COMPLETE REGRESSION OF ESTABLISHED MURINE HEPATOCELLULAR-CARCINOMA BYIN-VIVO TUMOR-NECROSIS-FACTOR-ALPHA GENE-TRANSFER

Background & Aims: Although tumor necrosis factor (TNF)-alpha, possess es a potent antitumor activity, systemic administration of TNF-alpha c auses severe side effects, To circumvent this, the efficacy of tumor c ell-targeted TNF-alpha gene therapy was investigated. Methods: Murine hepatocellular carcinoma (HCC) cells were infected with MNSM-Alb e/p-T NF-alpha retroviruses carrying the murine TNF-alpha gene under the tra nscriptional control of the murine albumin gene promoter, and antitumo r effects induced by TNF-alpha gene transfer were examined in vitro an d in vivo, Results: Although MNSM-Alb e/p-TNF-alpha retrovirally infec ted HCC cells showed the same in vitro cell growth as parental HCC cel ls, they lost their tumorigenicity when implanted in syngeneic mice an d induced tumor immunity against parental HCCs. The retrovirally infec ted HCC cells also significantly inhibited the tumorigenicity of previ ously implanted parental HCCs. Furthermore, intratumoral administratio n of MNSM-Alb e/p-TNF-alpha retroviruses showed the antitumor effect a gainst established HCCs, resulting in significantly prolonged survival periods, Most importantly, intratumoral implantation of MNSM-Alb e/p- TNF-alpha retroviral-producing cells completely abrogated established HCCs in mice. Conclusions: These results indicate the potential effica cy of transferring the TNF-alpha gene via retroviral vectors directly into tumors for gene therapy against HCCs.