Radiation therapy is the major treatment modality for primary malignant brain tumors. Since these tumors are typically nonmetastatic, local control with radiation should provide a cure. Brain tumors, however, are notoriously resistant to radiation, and attempts to decrease this resistance by chemical and physical means have not been effective in the clinical setting. Despite increasing evidence that genetic changes are involved in carcinogenic mechanisms, little is known about how these genetic changes may affect radioresistance. Resistance to ionizing radiation among some carcinomas has been linked to expression of certain oncogenes, such as raf, ras, and myc. The relationship between oncogene expression and radiation resistance in malignant brain tumors has not yet been studied. In this project, we will investigate the expression of raf, ras, and myc in glioblastoma cell lines and assess their possible role in radioresistance of these tumors. We will attempt to decrease their radioresistance in vitro by lowering oncogene expression. This will be achieved by introducing antisense constructs of the oncogenes via various mammalian expression vector systems. Oncogene expression levels will be quantitated by standard northern and western blot techniques, and the possible effect of decreased oncogene expression on radioresistance will be assessed by in vitro radiation survival curve analysis. If a relationship between oncogene expression and radioresistance is found for glioblastomas, oncogene modulated and unmodulated glioblastoma cells will be compared for differential protein expression using 2D-gel electrophoresis. This will identify other proteins, in the oncogene expression cascade, which may be important to the radioresistant phenotype. Such proteins will be characterized and cloned for further evaluation as potential therapeutic targets. Results from this project should determine the importance of oncogene expression to the radioresistant phenotype in glioblastoma, identify proteins that may participate in radioresistance mechanisms, and suggest different gene products as new potential targets for therapeutic intervention. Such findings may provide clinical strategies to improve the therapeutic ratio for the treatment of brain tumors.
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