Arundel-Suto C M, Scavone S V, Turner W R, Suto M J, Sebolt-Leopold J S
Department of Biological Chemistry, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Radiat Res. 1991 Jun;126(3):367-71.
The modifying effects of PD 128763 (3,4-dihydro-5-methyl-1(2H)-isoquinolinone), a potent inhibitor of poly(adenosine-diphosphate (ADP)-ribose) polymerase, on radiation-induced cell killing were examined in Chinese hamster V79 cells. This compound has an IC50 value against the purified enzyme approximately 50X lower than 3-aminobenzamide (3-AB), a widely used specific inhibitor of the enzyme. Exposure of exponentially growing cells to a noncytotoxic concentration (0.5 mM) of PD 128763 for 2 h immediately following X irradiation increased their radiation sensitivity, modifying both the shoulder and the slope of the survival curve. When recovery from sublethal damage and potentially lethal damage was examined in exponential and plateau-phase cells, respectively, postirradiation incubation with 0.5 mM PD 128763 was found not only to inhibit both these processes fully, but also to enhance further the level of radiation-induced cell killing. This is in contrast to the slight effect seen with the less potent inhibitor, 3-AB. The results presented suggest that the mechanism of radiosensitization by PD 128763 is related to the potent inhibition of poly(ADP-ribose) polymerase by this compound.
在中华仓鼠V79细胞中，研究了聚（二磷酸腺苷（ADP）-核糖）聚合酶的强效抑制剂PD 128763（3,4-二氢-5-甲基-1（2H）-异喹啉酮）对辐射诱导细胞杀伤的修饰作用。该化合物对纯化酶的IC50值比广泛使用的该酶特异性抑制剂3-氨基苯甲酰胺（3-AB）低约50倍。在X射线照射后立即将指数生长的细胞暴露于非细胞毒性浓度（0.5 mM）的PD 128763中2小时，可提高其辐射敏感性，改变存活曲线的肩部和斜率。当分别在指数期和平稳期细胞中检测亚致死损伤和潜在致死损伤的恢复情况时，发现用0.5 mM PD 128763进行照射后孵育不仅能完全抑制这两个过程，还能进一步提高辐射诱导的细胞杀伤水平。这与效力较弱的抑制剂3-AB所产生的轻微效果形成对比。所呈现的结果表明，PD 128763的放射增敏机制与该化合物对聚（ADP-核糖）聚合酶的强效抑制作用有关。
