The role of the glutathione S-transferases in resistance to cytotoxic compounds

• Main Author: Wareing, Clare Jane
• Published: University of Edinburgh 1991
• Subjects: 615
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.663483

The role that glutathione S-transferases (GST) play in the protection of tumour cells from cytotoxic insult was investigated. The possibility that GST may be involved in a stress-response was also explored. Derived drug-resistant tumour cell lines as well as showing various changes commonly associated with drug resistance, also show overexpression of certain GST. In the majority of drug resistant tumour cell models however, the ability of the drugs against which resistance is seen to act as GST substrates has not been demonstrated. For this reason, the known GST substrate, 1-chloro-2,4-dinitrobenzene (CDNB) was used to generate a tumour cell line resistant to this compound. The resultant CDNB resistant lung tumour cell line (CDNB<SUP>r</SUP>) exhibited marked overexpression of both alpha and pi class GST subunits. This cell line was also resistant to cumene hydroperoxide, a substrate for alpha class GST. However, no resistance to any of the anticancer drugs studied, was observed. The results demonstrated that the GST can protect cells against cytotoxic insult from certain alkylating agents and hydroperoxides and it is possible that the GST are involved in some sort of chemical stress response. However, in the CDNB resistant lung tumour cell line, GST do not appear to provide protection against a broad spectrum of anticancer drugs. The role of the human class pi enzyme in the resistance of human leukaemia cells to antitumour agents was also investigated. The results of this show that in certain instances, the pi class enzyme may be involved in resistance mechanisms of a number of drugs including chlorambucil. This work however highlighted the multifactoral nature of drug resistance. In conclusion, although the GST certainly appear to have the capacity to protect cells from cytotoxic compounds, it is evident that they are not the sole factor which determines the response of tumour cells to drug treatment.