CELLULAR-RESISTANCE TO OXIDATIVE STRESS IS ACCOMPANIED BY RESISTANCE TO CISPLATIN - THE SIGNIFICANCE OF INCREASED CATALASE ACTIVITY AND TOTAL GLUTATHIONE IN HYDROGEN PEROXIDE-RESISTANT FIBROBLASTS

Studies designed to better understand the involvement of cellular resi stance to oxidative stress in mechanisms of cellular resistance to cis platin were undertaken using H2O2-resistant variants of the HA1 Chines e hamster fibroblast cell line. H2O2-resistant cell lines were resista nt to clonogenic inactivation mediated by cisplatin with dose modifyin g factors at 10% survival of 1.5-3.0, relative to HA1 cells. The most cisplatin resistant of these cell lines(OC5) also demonstrated fewer D NA-DNA crosslinks induced by cisplatin, relative to HA1. Since H2O2-re sistant cells contained increased catalase activity as well as total g lutathione (GSH) content, the involvement of these cellular antioxidan ts in the resistance to cisplatin toxicity was evaluated. Treatment of HA1 and H2O2-resistant cell lines (OC5, OC14) with 9 mM aminotriazole reduced catalase activity by 60-65% but had no effect on the cytotoxi city of cisplatin. In contrast, treatment with 5 mM buthionine sulfoxi mine reduced total GSH by 90% and sensitized the cells to cisplatin cy to-toxicity. Furthermore, extracellular reaction of GSH with cisplatin prior to treating HA1 cells reduced the toxicity of the compound, ind icating that this reaction is capable of participating in the detoxifi cation of cisplatin. These results indicate that cellular adaptation t o oxidative stress renders cells resistant to DNA damage as well as to cytotoxicity associated with cisplatin treatment. Furthermore, increa ses in total GSH content (but not catalase activity) appear to partial ly account for cisplatin resistance demonstrated by H2O2-resistant cel ls. (C) 1993 Wiley-Liss, Inc.