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Godwin AK , Meister A , O'Dwyer PJ , Chin Shiou Huang , Hamilton TC , Anderson ME
High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis
Proceedings of the National Academy of Sciences of the United States of America. 1992 ;89(7) :3070-3074
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Abstract
Exposure of human ovarian tumor cell lines to cisplatin led to development of cell lines that exhibited increasing degrees of drug resistance, which were closely correlated with increase of the levels of cellular glutathione. Cell lines were obtained that showed 30- to 1000-fold increases in resistance; these cells also had strikingly increased (13- to 50-fold) levels of glutathione as compared with the drug-sensitive cells of origin. These levels of resistance to cisplatin and the cellular glutathione levels are substantially greater than previously reported. Very high cisplatin resistance was associated with enhanced expression of mRNAs for ?- glutamylcysteine synthetase and ?-glutamyl transpeptidase; immunoblots showed increase of ?-glutamylcysteine synthetase but not of glutathione synthetase. Glutathione S-transferase activity was unaffected, as determined with chlorodinitrobenzene as a substrate. These studies suggest the potential value of examining regulation of glutathione synthesis as an indicator of clinical prognosis. The highly resistant cell lines are proving useful for studying the multiple mechanisms by which tumor cells acquire drug- and radiation-resistance.
Notes
00278424 (ISSN) Cited By: 307; Export Date: 31 May 2006; Source: Scopus CODEN: PNASA Language of Original Document: English Correspondence Address: Godwin, A.K.; Department of Medical Oncology; Fox Chase Cancer Center Philadelphia, PA 19111, United States Chemicals/CAS: 1 chloro 2,4 dinitrobenzene, 25567-67-3, 97-00-7; cisplatin, 15663-27-1, 26035-31-4, 96081-74-2; gamma glutamyltransferase, 85876-02-4; glutamate cysteine ligase, 9023-64-7; glutathione transferase, 50812-37-8; glutathione, 70-18-8, Cisplatin, 15663-27-1; Glutamate-Cysteine Ligase, EC 6.3.2.2; Glutathione Transferase, EC 2.5.1.18; Glutathione, 70-18-8; RNA, Messenger