| Summary: | Glutathione and glutathione-dependent enzymes play a central role in the protection of cells from cytotoxic chemicals. In particular, reduced glutathione (GSH) and glutathione S- transferases (GST's) have been studied in relation to intrinsic and acquired resistance of tumours to cytotoxic drugs. There are however, other glutathione-dependent enzymes which may also be involved in drug resistance: these include glutathione perox-idase (GPX) and the enzymes, fglutamyltranspeptides (fGT), fglutamyl cysteinyl synthetase ('yGCS) and glutathione reductase (GRD). The latter enzymes are involved in the maintenance of reduced GSH levels within cells. GSH and the above glutathione-dependent enzymes have been studied in a series of drug resistance models, a) drug resistant tumour cell lines generated in vitro and in vivo; b) chemotherapeutic agent induced resistance in normal bone marrow cells; c) in oxygen resistant lung cells and d) in preneoplastic foci, in order to evaluate whether GSH and associated glutathione-dependent enzymes form part of an adaptive response involved in protection against the environment. Several models of drug resistance involving cell lines in culture were taken for study. A CHO cell line resistant to chlorambucil, an ovarian cell line generated in vivo, resistant to cis-Platinum and chlorambucil, and a sarcoma cell line resistant to adriamycin. In all these cell lines GST, GSH and 7GT were significantly elevated. In the latter two cell lines selenium dependent GPX was also induced. In the CHO line the elevated GST activity was explained by a 40 fold induction of the alpha class Yc GST subunit and a 2 fold elevation in the Ya subunit. In mouse bone marrow cells following the administration in vivo of a low 'primary dose' of cyclophosphamide, transient increase in alpha Ya and particularly mu Yb GST subunits were found. These increases have been associated with a subsequent protection against a higher lethal dose of the same agent. The changes observed in GST isozyme composition were confined to the granulocyte population. Differences in selenium-dependent GPX, GSH and fGT were also found in cells resistant to high oxygen, with only marginal changes in GST sub-unit profiles. In preneoplastic foci, significant elevations in pi class Yf GST and also alpha Ya and mu Yb were detected. Selenium- dependent GPX was decreased and TfGCS and GRD elevated in this model. These studies indicate therefore: 1) GST levels in certain cells appear to be directly related to resistance to cytotoxic chemicals; 2) Changes in GST expression associated with preneoplasia and in acquired drug resistance are not confined to one sub group of GST enzymes; 3) Changes in GST expression are often paralleled by changes in GSH and other glutathione- dependent enzymes; 4) The most consistent phenotypic changes observed in the drug resistant models studied were in GSH and fGT levels; 5) There seemed to be an inverse relationship in the regulation of selenium and non-selenium-dependent GPX activity in different drug resistant models. GSH and glutathione-dependent enzyme changes in acquired drug resistance, appear to be due to an adaptive response which may be of central importance in the resistance of tumours to chemotherapeutic agents.
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