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Cancer gene therapy using a novel secretable trimeric TRAIL

Gene Therapy volume 13, pages 330–338 (2006)Cite this article

Abstract

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a member of the TNF family, is a type II transmembrane cytokine molecule. Soluble TRAIL has been shown to induce apoptosis in a wide variety of cancer cells in vitro and to suppress tumor growth specifically without damaging normal cells and tissues in vivo. In our previous report, we have demonstrated that an artificial gene encoding the polypeptide composed of the three functional elements (a secretion signal, a trimerization domain and an apoptosis-inducing moiety of TRAIL gene sequence) expresses and secretes highly apoptotic trimeric TRAIL into the culture supernatant. Here, as an approach to TRAIL-based cancer gene therapy, we developed an adenoviral vector delivering the gene that encodes our secretable trimeric TRAIL (stTRAIL). This adenovirus (Ad-stTRAIL) potently induced apoptosis in vitro in cancer cell lines such as HeLa, MDA-MB-231, A549, HCT116 and U-87MG. In an animal xenograft tumor model bearing a human glioma cell line U-87MG, intratumoral delivery of Ad-stTRAIL dramatically suppressed tumor growth without showing detectable adverse side effects. Histological analysis revealed that Ad-stTRAIL suppresses tumor growth by inducing apoptotic cell death. Contrary to the known rapid clearance of systemically delivered TRAIL protein from the blood circulation, stTRAIL expressed by Ad-stTRAIL in tumor tissues persisted for more than 4 days. In a comparison of tumor suppressor activity between Ad-stTRAIL and Ad-flTRAIL (delivering the full-length TRAIL gene) after mixing infected cells with uninfected cells and implanting these mixed cells in nude mice, Ad-stTRAIL showed higher tumor suppressor activity than that of Ad-flTRAIL. Our data reveal that a gene therapy using Ad-stTRAIL has a promising potential to treat human cancers including gliomas.

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Acknowledgements

We thank Sarah K McAshan and Michaele Armstrong for critical reading of the manuscript.

Author information

Author notes

  1. H Mushiake

    Present address: Department of Surgery and Bioengineering, Advanced Clinical Research Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

  2. C-Y Kim and M Jeong: These authors contributed equally to this work.

Authors and Affiliations

  1. Research Laboratories of Dong-A Pharmaceutical Co., Ltd, Kyunggi-Do, Korea

    C-Y Kim, M Jeong, H Mushiake, B-M Kim & W-B Kim

  2. Genenmed Inc., Jongno-Gu, Seoul, Korea

    J P Ko

  3. Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    M-H Kim, M Kim, T R Billiar & D-W Seol

  4. Research Center for Resistant Cells and Department of Biochemistry, Chosun University School of Medicine, Dong-Gu, Gwangju, Korea

    T-H Kim

  5. Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    P D Robbins

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  1. C-Y Kim
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Correspondence to D-W Seol.

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Kim, CY., Jeong, M., Mushiake, H. et al. Cancer gene therapy using a novel secretable trimeric TRAIL. Gene Ther 13, 330–338 (2006). https://doi.org/10.1038/sj.gt.3302658

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