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Dual Effects of Pyrazofurin and 3-Deazauridine upon Pyrimidine and Purine Biosynthesis in Mouse L1210 Leukemia¹

Department of Biochemistry, University of Sydney, Sydney, N.S.W., 2006, Australia

Pyrazofurin (NSC 143095) as the monophosphate derivative is a potent inhibitor of orotidine 5'-monophosphate (OMP) decarboxylase of the pyrimidine pathway and has been proposed to inhibit 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (EC 2.1.2.3) of the purine pathway (J. F. Worzalla, and M. J. Sweeney, Pyrazofurin inhibition of purine biosynthesis via 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranosyl 5'-monophosphate formyltransferase. Cancer Res., 40: 1482–1485, 1980). Measurement of levels of pyrimidine and purine intermediates in cultured mouse L1210 leukemia cells has shown that 25 µM pyrazofurin induces an 8-fold accumulation of OMP and large accumulations of intermediates proximal to the blockade with abrupt decreases in uridine and cytidine nucleotides. Considerable increases in the cellular concentrations of N-succino-AICAR (SAICAR), AICAR, 5-formamidoimidazole-4-carboxamide ribotide (FAICAR), IMP, XMP, and GMP at later times indicate that AICAR transformylase is not significantly inhibited in cultured cells; rather the purine pathway and the GMP branch are stimulated. However, addition of 25 µM 3-deazauridine (NSC 126849) to leukemia cells did result in inhibition of AICAR transformylase: AICAR and SAICAR accumulated, IMP disappeared and there was a large accumulation of guanosine nucleotides. Blockade of pyrimidine biosynthesis by derivatives of pyrazofurin or 3-deazauridine spares 5-phosphoribosyl-1-pyrophosphate and L-glutamine, elevated concentrations of which may stimulate initial reactions of purine biosynthesis and the reaction XMP GMP.

¹ This work was supported by Grant A08415281 from the Australian Research Council and Grants AI 183 and AK 123 from the Utah Foundation for HPLC detectors.

² Supported by a postgraduate scholarship from the Anti-Cancer Council of Victoria.

³ To whom requests for reprints should be addressed.

Received 9/23/88. Revised 1/18/89. Accepted 2/13/89.