¹Department of Neurosurgery and Clinical Neuroscience, Kyoto University Graduate School of Medicine, Kyoto, Japan

² Department of Neurosurgery, Georgetown University Medical Center, Washington DC, USA

³Department of Ophthalmology and Visual Sciences, Kyoto University Hospital, Kyoto, Japan

⁴ Department of Microbiology and Immunology, Georgetown University Medical Center, Washington DC, USA

^aCorrespondence: SD Rabkin, Department of Neurosurgery, Georgetown University Medical Center, 3970 Reservoir Road NW, Washington, DC 20007, USA

Targeting viral vectors to appropriate cell types so that normal cells are not adversely affected is an important goal for gene therapy. Previously, we described a novel approach to viral gene therapy using a conditional, replication-competent herpes simplex virus (HSV), where replication and associated cytotoxicity are limited to a specific cell-type by the regulated expression of an essential immediate-early viral gene product. In this report we analyze the hepatoma-specific replication, cytotoxicity and anti-tumor effect of recombinant HSV G92A, regulated by the albumin enhancer/promoter. G92A efficiently replicated in vitro in two human hepatoma cell lines expressing albumin, but not in four human non-hepatoma, albumin-non- expressing tumor cell lines, while all cell lines were equally susceptible to a tissue nonspecific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutaneous xenografts of human hepatoma cells (Hep3B) in athymic mice, but not in non-hepatoma subcutaneous tumors (PC3 and HeLa), whereas, hrR3 replicated well in both tumor types. Intratumoral inoculation of G92A inhibited the growth of established subcutaneous hepatoma tumors in nude mice, but not prostate tumors. Replication-competent viral vectors controlled by cell-specific transcriptional regulatory sequences provide a new therapeutic strategy for tumor therapy.

HSV; hepatocellular carcinoma; transcriptional regulation; virus replication; albumin enhancer