THE INTRINSIC RADIORESISTANCE OF GLIOBLASTOMA-DERIVED CELL-LINES IS ASSOCIATED WITH A FAILURE OF P53 TO INDUCE P21(BAX) EXPRESSION

Radiation is the primary modality of therapy for all commonly occurrin g malignant brain tumors, including medulloblastoma and glioblastoma, These two brain tumors, however, have a distinctly different response to radiation therapy, Medulloblastoma is very sensitive to radiation t herapy, whereas glioblastoma is highly resistant, and the long-term su rvival of medulloblastoma patients exceeds 50%, while there are few lo ng-term survivors among glioblastoma patients. p53-mediated apoptosis is thought to be an important mechanism mediating the cytotoxic respon se of tumors to radiotherapy. In this study, we compared the response to radiation of five cell lines that have wild-type p53: three derived from glioblastoma and two derived from medulloblastoma, We found that the medulloblastoma-derived cell lines underwent extensive radiation- induced apoptotic cell death, while those from glioblastomas did not e xhibit significant radiation-induced apoptosis, p53-mediated induction of p21(BAX) is thought to be a key component of the pathway mediating apoptosis after the exposure of cells to cytotoxins, and the expressi on of mRNA encoding p21(BAX) was correlated with these cell lines unde rgoing radiation-induced apoptosis, The failure of p53 to induce p21(B AX) expression in glioblastoma-derived cell lines is likely to be of b iologic significance, since inhibition of p21(BAX) induction in medull oblastoma resulted in a loss of radiation-induced apoptosis, while for ced expression of p21(BAX) in, glioblastoma was sufficient to induce a poptosis, The failure of p53 to induce p21(BAX) in, glioblastoma-deriv ed cell lines suggests a distinct mechanism of radioresistance and may represent a critical factor in determining therapeutic responsiveness to radiation in glioblastomas.