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Human neural stem cells transduced with IFN-β and cytosine deaminase genes intensify bystander effect in experimental glioma

Cancer Gene Therapy volume 17, pages 299–306 (2010)Cite this article

Abstract

Previously, we have shown that the genetically modified human neural stem cells (NSCs) show remarkable migratory and tumor-tropic capability to track down brain tumor cells and deliver therapeutic agents with significant therapeutic benefit. Human NSCs that were retrovirally transduced with cytosine deaminase (CD) gene showed remarkable ‘bystander killer effect’ on the glioma cells after application of the prodrug, 5-fluorocytosine (5-FC). Interferon-β (IFN-β) is known for its antiproliferative effects in a variety of cancers. In our pilot clinical trial in glioma, the IFN-β gene has shown potent antitumor activity in patients with malignant glioma. In the present study, we sought to examine whether human NSCs genetically modified to express both CD and IFN-β genes intensified antitumor effect on experimental glioma. In vitro studies showed that CD/IFN-β-expressing NSCs exerted a remarkable bystander effect on human glioma cells after the application of 5-FC, as compared with parental NSCs and CD-expressing NSCs. In animal models with human glioma orthotopic xenograft, intravenously infused CD/IFN-β-expressing NSCs produced striking antitumor effect after administration of the prodrug 5-FC. Furthermore, the same gene therapy regimen prolonged survival periods significantly in the experimental animals. The results of the present study indicate that the multimodal NSC-based treatment strategy might have therapeutic potential against gliomas.

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Acknowledgements

This work was supported by grants from a Grant-in-Aid (C) for Scientific Research from the Ministry of Health, Labor and Welfare, Japan (AN), and from the Korean Ministry of Health and Family Affair (SUK).

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Authors and Affiliations

  1. Department of Neurosurgery, Nagoya University School of Medicine, Nagoya, Japan

    S Ito, A Natsume, S Shimato, M Ohno, T Kato, P Chansakul & T Wakabayashi

  2. Center for Genetic and Regenerative Medicine, Nagoya University School of Medicine, Nagoya, Japan

    A Natsume & S Shimato

  3. Division of Neurology, Department of Medicine, UBC Hospital, University of British Columbia, Vancouver, Canada

    S U Kim

  4. Medical Research Institute, Chungang University College of Medicine, Seoul, Korea

    S U Kim

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  1. S Ito
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  2. A Natsume
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Correspondence to A Natsume or S U Kim.

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Ito, S., Natsume, A., Shimato, S. et al. Human neural stem cells transduced with IFN-β and cytosine deaminase genes intensify bystander effect in experimental glioma. Cancer Gene Ther 17, 299–306 (2010). https://doi.org/10.1038/cgt.2009.80

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  • DOI: https://doi.org/10.1038/cgt.2009.80

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