Enhanced anti-tumor effects of herpes simplex virus thymidine kinase/ganciclovir system by codelivering monocyte chemoattractant protein-1 in hepatocellular carcinoma

The therapeutic efficacy of herpes simplex virus thymidine kinase/ganciclov ir (HSV-tk/GCV) system in many types of tumors is unsatisfactory due to the insufficient spread of gene transfer and insufficient cell killing. In the current study, we investigated whether adenovirally delivered monocyte che moattractant protein (MCP)-1 potentiates the antitumor effects of the HSV-t k/GCV system in hepatocellular carcinoma (HCC) cells. Subcutaneous tumor fo ci of the human HCC cell line, HuH7, established in athymic mice were direc tly transduced with a recombinant adenovirus (rAd) harboring an HSV-tk gene driven by a human alpha -fetoprotein promoter, followed by GCV administrat ion. Subsequently, another rAd expressing MCP-1 under the universal CAG pro moter was injected. The growth of tumors was markedly suppressed by codeliv ering HSV-tk and MCP-1 genes compared to that by either HSV-tk/GCV or MCP-1 delivery. in the tumor tissues, monocyte/macrophage infiltration was detec ted immunohistochemically, The antitumor effects of the rAd expressing MCP- 1 were markedly reduced by the administration of carrageenan, a compound kn own to inactivate macrophage. These results indicate that adenovirally deli vered MCP-1 enhanced the antitumor effects of the HSV-tk/GCV system synergi stically by recruitment/activation of macrophages in tumor tissues, suggest ing an effective immunotherapy for HCC and other lineages of tumors when us ed adjuvantly with a suicide gene.