Inhibition of melanoma growth by adenoviral-mediated HSV thymidine kinase gene transfer in vivo

To assess the potential of an in vivo, adenovirus-mediated gene therapy approach for the treatment of malignant melanoma, the efficacy of adenovirus-mediated herpes simplex virus thymidine kinase gene (HSV-Ek) transfer and administration of ganciclovir (GCV) was investigated using a nude mouse model. Initially, B16 murine melanoma cells were efficiently transduced in vitro by a recombinant replication-defective adenovirus containing the HSV-tk gene (ADV/RSVtk), and rendered sensitive to cell killing by 10 μg/ml GCV. A significant 'bystander effect' was observed at low multiplicity of infection in comparison of cell killing to control B16 transduction by adenovirus containing the β-galactosidase gene (ADV/RSV-β-gal). In vivo, melanomas established from subcutaneous injection of 4 x 10⁵ B16 cells were injected after 14 d with 1 x 10¹⁰ ADV/RSV-tk viral particles. Subsequent treatment for 6 d with GCV resulted in an inhibition of melanoma growth, with an approximately 40-50% reduction in melanoma volume in comparison to controls in repeated experiments. These data demonstrate that adenovirus-mediated gene transfer can function as an efficient delivery system to reduce established tumor burden in vivo. This result may hold significant promise for the development of effective in situ gene therapy for melanoma in humans.