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 therap y approach for the treatment of malignant melanoma, the efficacy of ad enovirus-mediated herpes simplex virus thymidine kinase gene (HSV-Ek) transfer and administration of ganciclovir (GCV) was investigated usin g a nude mouse model. Initially, B16 murine melanoma cells were effici ently transduced in vitro by a recombinant replication-defective adeno virus containing the HSV-tk gene (ADV/RSVtk), and rendered sensitive t o cell killing by 10 mu g/ml GCV, A significant ''bystander effect'' w as observed at low multiplicity of infection in comparison of cell kil ling to control B16 transduction by adenovirus containing the beta-gal actosidase gene (ADV/RSV-beta-gal), In vivo, melanomas established fro m subcutaneous injection of 4 x 10(5) B16 cells were injected after 14 d with 1 x 10(10) ADV/RSV-tk viral particles, Subsequent treatment fo r 6 d with GCV resulted in an inhibition of melanoma growth, with an a pproximately 40-50% reduction in melanoma volume in comparison to cont rols in repeated experiments, These data demonstrate that adenovirus-m ediated gene transfer can function as an efficient delivery system to reduce established tumor burden in vivo. This result map hold signific ant promise for the development of effective in situ gene therapy for melanoma in humans.