Gantchev T G, Hunting D J
Department of Nuclear Medicine and Radiobiology, Faculty of Medicine, University of Sherbrooke, Quebec, Canada.
Anticancer Drugs. 1997 Feb;8(2):164-73. doi: 10.1097/00001813-199702000-00007.
The effects of glutathione (GSH) depletion by buthionine sulfoximane (BSO) or by photosensitization-induced oxidative stress using metallo-phthalocyanines (MePcS4) on etoposide (VP-16) cytotoxicity against K562 human leukemic cells were investigated. Both treatments enhanced VP-16 toxicity in a markedly synergistic way, as revealed by combination index analysis procedure. Synergistic drug interactions were accompanied by a supra-additive induction of DNA strand breaks. The proposed role of intracellular GSH in preventing metabolic transformations of VP-16 and thus decreasing its toxicity was confirmed by electron spin resonance (ESR) monitoring of the accumulation of the VP-16 phenoxyl radical in cell cytoplasm subjected to GSH depletion. Taken together the results emphasize the beneficial effect of GSH-related oxidative stress in enhancement of etoposide toxicity and possibly in its anticancer applications.
研究了丁硫氨酸亚砜胺（BSO）导致的谷胱甘肽（GSH）耗竭或使用金属酞菁（MePcS4）通过光敏化诱导氧化应激对依托泊苷（VP-16）针对K562人白血病细胞的细胞毒性的影响。如联合指数分析程序所示，两种处理均以明显协同的方式增强了VP-16的毒性。协同药物相互作用伴随着DNA链断裂的超加性诱导。通过电子自旋共振（ESR）监测GSH耗竭的细胞质中VP-16苯氧自由基的积累，证实了细胞内GSH在预防VP-16代谢转化并因此降低其毒性方面的作用。综合这些结果强调了与GSH相关的氧化应激在增强依托泊苷毒性以及可能在其抗癌应用中的有益作用。
