ADENOVIRAL-MEDIATED HERPES-SIMPLEX VIRUS-THYMIDINE KINASE GENE-TRANSFER IN-VIVO FOR TREATMENT OF EXPERIMENTAL HUMAN-MELANOMA

To assess the efficacy of an in vivo adenoviral-mediated cytotoxic gen e therapy, human melanomas were established in nude mice and transduce d with herpes simplex virus-thymidine kinase (tk) followed by treatmen t with ganciclovir (GCV), In initial experiments, adenovirus (adv) con taining the beta-galactosidase reporter gene was employed to determine melanoma cell infectivity in vitro. In comparison to murine melanoma cell lines B16 and K1735-M2, human A375-SM cells exhibited up to a 10- fold greater susceptibility to adenoviral transduction, similar to the degree of infectivity found for human epidermal HaCa T cells, In addi tion, human A375-SM melanoma cells exhibited a greater sensitivity in vitro to the cytotoxic effects of transduction with tk-adv and treatme nt with GCV, which was mediated by a strong bystander effect. In vivo, intratumoral injection of relatively large human melanomas (160 mm(3) ) with 1.2 x 10(9) pfu of tk-adv, followed by intraperitoneal GCV trea tment (60 mg/kg twice daily) over 4 days, typically resulted in a 50% reduction in melanoma growth rate compared to mock or untreated contro ls. Moreover, histometrical analysis employing a rigorous computerized imaging system revealed that the residual viable tumor area in the tk -adv/GCV-treated group was only one-fifth that of solvent controls, Th ese data show that adv is a highly efficient in vivo gene delivery sys tem to treat experimental human melanomas, In comparison to a previous murine melanoma study, human melanomas appeared to exhibit a greater sensitivity to this cytotoxic treatment in vivo, which may hold signif icant promise for development of effective gene therapy modalities to treat melanoma in humans.