Researchers have created a modified adenovirus that generates a functional promoter/heterologous gene construct exclusively in liver tumor cells. The vector design could ultimately be useful for specifically targeting expression of therapeutic genes in tumors, reducing side effects and enhancing therapeutic efficacy. André Lieber and his colleagues at the University of Washington engineered an adenovirus vector deleted for early gene E1B with a set of inverted repeats flanking a β-galactosidase marker gene in inverse 3′–5′ orientation to a respiratory syncitial virus (RSV) promoter. When this virus infects liver tumor cells, homologous recombination between the inverted repeats mediates precise rearrangements within the viral genome, bringing the RSV promoter into conjunction with the marker and resulting in gene expression. In vitro studies using hydroxyurea to specifically inhibit adenoviral DNA replication demonstrated the dependence of genomic rearrangement on viral DNA replication, which in turn occurs specifically in Tumor cells. After a single systemic administration of the virus into a mouse model, transgene expression occurred specifically in liver metastases derived from human tumors, whereas other tissues demonstrated no such activity. The authors suggest the strategy is readily applicable to other forms of oncolytic adenovirus such as Onyx's commercial adenovirus vectors (Nat. Med. 7, 240–243, 2000).