Primary malignant brain tumors respond poorly to treatment with chemotherapy or radiotherapy. The great majority of these tumors ar resistant to long-term control, and patients survive usually only a couple of years after diagnosis. Alterations in expression of p53 and bcl-2 gene family members influence cell growth and apoptotic cell death in a number of types of tumors, but their roles, either individually or together, in evaluating the biological behavior of gliomas have not been well defined. This proposal is directed towards evaluating the importance of p53 and bcl-2 gene family member function on cellular proliferation and death in gliomas following treatment with the DNA damaging agents commonly used clinically, as well with newer treatment strategies undergoing laboratory and/or clinical investigations. With use of two human glioma cell lines, U87 (which expressed wild type p53) and U373 ( which expresses only mutant p53), the hypotheses that regulation of the ratio of promotors of apoptosis (i.e. bax and its homologues) to in-hibitors of apoptosis (i.e. bcl-2 and its homologues) will determine radio-and chemo-sensitivity in gliomas will be tested. Clones will be constructed that over-express wild type p53, bax, bcl-2, or bcl-x. The effects of these transfections on chemo- and radio-sensitivity will be correlated with the changes in the ratio of promotors to inhibitors of apoptosis. This hypothesis will be tested in clinically derived tumor specimens a s well. With assistance from the Washington University Tumor Bank , Molecular diagnosis core and neuro-oncology tumor board, patient's clinical responses to treatment will be correlated with molecular changes in expression of p53 and bcl-2 gene family members measured in fresh tissue specimens obtained from the neurosurgery operating rooms. This strategy will allow for the determination of the importance of functional p53, and its interactions with members of the bcl-2 gene family in determining response to both traditional and new chemo- and radio-therapy treatments.
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