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Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells

Gene Therapy volume 17, pages 1363–1371 (2010)Cite this article

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Abstract

Glioblastoma multiforme (GBM) is one of the most formidable brain tumors with a mean survival period of approximately 12 months. To date, a combination of radiotherapy and chemotherapy with an oral alkylating agent, temozolomide (TMZ), has been used as first-line therapy for glioma. However, the efficacy of chemotherapy for treating GBM is very limited; this is partly because of the high activity levels of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) in tumor cells, which creates a resistant phenotype by blunting the therapeutic effect of alkylating agents. Thus, MGMT may be an important determinant of treatment failure and should be considered as a suitable target for intervention, in an effort to improve the therapeutic efficacy of TMZ. In this study, we showed that small-interfering RNA (siRNA)-based downregulation of MGMT could enhance the chemosensitivity of malignant gliomas against TMZ. Notably, TMZ-resistant glioma-initiating cells with increased DNA repair and drug efflux capabilities could be efficiently transduced with MGMT-siRNA by using a novel liposome, LipoTrust. Accordingly, such transduced glioma-initiating cells could be sensitized to TMZ in both in vitro and in vivo tumor models. Taken together, this study provides an experimental basis for the clinical use of such therapeutic combinations.

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Authors and Affiliations

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

    T Kato, A Natsume, H Toda, H Iwamizu, K Yuki, K Motomura & T Wakabayashi

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

    A Natsume

  3. Hokkaido System Science, Hokkaido, Japan

    T Sugita & R Hachisu

  4. Division of Diagnostic Pathology, Shizuoka Cancer Center Hospital, Shizuoka, Japan

    T Sugita & R Hachisu

  5. Department of Neurosurgery, University of California at San Francisco, San Francisco, CA, USA

    R Watanabe & K Bankiewicz

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  1. T Kato
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Correspondence to A Natsume.

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Kato, T., Natsume, A., Toda, H. et al. Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells. Gene Ther 17, 1363–1371 (2010). https://doi.org/10.1038/gt.2010.88

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