Hunting D J, Gowans B J, Henderson J F
Mol Pharmacol. 1985 Aug;28(2):200-6.
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.
已测定聚（ADP - 核糖）合成抑制剂对细胞生长及核苷酸代谢若干参数的影响。在产生相似程度聚（ADP - 核糖）合成抑制作用的浓度下，3 - 乙酰氨基苯甲酰胺（1 mM）对L1210细胞生长无影响，3 - 氨基苯甲酰胺（5 mM）有轻微抑制作用，而3 - 甲氧基苯甲酰胺（5 mM）是一种强效生长抑制剂。在2小时的孵育过程中，无论细胞是否用N - 甲基 - N - 亚硝基脲处理，这些抑制剂均不影响核糖核苷酸或脱氧核糖核苷酸的浓度；然而，N - 甲基 - N - 亚硝基脲处理使dCTP浓度降低了50%。在24小时的孵育过程中，3 - 氨基苯甲酰胺和3 - 乙酰氨基苯甲酰胺不会降低用未透析或透析血清培养的细胞中的核糖核苷酸浓度。相比之下，3 - 甲氧基苯甲酰胺会使在用未透析血清培养的细胞中UTP耗竭，并使在用透析血清培养的细胞中所有嘌呤和嘧啶核糖核苷酸耗竭。3 - 氨基苯甲酰胺和3 - 乙酰氨基苯甲酰胺对次黄嘌呤向ATP和GTP的转化无影响，但略微抑制甲酸掺入ATP和GTP。3 - 甲氧基苯甲酰胺抑制次黄嘌呤和甲酸掺入嘌呤核糖核苷酸。3 - 氨基苯甲酰胺、3 - 乙酰氨基苯甲酰胺和3 - 甲氧基苯甲酰胺均抑制甘氨酸掺入ATP和GTP，并降低胸苷掺入DNA的量以及dTTP池的表观比活性。我们得出结论，聚（ADP - 核糖）合成的抑制几乎不会引起生长抑制，对嘌呤或嘧啶核苷酸的从头合成也无影响。所有抑制剂对甘氨酸和甲酸代谢的影响可能与ADP - 核糖合成的抑制有关，也可能是抑制剂的次要作用。3 - 甲氧基苯甲酰胺引起的生长抑制和核苷酸浓度降低显然是该药物的次要作用，可能是由于磷酸核糖焦磷酸合成受到抑制所致。
