Dual effects of pyrazofurin and 3-deazauridine upon pyrimidine and purine biosynthesis in mouse L1210 leukemia.
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.
Sant
M E
ME
Department of Biochemistry, University of Sydney, N.S.W., Australia.
Lyons
S D
SD
Kemp
A J
AJ
McClure
L K
LK
Szabados
E
E
Christopherson
R I
RI
D015092:3-Deazauridine / Q000494:pharmacology*; D000217:Acyltransferases / Q000037:antagonists & inhibitors; D000577:Amides; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001639:Bicarbonates / Q000378:metabolism; D019877:Hydroxymethyl and Formyl Transferases; D007939:Leukemia L1210 / Q000378:metabolism*; D051379:Mice; D009964:Orotidine-5'-Phosphate Decarboxylase / Q000037:antagonists & inhibitors; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D011687:Purines / Q000096:biosynthesis*; D011720:Pyrazoles; D011743:Pyrimidines / Q000096:biosynthesis*; D012263:Ribonucleosides / Q000494:pharmacology*; D012266:Ribose; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000031:analogs & derivatives*
D000577:Amides; D000903:Antibiotics, Antineoplastic; D001639:Bicarbonates; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D012263:Ribonucleosides; D015092:3-Deazauridine; C002997:pyrazofurin; D012266:Ribose; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases; D009964:Orotidine-5'-Phosphate Decarboxylase; D014529:Uridine