Role of the glutathione redox cycle in acquired and de novo multidrug resistance.

Drug resistance represents a major obstacle to successful cancer chemotherapy. However, the specific biochemical mechanisms responsible for clinical drug resistance are unknown. In these studies resistance to the antitumor agent adriamycin was found to involve two mechanisms, one that decreased drug accumulation by the P170 mechanism and another that altered the glutathione redox cycle, an important pathway in the detoxification of reactive oxygen. This dual mechanism of drug resistance was demonstrated in cell lines that had acquired the multidrug-resistant phenotype and in human colorectal cancer cells with de novo resistance. These studies support a model of acquired and de novo multidrug resistance that includes alterations in both drug accumulation and the glutathione redox cycle.