Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors.
Potentiation of temozolomide-induced cytotoxicity: a comparative study of the biological effects of poly(ADP-ribose) polymerase inhibitors.
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替莫唑胺诱导的细胞毒性的增强：对聚（ADP-核糖）聚合酶抑制剂的生物学作用的比较研究。
DOI：
10.1038/bjc.1995.423
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发表时间：
1995-10
影响因子：
8.8
通讯作者：
Durkacz, B W
中科院分区：
文献类型：
--
作者：
Boulton, S;Pemberton, L C;Porteous, J K;Curtin, N J;Griffin, R J;Golding, B T;Durkacz, B W
比较了4种聚腺苷二磷酸核糖聚合酶抑制剂[3-氨基苯甲酰胺、苯甲酰胺、3，4-二氢-5-甲氧基异喹啉-1(2H)-酮(PD 128763)和8-羟基-2-甲基喹唑啉-4(3H)-酮(NU1025)]对多种生物终点的影响。评估了以下参数：它们在渗透性L1210细胞中抑制酶的能力；它们增强替莫唑胺的细胞毒性(包括化合物本身的细胞毒性)的能力；它们增加替莫唑胺诱导的DNA链断裂的净水平和抑制替莫唑胺诱导的NAD耗竭的能力。PD 128763和NU1025与PADPRP抑制剂效力相当，分别是苯甲酰胺和3-氨基苯甲酰胺的40倍和50倍。所有化合物都以浓度依赖的方式增强了替莫唑胺处理的细胞的细胞毒性并增加了DNA链断裂水平。这些化合物作为PADPRP抑制剂的效力与它们对细胞存活和DNA修复的影响之间有很好的相关性。替莫唑胺治疗导致细胞NAD水平下降，这一作用被PADPRP抑制剂消除。总而言之，新一代PADPRP抑制剂作为化学增强剂的有效性至少是3-氨基苯甲酰胺的50倍，并且可以在完整细胞中以微摩尔而不是毫摩尔的浓度使用。
Four poly(ADP-ribose) polymerase (PADPRP) inhibitors [3-aminobenzamide, benzamide, 3,4-dihydro-5-methoxyisoquinolin-1(2H)-one (PD 128763) and 8-hydroxy-2-methylquinazolin-4(3H)-one (NU1025)] were compared with respect to their effects on a number of biological end points. The following parameters were assessed: their ability to inhibit the enzyme in permeabilised L1210 cells; their ability to potentiate the cytotoxicity of temozolomide (including the cytotoxicity of the compounds per se); their ability to increase net levels of temozolomide-induced DNA strand breaks and inhibit temozolomide-induced NAD depletion. PD 128763 and NU1025 were equipotent as PADPRP inhibitors, and 40- and 50-fold more potent than benzamide and 3-aminobenzamide respectively. All the compounds acted in a concentration-dependent manner to potentiate the cytotoxicity and increase DNA strand break levels in cells treated with temozolomide. There was an excellent correlation between the potency of the compounds as PADPRP inhibitors and their effects on cell survival and DNA repair. Temozolomide treatment caused a decrease in cellular NAD levels, and this was abolished by the PADPRP inhibitors. In conclusion, the new generation of PADPRP inhibitors are at least 50-fold more effective than 3-aminobenzamide as chemopotentiators, and can be used at micromolar rather than millimolar concentrations in intact cells.