New strategies for the genetic therapy of primary liver carcinoma

Summary Genetically-based strategies open up new perspectives for the therapy of primary liver carcinoma. Suicide genes specifically targeted to hepatoma cells are able to activate innocuous prodrugs, leading to the toxification of genetically-modified as well as neighbouring cells (bystander effect). Since serious local and systemic side-effects have to be avoided, in vivo application of this new strategy requires the generation of hepatotropic vector systems. Based on the distinct ligand-receptor interaction of Sendai virus F envelope protein, with the liver specific asialoglycoprotein receptor (ASGP-R), we have developed two new ASGP-R restricted viral vector systems: recombinant hepatotropic Sendai virus vectors and retroviral MoMLV(SeV-F) pseudotypes. In combination with hepatoma-specific expression cassettes, currently under development, and topical vector application techniques, an efficient, safe and hepatoma-restricted transfer of therapeutic genes seems to be achievable. New molecular principles, such as the VP22 potentiated bystander effect, might help to achieve major clinical progress, especially in the adjuvant treatment of microscopic hepatoma nodules.