Use of viral fusogenic membrane glycoproteins as novel therapeutic transgenes in gliomas

Malignant gliomas are the most common primary brain tumors in adults and, w ith few exceptions, have a dismal prognosis despite the therapeutic use of surgery, radiation therapy, and chemotherapy. Because CNS gliomas rarely me tastasize, they represent an attractive target for gene therapy through loc al gene delivery. Here we report on the use of two different fusogenic memb rane glycoproteins (FMGs), the measles virus proteins F and H (MV-F and MV- H) and a mutated form of the retroviral envelope protein of the gibbon ape leukemia virus (GALV.fus), as a novel class of therapeutic transgenes in gl iomas. Transfection of U87 and U118 cells with MV-F and MV-H cDNA or GALV.f us cDNA led in 48 hr to massive syncytial formation followed by cell death. FMG-mediated cytotoxicity in the U87 and U118 cell lines was superior to t he cytotoxicity caused by transfection with HSV-tk cDNA followed by gancicl ovir (GCV) treatment at all time points. At high-density cell seeding, addi tion of tumor cells transfected with MV-F and H killed at least 1 log more cells than by HSV-tk + GCV treatment, indicating higher bystander effect. S imilar results were obtained with GALV.fus. The mechanism of syncytial deat h in cultured glioma cell lines was predominantly apoptotic. Transfection o f U87 cells with F + H or GALV.fus expression constructs completely suppres sed their tumorigenicity. Treatment of established U87 xenografts in nude m ice with a combination of F and H adenoviruses at 1:1 ratio led to complete tumor regression, significantly higher antitumor effect, and prolongation of survival as compared with control animals treated with a GFP adenovirus. In summary, the viral fusogenic membrane glycoproteins (GALV and the MV-F + MV-H combination) are potent therapeutic transgenes with potential utilit y in the gene therapy of gliomas.