Multidrug resistance in ovarian cancer

The development of acquired resistance has limited the effectiveness of chemotherapy in the treatment of ovarian cancer. Experimental model systems were developed to study the mechanisms associated with primary resistance to chemotherapeutic agents and broad cross-resistance (multidrug resistance) which is characteristic of human ovarian cancer. Doxorubicin-resistant cell lines developed in vitro by exposure of a sensitive cell line to increasing concentrations of doxorubicin develop resistance on the basis of a decrease in drug accumulation and have increased expression of the mdr-1 gene. This gene encodes for a membrane glycoprotein and leads to a decreased drug accumulation in drug resistant cell lines. Cell lines established from patients refractory to doxorubicin-containing combinations, however, do not demonstrate a decrease in drug accumulation. Studies are in progress on the measurement of mdr-1 levels in tumors of patients undergoing treatment to determine whether agents, such as verapamil may be useful in the treatment of drug resistant gynecologic cancers. Human ovarian cancer cell lines from drug resistant patients also has been demonstrated to increase levels of glutathione. Lowering of glutathione levels with buthionine sulfoximine (BSO), which irreversibly inhibits the enzyme gamma-glutamyl cysteine synthetase, leads to a marked potentiation of the cytotoxicity of melphalan both in vitro and in vivo in a nude mouse model of human ovarian cancer. Based on those studies, BSO is undergoing toxicologic evaluation before initiation of clinical trials in drug resistant patients. Our studies demonstrate that drug resistance in human ovarian cancer is likely due to interaction of multiple factors. However, biochemical intervention in some of the key steps leading to drug resistance has been demonstrated experimentally feasible and indicates that pharmacologic reversal of drug resistance is a clinical possibility.