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Enhancement of antitumor activity of gammaretrovirus carrying IL-12 gene through genetic modification of envelope targeting HER2 receptor: a promising strategy for bladder cancer therapy

Cancer Gene Therapy volume 17, pages 37–48 (2010)Cite this article

Abstract

The objective of this study was to develop an HER2-targeted, envelope-modified Moloney murine leukemia virus (MoMLV)-based gammaretroviral vector carrying interleukin (IL)-12 gene for bladder cancer therapy. It displayed a chimeric envelope protein containing a single-chain variable fragment (scFv) antibody to the HER2 receptor and carried the mouse IL-12 gene. The fragment of anti-erbB2scFv was constructed into the proline-rich region of the viral envelope of the packaging vector lacking a transmembrane subunit of the carboxyl terminal region of surface subunit. As compared with envelope-unmodified gammaretroviruses, envelope-modified ones had extended viral tropism to human HER2-expressing bladder cancer cell lines, induced apoptosis, and affected cell cycle progression despite lower viral titers. Moreover, animal studies showed that envelope-modified gammaretroviruses carrying IL-12 gene exerted higher antitumor activity in terms of retarding tumor growth and prolonging the survival of tumor-bearing mice than unmodified ones, which were associated with enhanced tumor cell apoptosis as well as increased intratumoral levels of IL-12, interferon-γ, IL-1β, and tumor necrosis factor-α proteins. Therefore, the antitumor activity of gammaretroviruses carrying the IL-12 gene was enhanced through genetic modification of the envelope targeting HER2 receptor, which may be a promising strategy for bladder cancer therapy.

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Acknowledgements

This study was supported by the National Science Council of Taiwan (Grants NSC-94-2314-B-006-090, NSC-93-2314-006-070, NSC-92-2314-B-006-135, and NSC-91-2314-B-006-148) and Hospital of Department of Health, Executive Yuan, Taiwan (Grants 93033 and 9413).

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Authors and Affiliations

  1. Institute of Clinical Medicine, National Cheng Kung University Medical College, Tainan, Taiwan

    Y-S Tsai, A-L Shiau & C-L Wu

  2. Department of Urology, National Cheng Kung University Hospital, Dou-Liou Branch, Yunlin, Taiwan

    Y-S Tsai

  3. Department of Urology, National Cheng Kung University Medical College, Tainan, Taiwan

    Y-S Tsai, H-T Tsai & T-S Tzai

  4. Department of Microbiology and Immunology, National Cheng Kung University Medical College, Tainan, Taiwan

    A-L Shiau & Y-F Chen

  5. Department of Biochemistry and Molecular Biology, National Cheng Kung University Medical College, Tainan, Taiwan

    C-L Wu

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  1. Y-S Tsai
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Correspondence to T-S Tzai or C-L Wu.

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Tsai, YS., Shiau, AL., Chen, YF. et al. Enhancement of antitumor activity of gammaretrovirus carrying IL-12 gene through genetic modification of envelope targeting HER2 receptor: a promising strategy for bladder cancer therapy. Cancer Gene Ther 17, 37–48 (2010). https://doi.org/10.1038/cgt.2009.41

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