Ciaccio PJ. Tew KD. 1996. Adaptive response to glutathione S-transferase inhibitors. Brit J Cancer 74:S93–S98
Glutathione S-transferases (GST) are phase II detoxification enzymes that belong to a multigene family consisting of cytosolic a, 7r, ,u, 0, and microsomal classes. They exhibit overlapping and broad specificities for their ability to conjugate substrates to glutathione. Since GSTs catalyse the conjugation of glutathione to a number of anti-cancer agents, their overexpression in human tumours is of particular significance to the problem of drug resistance. The evidence of a role for GSTs in alkylating agent resistance is substantial. For example (a) the alkylating agents chlorambucil, melphalan, cyclosphosphamide metabolites and others are substrates for GSTs (Dulik et al., 1986, 1990; Ciaccio et al., 1990, 1991; Bolton et al., 1991; Yuan et al., 1991); (b) GSTs are overexpressed in alkylating agentresistant cell lines that exhibit collateral resistance to other alkylating agents (Wang and Tew, 1985; Batist et al., 1986; Lewis et al., 1988; Buller et al., 1987; Robson et al., 1987); (c) transfected GSTa class cDNAs confer resistance to nitrogen mustards in yeast and and mammalian cells (Black et al., 1990); (d) transfection of antisense GST cDNAs gives rise to sensitivity to alkylating agents (Greenbaum et al., 1994). GST inhibitors are of clinical interest since they can modulate cellular resistance to anti-cancer drugs. The drug ethacrynic acid (EA) inhibits the GST-mediated conjugation of chlorambucil with glutathione at physiologically achievable plasma concentrations (Ciaccio et al., 1991) and partially reversed chlorambucil resistance in a chronic lymphocytic leukaemia patient (Petrini et al., 1993). EA also inhibited GST activity involved in the metabolic disposition of thiotepa in a phase I clinical trial (O’Dywer et al., 1991). More recently, certain glutathione analogue-based GST inhibitors have been found to potentiate chlorambucil cytotoxicity in human colon carcinoma HT29 cells (Morgan et al., 1995). Unlike EA, these agents were designed to be selective inhibitors of specific GST isozyme classes (Flatgaard et al., 1993). One agent, T.199 (y-glutamyl-S(benzyl)cysteinyl-R(-)- phenyl glycine diethyl ester), selectively inhibited GST class ir enzymes and potentiated the effects of nitrogen mustards in GSTir-expressing HT29 cells. Both EA and T.199 sensitised HT29 tumour xenografts in SCID mice to melphalan (Clapper et al., 1990; Morgan et al., 1995).