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Adenovirus-mediated gene transfer to orthotopic hepatocellular carcinomas in athymic nude mice

Cancer Gene Therapy volume 8, pages 573–579 (2001)Cite this article

Abstract

Gene therapy may become an option for the treatment of malignant tumors such as hepatocellular carcinoma (HCC), once safe and efficient vector systems have been established. Due to their stability in vivo , recombinant adenoviral vectors are promising vectors for gene delivery to HCC. To study the characteristics of gene delivery into HCCs by recombinant adenoviral vectors in vivo , we established an in situ HCC model in the livers of athymic nude mice by intrahepatic injection of human HCC cells. Recombinant adenovirus vectors expressing β-galactosidase (Ad2CMVβgal) were injected via the tail vein of mice bearing HCC or directly into intrahepatic tumors. Levels of β-galactosidase expression in tumor tissue and surrounding normal liver were analyzed by histochemistry or for quantification by a chemiluminescence assay in tissue homogenates. Following tail vein injection, high levels of β-galactosidase expression were found in the liver, but virtually no gene expression could be detected in the tumor tissue. In contrast, after direct injection of Ad2CMVβgal into intrahepatic HCCs, high levels of β-galactosidase expression were detected in the tumor tissue. However, single transduced hepatocytes scattered throughout the normal liver could also be identified. These results indicate that barriers such as the endothelial lining of the tumor vasculature impair the efficiency of adenoviral vectors for gene delivery into HCCs by intravenous administration, which can be overcome by direct injection into the tumor tissue. However, due to the observed transduction of disseminated hepatocytes following intratumoral administration, additional HCC-specific targeting to further enhance the safety of adenoviral vectors may be required. Cancer Gene Therapy (2001) 8, 573–579

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Acknowledgements

This work was supported, in part, by Grants CA35711 and AA-08169 from National Institutes of Health and a grant from Genzyme. Seung Kew Yoon is the recipient of a grant from the Korea Science and Engineering Foundation (KOSEF). L.M. was supported by Grants Mo 699/2-1 and Mo 699/2-2 from the Deutsche Forschungsgemeinschaft, Bonn, Germany.

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Authors and Affiliations

  1. Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Boston, Massachusetts

    Seung Kew Yoon, Jack R Wands & Leonhard Mohr

  2. Department of Internal Medicine, College of Medicine, Catholic University of Korea, Seoul, South Korea

    Seung Kew Yoon

  3. Genzyme Corporation, Framingham, Massachusetts

    Donna Armentano

  4. The Liver Research Center, Rhode Island Hospital, Providence, Rhode Island

    Jack R Wands

  5. Department of Medicine II, University Hospital, Freiburg, Germany

    Leonhard Mohr

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  1. Seung Kew Yoon
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  2. Donna Armentano
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  4. Leonhard Mohr
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Correspondence to Leonhard Mohr.

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Yoon, S., Armentano, D., Wands, J. et al. Adenovirus-mediated gene transfer to orthotopic hepatocellular carcinomas in athymic nude mice. Cancer Gene Ther 8, 573–579 (2001). https://doi.org/10.1038/sj.cgt.7700345

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