ENHANCEMENT OF ETOPOSIDE (VP-16) CYTOTOXICITY BY ENZYMATIC AND PHOTODYNAMICALLY INDUCED OXIDATIVE STRESS

The effects of glutathione (GSH) depletion by buthionine sulfoximane ( BSO) or by photosensitization-induced oxidative stress using metallo-p hthalocyanines (MePcS(4)) on etoposide (VP-16) cytotoxicity against K5 62 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 accompani ed by a supra-additive induction of DNA strand breaks. The proposed ro le of intracellular GSH in preventing metabolic transformations of VP- 16 and thus decreasing its toxicity was confirmed by electron spin res onance (ESR) monitoring of the accumulation of the VP-16 phenoxyl radi cal in cell cytoplasm subjected to GSH depletion. Taken together the r esults emphasize the beneficial effect of GSH-related oxidative stress in enhancement of etoposide toxicity and possibly in its anticancer a pplications.