Cellular Resistance to Oxaliplatin and Drug Accumulation Defects

Abstract

Platinum drugs are employed in a wide range of solid tumors, and represent the mainstay of the first-line therapy of ovarian carcinoma. Although cisplatin has shown efficacy in the treatment of different types of tumors including ovarian carcinoma, resistance to treatment is a major limitation. At present, one of the most clinically relevant cisplatin analogues is the mononuclear compound oxaliplatin, which has shown activity and a favorable pharmacological profile in clinical therapy. In cellular models, oxaliplatin exhibits activity in some cell lines with acquired resistance to cisplatin, whereas in other models cross-resistance with cisplatin is observed. In general, oxaliplatin and cisplatin exhibit different pattern of cytotox-icity, indicating differences in drug-DNA interaction and/or cellular response or detoxification. Thus, differences in the influx or efflux mechanisms for these drugs could contribute to their unique patterns of clinical activity and at least in part to sensitivity profiles. Impaired drug accumulation has been recognized over the years as a frequent feature of cells resistant to cisplatin and more recently as an alter ation of oxaliplatin-resistant models. The present chapter reviews recent studies on the molecular alterations of cells resistant to oxaliplatin, with particular reference to accumulation defects and will revisit recent literature in an attempt to describe a tentative picture of why resistant cells may display impaired accumulation.