Delayed Morbidity and Mortality of Albumin/SV40 T-Antigen Transgenic Mice after Insertion of an α-Fetoprotein/Herpes Virus Thymidine Kinase Transgene and Treatment with Ganciclovir

Abstract

The α-fetoprotein (AFP) gene is normally expressed in fetal liver and transcriptionally silent in adult tissues, but can be abnormally reactivated in hepatocellular carcinoma (HCC). We linked 7.6 kb of 5′-flanking DNA from the mouse AFP gene to the herpes simplex virus (HSV) thymidine kinase gene (tk), and a line of transgenic mice was produced that expressed TK in a pattern similar to endogenous AFP. When these AFP/tk transgenic mice were crossed to another transgenic line that develops multifocal HCC due to expression of a SV40 large T-antigen transgene under regulation of the albumin promoter/enhancer complex, a significant delay of tumor progression could be achieved by administration of ganciclovir (GCV), a cytotoxic compound that is a substrate for phosphorylation by viral, but not mammalian, TK. Control animals carrying only the tk gene were unaffected by GCV treatment. These results illustrate the feasibility of prophylactic gene therapy for ablation of cancer, utilizing a strategy in which the tk gene is regulated by a promoter expected to be active only in tumor cells.

Overview summary

A variety of strategies are emerging for gene therapy of solid tumors. In the present experiments, we use transgenic mice to demonstrate that activation of α-fetoprotein (AFP) in liver cancers can be exploited to direct expression of viral thymidine kinase genes tk specifically to the cancer cells. Subsequent treatment with ganciclovir leads to suppression of tumor growth. Results suggest that hepatocellular carcinoma might be well controlled or even cured entirely through development of an effective, prophylactic somatic gene therapy protocol with AFP/tk hybrid genes in individuals with a known risk for development of this tumor.