PROTOONCOGENE BCL-2 GENE-TRANSFER ABROGATES FAS APO-1 ANTIBODY-MEDIATED APOPTOSIS OF HUMAN-MALIGNANT GLIOMA-CELLS AND CONFERS RESISTANCE TOCHEMOTHERAPEUTIC DRUGS AND THERAPEUTIC IRRADIATION/

The majority of human malignant glioma cells express Fas/APO-1 and are susceptible to Fas/APO-1 antibody-mediated apoptosis in vitro, The se nsitivity of Fas/APO-1-positive glioma cell lines to Fas/APO-1 antibod y-mediated killing correlates inversely with the constitutive expressi on of the antiapoptotic protooncogene bcl-2, Here we report that BCL-2 protein expression of human glial tumors in vivo correlates with mali gnant transformation in that BCL-2 immunoreactive glioma cells were mo re abundant in WHO grade III/IV gliomas than in grade I/II gliomas, Fa s/APO-1 antibody-sensitive human glioma cell lines stably transfected, vith a murine bcl-2 cDNA acquired resistance to Fas/APO-1 antibody-med iated apoptosis, Forced expression of bcl-2 also attenuated TNF alpha- mediated cytotoxicity of glioma cell lines in the presence of actinomy cin D and cycloheximide and conferred partial protection from irradiat ion and the cancer chemotherapy drugs, cisplatin and BCNU, Preexposure of the glioma cell lines to the cytokines, IFN gamma and TNF alpha, w hich sensitize for Fas/APO-1-dependent killing, partially overcame bcl -2-mediated rescue from apoptosis, suggesting that multimodality immun otherapy involving cytokines and Fas/APO-1 targeting might eventually provide a promising approach to the treatment of human malignant gliom as.