COMPARISON OF CYTOSINE DEAMINASE/5-FLUOROCYTOSINE VERSUS HERPES SIMPLEX VIRUS THYMIDINE KINASE/GANCICLOVIR ENZYME/PRODRUG SYSTEMS IN GLIOBLASTOMA GENE THERAPY.

Abstract

Cytosine deaminase (CD)/5-fluorocytosine (5-FC) and herpes simplex virus thymidine kinase (HSVtk)/ganciclovir (GCV) systems are the most well-studied and extensively used suicide gene/prodrug systems in cancer gene therapy. In this study, we evaluated and compared the inhibitory effects of HSVtk/GCV and CD/5-FC on glioma development. In vitro results indicate that when delivered by suicide gene expression in the U87 glioma cell line and in neural stem cells (NSCs), the CD/5-FC system was able to induce a bystander killing effect stronger than that of the HSVtk/GCV system, thus being more effective in eliminating glioma cells. Intratumoral injection of NSCs expressing the CD gene into BALB/c nude mice harboring U87 glioma xenografts induced significant tumor regression, and tumor growth was inhibited when 5-FC was administered. Bacterial CD/5-FC and yeast CD/5-FC displayed similar anti-glioma effects in vitro and in vivo. These results suggested that the antiglioma effect of the CD/5-FC system is superior to the HSVtk/GCV system, with the former being more suitable for glioma gene therapy when used with NSCs as a delivery vehicle.