FADD GENE-THERAPY FOR MALIGNANT GLIOMAS IN-VITRO AND IN-VIVO

Fas/APO-1 (CD95), a cell surface cytokine receptor, triggers apoptotic cell death by specific agonist antibody, suggesting that Fas/APO-1 ma y be a promising target for treatment of tumors. In this study, we sho w that treatment with anti-Fas antibody effectively induced apoptosis in malignant glioma cell lines with high expression of Fas/APO-1 (n = 3), Malignant glioma cells with low or undetectable expression of Fas/ APO-1 (n = 6), however, were resistant to Fas/APO-1-dependent cytotoxi city. The purpose of this study, therefore, was to determine whether r esistant tumors could be made susceptible to apoptosis, FADD/MORT1 con stitutes a novel protein that associates specifically with the cytopla smic death domain of Fas/APO-1 and induces apoptosis, We investigated whether overexpression of FADD would induce apoptosis in malignant gli oma cells without activating Fas/APO-1, Results indicated that about 8 5% of malignant glioma cells, regardless of Fas/APO-1 expression level s, underwent apoptosis after transient transfection with FADD expressi on vector. To further improve gene transfer of FADD into malignant gli oma cells, we constructed a retroviral vector containing the FADD gene , The retroviral transfer of FADD gene significantly enhanced the tran sduction efficiency and effectively inhibited both in vitro and in viv o survival of malignant glioma cells through induction of apoptosis, T hese findings suggest that the FADD gene is a novel and useful tool fo r the treatment of malignant gliomas.