Complete regression of established murine hepatocellular carcinoma by in vivo tumor necrosis factor α gene transfer

Abstract

Background and Aims: Although tumor necrosis factor (TNF)-α possesses a potent antitumor activity, systemic administration of TNF-α causes severe side effects. To circumvent this, the efficacy of tumor cell-targeted TNF-α gene therapy was investigated. Methods: Murine hepatocellular carcinoma (HCC) cells were infected with MNSM-Alb e/p-TNF-α retroviruses carrying the murine TNF-α gene under the transcriptional control of the murine albumin gene promoter, and antitumor effects induced by TNF-α gene transfer were examined in vitro and in vivo. Results: Although MNSM-Alb e/p-TNF-α retrovirally infected HCC cells showed the same in vitro cell growth as parental HCC cells, they lost their tumorigenicity when implanted in syngeneic mice and induced tumor immunity against parental HCCs. The retrovirally infected HCC cells also significantly inhibited the tumorigenicity of previously implanted parental HCCs. Furthermore, intratumoral administration of MNSM-Alb e/p-TNF- α retroviruses showed the antitumor effect against established HCCs, resulting in significantly prolonged survival periods. Most importantly, intratumoral implantation of MNSM-Alb e/p-TNF-α retroviral-producing cells completely abrogated established HCCs in mice. Conclusions: These results indicate the potential efficacy of transferring the TNF-α gene via retroviral vectors directly into tumors for gene therapy against HCCs.