Glutathione S-transferase and drug sensitivity in malignant glioma.
Malignant gliomas are largely resistant to current approaches of adjuvant chemotherapy. Gluthatione S-transferases (GST) have been attributed a role in 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 with genetic or functional p53 status or with the expression of various BCL-2 family proteins. No evidence for GST-mediated protection from chemotherapeutic drugs became apparent. In contrast, high levels of GST-pi protein, probably the major source of GST activity in glioma cells, and of total GST activity correlated with enhanced sensitivity to vincristine-induced clonogenic cell death. Expression of GST-pi in human glioblastomas in vivo was confirmed by immunohistochemistry. Neither total, nor cytoplasmic or nuclear, GST-pi immunoreactivity correlated with the response to adjuvant radiotherapy or radiochemotherapy. A comparative analysis of primary and recurrent tumors showed that GST expression was not enhanced by radiochemotherapy in vivo. We conclude that GST does not account for the differential chemosensitivity of glioma cell lines in vitro and does not accumulate in glioma subpopulations that form recurrent tumors after radiochemotherapy in vivo.
Winter
S
S
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Strasse 3, 72076, Tübingen, Germany.
Strik
H
H
Rieger
J
J
Beck
J
J
Meyermann
R
R
Weller
M
M
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology* / Q000628:therapy; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects* / Q000201:enzymology*
D020033:Protein Isoforms; D012333:RNA, Messenger; D005982:Glutathione Transferase