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Generation of a recombinant Sendai virus that is selectively activated and lyses human tumor cells expressing matrix metalloproteinases

Gene Therapy volume 11, pages 1137–1145 (2004)Cite this article

Abstract

Malignant tumor cells often express matrix metalloproteinases (MMPs) at a high level to enable their dissemination and metastasis. Sendai virus (SeV), a nonsegmented negative strand RNA virus, spreads in the target tissues in vivo via cleavage activation of the viral fusion glycoprotein by a tissue-specific, trypsin-like enzyme. By deleting the viral matrix protein, we previously generated a recombinant SeV that does not bud to mature virions, but is highly fusogenic and spreads extensively from cell to cell in a trypsin-dependent manner. Here, we changed the tryptic cleavage site of the fusion glycoprotein of this virus to a site susceptible to MMPs. The resulting recombinant virus was no longer activated by trypsin but spread efficiently in cultured cells supplemented with MMP2 or MMP9 and in human tumor cell lines expressing these MMPs. Furthermore, the virus spread extensively in tumor cells xenotrasplanted to nude mice without disseminating to the surrounding normal cells, leading to the inhibition of the tumor growth in the mice. These results demonstrate the selective targeting and killing of human tumor cells by recombinant SeV technology and greatly advance the reemerging concept of oncolytic virotherapy, which currently appears to rely largely upon a natural preference of certain viruses for cancer cells.

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Acknowledgements

We thank B Moss, I Saito, H Iba and M Kobayashi for supplying experimental materials essential for this study; T Kanaya and H Ban for their excellent technical assistance and A Kato and Y Ueda for helpful discussions.

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Author notes

  1. H Kinoh and M Inoue: The first two authors contributed equally to this work

Authors and Affiliations

  1. DNAVEC Research Inc., Kannondai, Tsukuba-shi, Ibaraki, Japan

    H Kinoh, M Inoue, K Washizawa, T Yamamoto, S Fujikawa, Y Tokusumi, A Iida & M Hasegawa

  2. Toyama Institute of Health, Nakataigouyama, Kosugi-machi, Imizu-gun, Toyama, Japan

    Y Nagai

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Kinoh, H., Inoue, M., Washizawa, K. et al. Generation of a recombinant Sendai virus that is selectively activated and lyses human tumor cells expressing matrix metalloproteinases. Gene Ther 11, 1137–1145 (2004). https://doi.org/10.1038/sj.gt.3302272

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