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
✍ Scribed by Douglas R. Spitz; John W. Phillips; Donna T. Adams; C. Michael Sherman; Dennis F. Deen; Gloria C. Li
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- English
- Weight
- 847 KB
- Volume
- 156
- Category
- Article
- ISSN
- 0021-9541
No coin nor oath required. For personal study only.
✦ Synopsis
Studies designed to better understand the involvement of cellular resistance to oxidative stress in mechanisms of cellular resistance to cisplatin were undertaken using H,O,-resistant variants of the HA1 Chinese hamster fibroblast cell line. H,O,-resistant cell lines were resistant to clonogenic inactivation mediated by cisplatin with dose modifying 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 DNA-DNA crosslinks induced by cisplatin, relative to HA1. Since H,O,-resistant cells contained increased catalase activity as well as total glutathione (GSH) content, the involvement of these cellular antioxidants in the resistance to cisplatin toxicity was evaluated. Treatment of HA1 and H,O,-resistant cell lines (OC5, OC14) with 9 m M aminotriazole reduced catalase activity by 60-65% but had no effect on the cytotoxicity of cisplatin. In contrast, treatment with 5 rnM buthionine sulfoximine reduced total GSH by 90% and sensitized the cells to cisplatin cytotoxicity. Furthermore, extracellular reaction of GSH with cisplatin prior to treating HA1 cells reduced the toxicity of the compound, indicating that this reaction is capable of participating i n the detoxification of cisplatin. These results indicate that cellular adaptation to oxidative stress renders cells resistant to DNA damage as well as to cytotoxicity associated with cisplatin treatment.