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Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector

Cancer Gene Therapy volume 11, pages 450–456 (2004)Cite this article

Abstract

One strategy for improving selectivity of gene therapy is the use of a replication-activated adenovirus vector that mediates transgene expression specifically in tumor cells through homologous recombination of viral genomes. In this study, we compared replication-activated adenovirus containing inverted repeats (Ad.IR-BG) with IR-deficient virus (Ad.BG) for selective gene expression in hepatocellular carcinoma and colon carcinoma metastases in the liver. We found that Ad.IR-BG conferred specific gene expression in both carcinoma cells, with minimal expression in hepatocytes and colon epithelial cells. This occurred through viral DNA recombination in Ad.IR-BG-infected tumor cells but not in normal cells. Hydroxyurea, which blocks DNA replication, inhibited DNA recombination and β-gal expression in Ad.IR-BG-infected but not Ad.BG-infected tumor cells. Finally, systemic injection of Ad.IR-BG into tumor xenografts in nude mice significantly improved selectivity of gene expression in tumors with minimal expression in normal tissues. Viral DNA recombination, which was absent in normal liver, was detected in Ad.IR-BG-infected tumors but not in Ad.BG-infected tissue. These findings demonstrated that replication-activated adenovirus can mediate tumor-specific gene expression through viral DNA recombination, which is otherwise deficient in normal cells.

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Acknowledgements

We thank Mary Davis (Department of Radiation Oncology, University of Michigan) for reviewing this manuscript.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan, 48109, USA

    Xiao W Huang, Theodore S Lawrence & Ming Zhang

  2. Division of Medical Genetics, Department of Medicine and Pathology, University of Washington, Seattle, 98195, Washington, USA

    Andre Lieber

  3. Liver Cancer Institute & Zhongshan Hospital, Fudan University, Shanghai, 200032, P.R. China

    Xiao W Huang & Zhao Y Tang

  4. INCELL Corporation, San Antonio, 78249, Texas, USA

    Mary P Moyer

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  1. Xiao W Huang
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  2. Andre Lieber
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  3. Zhao Y Tang
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  4. Theodore S Lawrence
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Correspondence to Ming Zhang.

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Supported by NIH grants CA80145, CA84117, Cancer Center Core Grant CA46592.

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Huang, X., Lieber, A., Tang, Z. et al. Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector. Cancer Gene Ther 11, 450–456 (2004). https://doi.org/10.1038/sj.cgt.7700719

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