Abstract
High mortality and therapy resistance of melanoma demand the development of new strategies, and overcoming apoptosis deficiency appears as particularly promising. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown high potential for apoptosis induction in melanoma cells and may be applicable for gene therapy because of its selective impact on tumor cells. We have constructed a conditional replication-competent adenoviral vector with TRAIL controlled by a tetracycline-inducible promoter (AdV-TRAIL). A variant E1A protein and the lack of E1B aimed at the restriction of viral replication to tumor cells. In particular, the replication gene E1A is controlled by a tyrosinase promoter with high selectivity for melanoma cells. AdV-TRAIL mediated strong expression of E1A and doxycycline-dependent induction of TRAIL selectively in melanoma cells, which resulted in tumor cell lysis and induction of apoptosis. In contrast, non-melanoma cells and normal human melanocytes appeared to be protected. Comparison of the AdV-TRAIL approach with a comparable CD95L vector revealed similar efficacy in vitro. In mouse xenotransplantation models, AdV-TRAIL demonstrated its activity by significant melanoma growth reduction. Melanoma cell killing by AdV-TRAIL was further improved in vitro by combinations with chemotherapeutics. We demonstrate that melanoma cells may be efficiently targeted by TRAIL-based gene therapy, and resistance may be overcome by combined chemotherapy.