Clinical Cancer Research, Vol 4, Issue 7 1737-1741, Copyright © 1998 by American Association for Cancer Research

ARTICLES

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

J Kigawa, Y Minagawa, X Cheng and N Terakawa
Department of Obstetrics and Gynecology, Tottori University School of Medicine, Yonago, Japan.

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.

This article has been cited by other articles:

				D. Pectasides, E. Pectasides, A. Psyrri, and T. Economopoulos Treatment Issues in Clear Cell Carcinoma of the Ovary: A Different Entity? Oncologist, November 1, 2006; 11(10): 1089 - 1094. [Abstract] [Full Text] [PDF]

				M. Haber, J. Smith, S. B. Bordow, C. Flemming, S. L. Cohn, W. B. London, G. M. Marshall, and M. D. Norris Association of High-Level MRP1 Expression With Poor Clinical Outcome in a Large Prospective Study of Primary Neuroblastoma J. Clin. Oncol., April 1, 2006; 24(10): 1546 - 1553. [Abstract] [Full Text] [PDF]

				H. Tsuda, Y. M. Ito, Y. Ohashi, K.-K. Wong, Y. Hashiguchi, W. R. Welch, R. S. Berkowitz, M. J. Birrer, and S. C. Mok Identification of Overexpression and Amplification of ABCF2 in Clear Cell Ovarian Adenocarcinomas by cDNA Microarray Analyses Clin. Cancer Res., October 1, 2005; 11(19): 6880 - 6888. [Abstract] [Full Text] [PDF]

				H. Sultana, J. Kigawa, Y. Kanamori, H. Itamochi, T. Oishi, S. Sato, S. Kamazawa, M. Ohwada, M. Suzuki, and N. Terakawa Chemosensitivity and p53-Bax pathway-mediated apoptosis in patients with uterine cervical cancer Ann. Onc., February 1, 2003; 14(2): 214 - 219. [Abstract] [Full Text] [PDF]

				Y. Ohishi, Y. Oda, T. Uchiumi, H. Kobayashi, T. Hirakawa, S. Miyamoto, N. Kinukawa, H. Nakano, M. Kuwano, and M. Tsuneyoshi ATP-binding Cassette Superfamily Transporter Gene Expression in Human Primary Ovarian Carcinoma Clin. Cancer Res., December 1, 2002; 8(12): 3767 - 3775. [Abstract] [Full Text] [PDF]

				H. Itamochi, J. Kigawa, T. Sugiyama, Y. Kikuchi, M. Suzuki, and N. Terakawa Low Proliferation Activity May Be Associated With Chemoresistance in Clear Cell Carcinoma of the Ovary Obstet. Gynecol., August 1, 2002; 100(2): 281 - 287. [Abstract] [Full Text] [PDF]

				V. Vukovic, T. Nicklee, and D. W. Hedley Microregional Heterogeneity of Non-Protein Thiols in Cervical Carcinomas Assessed by Combined Use of HPLC and Fluorescence Image Analysis Clin. Cancer Res., May 1, 2000; 6(5): 1826 - 1832. [Abstract] [Full Text]

				M. Nishiyama, W. Yamamoto, J.-S. Park, R. Okamoto, H. Hanaoka, H. Takano, N. Saito, M. Matsukawa, T. Shirasaka, and M. Kurihara Low-Dose Cisplatin and 5-Fluorouracil in Combination CanRepress Increased Gene Expression of Cellular Resistance Determinants to Themselves Clin. Cancer Res., September 1, 1999; 5(9): 2620 - 2628. [Abstract] [Full Text] [PDF]