Gamma-glutamyl cysteine synthetase up-regulates glutathione and multidrug resistance-associated protein in patients with chemoresistant epithelial ovarian cancer.

Cellular detoxification, such as that mediated by the glutathione (GSH) system, is involved in the metabolism of various cytotoxic agents. Little is known, however, about the clinical relevance of cellular detoxification in chemoresistance. To elucidate the relevance of the GSH system to the resistance to chemotherapy observed in patients with ovarian cancer, we assayed the expression of mRNA encoded by the multidrug resistance-associated protein (MRP) and gamma-glutamyl cysteine synthetase (gamma-GCS) genes, as well as the level of GSH protein in 32 patients with epithelial ovarian cancer after chemotherapy. Tumors of 14 of the 32 patients responded to chemotherapy, whereas 18 did not. The levels of MRP and gamma-GCS transcripts in tumors from nonresponders were each about 2-fold higher than in responders. In contrast, the level of GSH did not differ between the two groups. We observed coordinated expression of gamma-GCS mRNA and GSH protein levels, and between gamma-GCS and MRP in nonresponders, but not in responders. Expression of MRP-encoded mRNA did not correlate to GSH level, however, in either group. These results suggest that gamma-GCS may up-regulate GSH and MRP expression in tumors unresponsive to chemotherapeutic agents, and that the GSH system may be involved in the mechanism of chemoresistance in ovarian cancer.