Glutathione Stransferase

In addition to DNA repair, resistance to alkylating agents and other therapies can come about through detoxification. The family of glutathione-S-transferase (GST) enzymes catalyze the conjugation of electro-philic compounds with glutathione. These include various carcinogens, chemotherapeutic agents, and their metabolites [97,128-134]. There are 5 families of GSTs: a(GSTA), m(GSTM), p(GSTP), 9(GSTT) and Z(GSTZ) [130,131]. Earlier work demonstrated the importance of the GSTP, GSTM, and GSTT isoforms in resistance to chemotherapeutic agents such as BCNU and cisplatin; however, there were conflicting reports in the literature as to the isoforms most involved in therapy resistance in various human and animal cancers [97,129,131-133,135,137-144]. Work in our laboratory agreed with data obtained in other laboratories in that cells from some tumors demonstrated over-expression of one or more of these genes, while others did not [145]. Furthermore, even when BCNU resistant cells were cloned from a single tumor that did not express MGMT, the expression of various GST isoforms varied and there was no clear correlation between the expression of specific GST isoforms and BCNU resistance (Scheck et al., unpublished results).

The conflicting data on the relative importance of specific GST isoforms to chemotherapy resistance may be due, in part, to the fact that the genes encoding GSTM1, GSTT1, and GSTP1 are polymorphic [146,147], and numerous studies have shown that polymorphisms in GST enzymes can alter their ability to metabolize various substrates including carcinogens and chemotherapeutic agents [147-149]. A number of studies have found relationships between specific genotypes and the incidence of various cancers [147], including brain tumors [150-153]; however, there is inconsistency in the literature. This may be due, at least in part, to the fact that correlations with specific GST genotypes vary with the histological and genetic subtype and grade of pediatric and adult brain tumors.

Similar studies have found correlations between GST polymorphisms and survival in a number of tumor systems [128,154-157], including brain tumors [158,159]. Recent additional work has suggested that the observed increase in survival may be due to the presence of specific GST genotypes that result in reduced GST activity [128,157]; however, some investigators have found that tumors that recur following treatment do not show increased expression of GST suggesting that in these tumors GST may not be correlated to therapy resistance [141]. Furthermore, patients with genotypes leading to reduced GST activity are also at increased risk for adverse effects as a result of chemotherapy [158,160]. It is likely that future studies will indeed identify a role(s) for specific GST genotypes in treatment decisions, therapy resistance and survival; however, these analyses will have to include not only the histological subtype of tumor, but also an understanding of the overall genetic profile of the tumor including MGMT and DNA repair activities.

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