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.


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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