when ATP (20 mm) and MgCl2 (20 mm) were present, but 2 mm PF alone did not inhibit AICAR formyltransferase.

The inhibition of AICAR formyltransferase in vivo should result in a buildup of AICAR and a subsequent increase in the urinary excretion of 5-aminoimidazole-4-carboxamide (AIC), which is the normal urinary degradation product of AICAR. Male Sprague-Dawley rats given single i.p. doses of PF at 7.5, 10, or 30 mg/kg showed increased urinary excretions of AIC as the dose of PF was increased. A single dose of 10 mg/kg resulted in a 64% increase in the amount of urinary AIC (41 µg/day for the treated rats versus 25 µg/day for the untreated rats). A higher dose of 30 mg/kg resulted in a 233% increase in the urinary AIC (70 µg/day for the treated rats versus 21 µg/day for the untreated rats).

PF has a unique ability to inhibit the de novo biosynthesis of both purine and pyrimidine nucleotides.

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Presented in part at the 69th Annual Meeting of the American Association for Cancer Research in Washington, D. C., April 1978 (34).

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