Dual effects of pyrazofurin and 3-deazauridine upon pyrimidine and purine biosynthesis in mouse L1210 leukemia.

Abstract

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-beta-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 microM 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 microM 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.

• Authors: M E Sant, S D Lyons, A J Kemp, L K McClure, E Szabados, R I Christopherson
• Journal: Cancer research (Cancer Res) Vol. 49 Issue 10 Pg. 2645-50 (May 15 1989) ISSN: 0008-5472 [Print] United States
• PMID: 2713848 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amides
• Antibiotics, Antineoplastic
• Bicarbonates
• Purines
• Pyrazoles
• Pyrimidines
• Ribonucleosides
• 3-Deazauridine
• pyrazofurin
• Ribose
• Hydroxymethyl and Formyl Transferases
• Phosphoribosylaminoimidazolecarboxamide Formyltransferase
• Acyltransferases
• Orotidine-5'-Phosphate Decarboxylase
• Uridine

Topics

• 3-Deazauridine (pharmacology)
• Acyltransferases (antagonists & inhibitors)
• Amides
• Animals
• Antibiotics, Antineoplastic (pharmacology)
• Bicarbonates (metabolism)
• Hydroxymethyl and Formyl Transferases
• Leukemia L1210 (metabolism)
• Mice
• Orotidine-5'-Phosphate Decarboxylase (antagonists & inhibitors)
• Phosphoribosylaminoimidazolecarboxamide Formyltransferase
• Purines (biosynthesis)
• Pyrazoles
• Pyrimidines (biosynthesis)
• Ribonucleosides (pharmacology)
• Ribose
• Tumor Cells, Cultured
• Uridine (analogs & derivatives)