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Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma

Cancer Gene Therapy volume 19, pages 572–578 (2012)Cite this article

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Abstract

We evaluated a new therapeutic strategy for malignant glioma, which combines intratumoral inoculation of mesenchymal stem cells (MSCs) expressing cytosine deaminase gene with 5-fluorocytosine (5-FC) administration. For in vitro and in vivo experiments, MSCs were transfected with adenovirus carrying either enhanced green fluorescent protein gene (AdexCAEGFP) or cytosine deaminase gene (AdexCACD), to establish MSC-expressing EGFP (MSC-EGFP) or CD (MSC-CD). Co-culture of 9L glioma cells with MSC-CD in a medium containing 5-FC resulted in a remarkable reduction in 9L cell viability. The migratory ability of MSC-EGFP toward 9L cells was demonstrated by double-chamber assay. For the in vivo study, rats harboring 9L brain tumors were inoculated with MSC-EGFP or MSC-CD. Immunohistochemistry of rat brain tumors inoculated with MSC-EGFP showed intratumoral distribution of MSC-EGFP. Survival analysis of rats bearing 9L gliomas treated with intratumoral MSC-CD and intraperitoneal 5-FC resulted in significant prolongation of survival compared with control animals. In conclusion, molecular therapy combining suicide gene therapy and MSCs as a targeting vehicle represents a potential new therapeutic approach for malignant glioma, both with respect to the antitumor potential of this system and its neuroprotective effect on normal brain tissue.

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Acknowledgements

We thank H Wakimoto, M Arao and A Ishikawa for their technical assistance. The following medical students also contributed to the animal experiments: T Oka, K Tanaka, H Honda, K Seno and H Okura. This study was supported by grants-in-aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology to TI (No. 19591675), HK (No. 19591676) and KK (No. 20890133; No. 21791364).

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Authors and Affiliations

  1. Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan

    H Kosaka, T Ichikawa, K Kurozumi, H Kambara, S Inoue, T Maruo & I Date

  2. Innate Immunity Laboratory, Faculty of Advanced Life Science, Hokkaido University Graduate School of Life Science, Sapporo, Japan

    K Nakamura

  3. Department of Life Science, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan

    H Hamada

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  1. H Kosaka
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Correspondence to T Ichikawa.

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Kosaka, H., Ichikawa, T., Kurozumi, K. et al. Therapeutic effect of suicide gene-transferred mesenchymal stem cells in a rat model of glioma. Cancer Gene Ther 19, 572–578 (2012). https://doi.org/10.1038/cgt.2012.35

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