Glutathione S-transferase and drug sensitivity in malignant glioma

Malignant gliomas are largely resistant to current approaches of adjuvant c hemotherapy. Gluthatione S-transferases (GST) have been attributed a role i n the resistance of cancer cells, e.g., to nitrosoureas, Here, we assessed the expression levels of GST-pi and GST-mu RNA and protein as well as total GST activity in a panel of 12 human glioma cell lines and correlated these data with p53 status, BCL-2 family protein expression and drug sensitivity in these cells. Neither GST protein levels nor GST activity correlated wit h genetic or functional p53 status or with the expression of various BCL-2 family proteins. No evidence for GST-mediated protection from chemotherapeu tic drugs became apparent. In contrast, high levels of GST-pi protein, prob ably the major source of GST activity in glioma cells, and of total GST act ivity correlated with enhanced sensitivity to vincristine-induced clonogeni c cell death. Expression of GST-pi in human glioblastomas in vivo was confi rmed by immunohistochemistry. Neither total, nor cytoplasmic or nuclear, GS T-pi immunoreactivity correlated with the response to adjuvant radiotherapy or radiochemotherapy. A comparative analysis of primary and recurrent tumo rs showed that GST expression was not enhanced by radiochemotherapy in vivo . We conclude that GST does not account for the differential chemosensitivi ty of glioma cell lines in vitro and does not accumulate in glioma subpopul ations that form recurrent tumors after radiochemotherapy in vivo. (C) 2000 Elsevier Science B.V. All rights reserved.