Hepatoma-specific antitumor activity of an albumin enhancer promoter regulated herpes simplex virus in vivo

Targeting viral vectors to appropriate cell types so that normal cells are not adversely affected is an important goal for gene therapy. Previously, w e described a novel approach to viral gene therapy using a conditional, rep lication-competent herpes simplex virus (HSV), where replication and associ ated cytotoxicity are limited to a specific cell-type by the regulated expr ession of an essential immediate-early viral gene product. In this report w e analyze the hepatoma-specific replication, cytotoxicity and anti-tumor ef fect of recombinant HSV G92A, regulated by the albumin enhancer/promoter. G 92A efficiently replicated in vitro in two human hepatoma cell lines expres sing albumin, but not in four human non-hepatoma, albumin-non-expressing tu mor cell lines, while all cell lines were equally susceptible to a tissue n onspecific HSV recombinant, hrR3. In vivo, G92A replicated well in subcutan eous 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 gr owth of established subcutaneous hepatoma tumors in nude mice, but not pros tate tumors. Replication competent viral vectors controlled by cell-specifi c transcriptional regulatory sequences provide a new therapeutic strategy f or tumor therapy.