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Glutathione, a tripeptide thiol found in virtually all cells, functions in metabolism, transport, and cellular protection. It participates in the reduction of disulfides and other molecules, and conjugates with compounds of exogenous and endogenous origin. It protects cells against the destructive effects of reactive oxygen intermediates and free radicals. Modifications of glutathione metabolism may be achieved by administration of selective enzyme inhibitors, and also by giving compounds that increase glutathione synthesis. Such effects are useful in chemotherapy and radiation therapy and in protecting cells against the toxic effects of drugs, other foreign compounds, and oxygen.

High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis (y-glutamylcysteine ABSTRACTExposure 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 drugsensitive 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 r-glutamylcysteine synthetase and y-glutamyl transpeptidase; immunobots 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.

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