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Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma

Cancer Gene Therapy volume 10, pages 260–269 (2003)Cite this article

An Erratum to this article was published on 21 July 2003

Abstract

The efficacy of the suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system for the treatment of cancer is limited because of the insufficient gene transfer and the low killing activity. To enhance the antitumor activity, we determined whether recombinant adenovirus vector (rAd)s expressing both HSV-tk and monocyte chemoattractant protein-1 (MCP-1) genes could potentiate the destruction of hepatocellular carcinoma (HCC). The rAd Ad-tk-MCP1 harboring HSV-tk and MCP-1 genes in sequence under the universal CAG promoter was constructed with a bicistronic unit including the encephalomyocarditis virus-internal ribosomal entry site. The levels of HSV-tk expression and GCV-sensitive tumoricidal activity of Ad-tk-MCP1 were comparable to those of rAd expressing HSV-tk alone. The growth of subcutaneous tumors in athymic nude mice was markedly suppressed when tumors were treated with Ad-tk-MCP1 as opposed to another bicistronic vector Ad-MCP1-tk, rAd expressing either HSV-tk or MCP-1, or both of these vectors. The antitumor effects of Ad-tkMCP1 may be dependent on the activation of macrophages, since the recruitment of macrophages was observed tumor necrosis factor-α production was enhanced in the tumor tissue. Furthermore, the enhanced antitumor effect was abolished by inactivating macrophages with carrageenan treatment. These results demonstrated that a bicistronic rAd harboring both suicide and chemokine genes in sequence exerted the enhanced, macrophage-dependent, antitumor effects in a model of HCC and support the use of this strategy for the treatment of HCC.

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Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medical Science Kanazawa University, Kanazawa, Japan

    Tomoya Tsuchiyama, Shuichi Kaneko, Yasunari Nakamoto, Yoshio Sakai, Masao Honda & Naofumi Mukaida

  2. Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University Kanazawa, Japan

    Kenichi Kobayashi

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  1. Tomoya Tsuchiyama
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  2. Shuichi Kaneko
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  3. Yasunari Nakamoto
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  4. Yoshio Sakai
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  6. Naofumi Mukaida
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Correspondence to Shuichi Kaneko.

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Tsuchiyama, T., Kaneko, S., Nakamoto, Y. et al. Enhanced antitumor effects of a bicistronic adenovirus vector expressing both herpes simplex virus thymidine kinase and monocyte chemoattractant protein-1 against hepatocellular carcinoma. Cancer Gene Ther 10, 260–269 (2003). https://doi.org/10.1038/sj.cgt.7700571

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  • DOI: https://doi.org/10.1038/sj.cgt.7700571

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