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Prolonged, NK Cell-Mediated Antitumor Effects of Suicide Gene Therapy Combined with Monocyte Chemoattractant Protein-1 against Hepatocellular Carcinoma

Tomoya Tsuchiyama^*, Yasunari Nakamoto^*, Yoshio Sakai^*, Yohei Marukawa^*, Masaaki Kitahara^*, Naofumi Mukaida and Shuichi Kaneko^1,*

^* Department of Gastroenterology, Graduate School of Medical Science and Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Japan

Tumor recurrence rates remain high after curative treatments for hepatocellular carcinoma (HCC). Immunomodulatory agents, including chemokines, are believed to enhance the antitumor effects of tumor cell apoptosis induced by suicide gene therapy. We therefore evaluated the immunomodulatory effects of a bicistronic recombinant adenovirus vector (rAd) expressing both HSV thymidine kinase and MCP-1 on HCC cells. Using an athymic nude mouse model (BALB/c-nu/nu), primary s.c. tumors (HuH7; human HCC cells) were completely eradicated by rAd followed by treatment with ganciclovir. The same animals were subsequently rechallenged with HCC cells, tumor development was monitored, and the recruitment or activation of NK cells was analyzed immunohistochemically or by measuring IFN- mRNA expression. Tumor growth was markedly suppressed as compared with that in mice treated with a rAd expressing the HSV thymidine kinase gene alone (p < 0.001). Suppression of tumor growth was associated with the elevation of serum IL-12 and IL-18. During suppression, NK cells were recruited exclusively, and Th1 cytokine gene expression was enhanced in tumor tissues. The antitumor activity, however, was abolished either when the NK cells were inactivated with anti-asialo GM1 Ab or when anti-IL-12 and anti-IL-18 Abs were administered. These results indicate that suicide gene therapy, together with delivery of MCP-1, eradicates HCC cells and exerts prolonged NK cell-mediated antitumor effects in a model of HCC, suggesting a plausible strategy to prevent tumor recurrence.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Shuichi Kaneko, Department of Gastroenterology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan. E-mail address: skaneko{at}medf.m.kanazawa-u.ac.jp

² Abbreviations used in this paper: HCC, hepatocellular carcinoma; AGM1, asialo GM1; BNL, BNL 1ME A.7R.1 HCC cell line; DC, dendritic cell; GCV, ganciclovir; HSV-tk, HSV thymidine kinase; MMC, mitomycin C; MOI, multiplicity of infection; rAd, recombinant adenovirus vector; Ad-tk, rAd expressing HSV-tk; Ad-tk-MCP1, rAd expressing both HSV-tk and MCP-1; Ad-MCP1, rAd expressing MCP-1; Ad-lacZ, rAd expressing lacZ; TCID₅₀, 50% tissue culture infectious dose.

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