Specificity of inhibitors of poly(ADP-ribose) synthesis. Effects on nucleotide metabolism in cultured cells.
The effects of inhibitors of poly(ADP-ribose) synthesis on cell growth and several parameters of nucleotide metabolism have been determined. At concentrations which produced similar inhibitions of poly(ADP-ribose) synthesis, 3-acetylaminobenzamide (1 mM) had no effect on L1210 cell growth, 3-aminobenzamide (5mM) was slightly inhibitory and 3-methoxybenzamide (5 mM) was a potent inhibitor of growth. During a 2-h incubation, none of the inhibitors affected ribo- or deoxyribonucleotide concentrations in cells treated with or without N-methyl-N-nitrosourea; however, N-methyl-N-nitrosourea treatment reduced dCTP concentrations by 50%. During a 24-hr incubation, 3-aminobenzamide and 3-acetylaminobenzamide did not lower ribonucleotide concentrations in cells grown with either undialyzed or dialyzed serum. In contrast, 3-methoxybenzamide caused a depletion of UTP in cells grown with undialyzed serum and caused a depletion of all purine and pyrimidine ribonucleotides in cells grown with dialyzed serum. 3-Aminobenzamide and 3-acetylaminobenzamide had no effect on the conversion of hypoxanthine to ATP and GTP but did slightly inhibit incorporation of formate into ATP and GTP. 3-Methoxybenzamide inhibited incorporation of both hypoxanthine and formate into purine ribonucleotides. 3-Aminobenzamide, 3-acetylaminobenzamide, and 3-methoxybenzamide all inhibited glycine incorporation into ATP and GTP and reduced both the incorporation of thymidine into DNA and the apparent specific activity of the dTTP pool. We conclude that inhibition of poly(ADP-ribose) synthesis causes little or no growth inhibition and has no effect on purine or pyrimidine nucleotide synthesis de novo. The effect of all the inhibitors on glycine and formate metabolism may be related to an inhibition of ADP-ribose synthesis or may be a secondary effect of the inhibitors. The growth inhibition and the reduction in nucleotide concentration caused by 3-methoxybenzamide are apparently secondary effects of this drug and may result from an inhibition of phosphoribosyl pyrophosphate synthesis.
Hunting
D J
DJ
Gowans
B J
BJ
Henderson
J F
JF
D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D006224:Cricetinae; D004247:DNA / Q000096:biosynthesis; D003854:Deoxyribonucleotides / Q000378:metabolism*; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D009702:Nucleoside Diphosphate Sugars / Q000096:biosynthesis*; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012265:Ribonucleotides / Q000378:metabolism*
D001549:Benzamides; D003854:Deoxyribonucleotides; D009702:Nucleoside Diphosphate Sugars; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012265:Ribonucleotides; D009243:NAD; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; D008770:Methylnitrosourea; C024785:5-methylnicotinamide; C025160:3-aminobenzamide; D004247:DNA; D009244:NAD+ Nucleosidase; C025159:3-methoxybenzamide