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Pyrazofurin Inhibition of Purine Biosynthesis via 5-Aminoimidazole-4-carboxamide-1-ß-D-ribofuranosyl 5'-Monophosphate Formyltransferase¹

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

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-ß-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 x 10^-5 M. 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.

¹ Presented in part at the 69th Annual Meeting of the American Association for Cancer Research in Washington, D. C., April 1978 (34).

² To whom requests for reprints should be addressed, at Lilly Research Laboratories, MC305, Eli Lilly and Company, 307 East McCarty Street, Indianapolis, Ind. 46285.

Received 5/10/79. Accepted 1/31/80.