LIMITED EFFICACY OF THE HSV-TK GCV SYSTEM FOR GENE-THERAPY OF MALIGNANT GLIOMAS AND PERSPECTIVES FOR THE COMBINED TRANSDUCTION OF THE INTERLEUKIN-4 GENE/

The growth of U-87 or C6 gliomas co-implanted in nude mice with retrov iral producer cells (VPC) expressing the herpes simplex virus-thymidin e kinase (HSV-tk) gene is only partially impaired by treatment with ga nciclovir (GCV), The effect of GCV is even less evident when C6 and VP C are co-implanted into the rat brain, Furthermore, tumors from C6 cel ls carrying the HSV-tk gene are not eradicated by GCV, although they r emain sensitive to GCV when replated in vitro, These limits of the HSV -tk/GCV system in glioma gene therapy may be due to insufficient gene transfer and/or insufficient delivery of GCV to glioma cells, Combinat ion of HSV-tk and one or more cytokines may improve the antitumor effi cacy, Among cytokines, interleukin-4 (IL-4) has already been shown to be active against gliomas, In nude mice, GCV treatment inhibited tumor growth more effectively after co-injection of C6 cells with a mixture of VPC transducing IL-4 and HSV-tk genes than after co-injection with either IL-4 or HSV-tk WC only, In immunocompetent Sprague-Dawley rats , co-injection of IL-4 VPC and C6 cells was also effective in inhibiti ng the growth of C6 brain tumors, 38% of the animals surviving for at least 2 months, Furthermore, increased and prolonged antitumor efficac y was obtained by transducing both IL-4 and HSV-tk genes.