Selenium compounds prevent the induction of drug resistance by cisplatin in human ovarian tumor xenografts in vivo

Abstract

Purpose: The development of drug resistance is a major cause for the failure of chemotherapy, particularly in ovarian cancer. Most previous research has focused on approaches to reverse drug resistance once it has arisen, that is, on the use of agents which can make drug-resistant tumors more sensitive to chemotherapy. We have suggested the feasibility of an alternative approach: the use of specific agents to prevent the development of resistance. Methods: We designed an in vivo system to assay for the ability of compounds to prevent the induction of resistance by cisplatin. In this system, mice bearing tumors (which originated from A2780 human ovarian tumor cells) were treated with a low dose (2.6 mg/kg) of cisplatin and the tumors rapidly developed resistance to subsequent cisplatin treatment. Cell lines initiated from these tumors retained the resistant phenotype even after several months in culture. Results: When either selenite or selenomethionine were administered (i.p., 1.5 mg/kg) close to the time of the initial cisplatin treatment, the induction of resistance was prevented. Similar treatments with sulfite or methionine had no effect on the induction of resistance by cisplatin. Studies in cells from treated tumors have indicated that the selenium compounds may prevent the induction of resistance by preventing a cisplatin-induced increase in glutathione level. Conclusions: Selenium compounds specifically prevent the induction by cisplatin of drug resistance in human ovarian tumors in vivo.