Dual targeting of adenoviral vectors at the levels of transduction and transcription enhances the specificity of gene expression in cancer cells

Adenoviral (Ad) vector-mediated strategies for cancer gene therapy mandate a vector that is capable of efficient expression of the therapeutic gene specifically within the target tumor cells. In one approach to the development of cancer cell-specific vectors, Ad vectors have been targeted at the level of transduction to achieve the selective delivery of the therapeutic gene. In an alternative approach to the derivation of cancer cell-specific vectors, Ad vectors have been targeted at the level of transcription by placing the therapeutic gene under the control of transcriptional regulatory sequences that are activated in tumor cells, but not in normal cells, and therefore target expression selectively to the tumor cell. In this report, we demonstrate that a higher degree of specificity for cancer cells can be achieved by combining the complementary approaches of transductional and transcriptional targeting, each of which is imperfect or "leaky" by itself.