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HSV-1 amplicon-mediated post-transcriptional inhibition of Rad51 sensitizes human glioma cells to ionizing radiation

Gene Therapy volume 14, pages 1143–1151 (2007)Cite this article

Abstract

Standard treatment for glioblastoma multiforme and other brain tumors consists of surgical resection followed by combined radio-/chemotherapy. However, radiation resistance of tumor cells limits the success of this treatment, and the tumors invariably recur. Therefore, the selective inhibition of molecular mediators of radiation resistance may provide therapeutic benefit to the patient. One of these targets is the Rad51 protein, which is a key component of the homologous recombinational repair of DNA double-strand breaks. Here, we investigated whether post-transcriptional silencing of Rad51 by herpes simplex virus-type 1 (HSV-1) amplicon vector-mediated short interfering RNA expression can enhance the antitumor effect of radiation therapy. We demonstrate that these vectors specifically and efficiently inhibited the radiation-induced recruitment of Rad51 into nuclear foci in human glioma cells. The combination of vector-mediated silencing of Rad51 expression and treatment with ionizing radiation resulted in a pronounced reduction of the survival of human glioma cells in culture. In athymyc mice, a single intratumoral injection of Rad51-specific HSV-1 amplicon vector followed by a single radiation treatment resulted in a significant decrease in tumor size. In control animals, including mice that received an intratumoral injection of Rad51-specific amplicon vector but no radiation treatment, the tumor sizes increased.

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Acknowledgements

We thank Kati Zlinszky for technical assistance. This work was supported in part by the Cancer League of Kanton Zurich, the Swiss National Science Foundation (No. 3100A0-100195), and the 6th FW European Molecular Imaging Laboratories (EMIL)-NoE for Combating Cancer (LSHC-CT-2004-503569).

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Author notes

  1. O Saydam

    Present address: 6Current address: Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, MA, USA.,

  2. O Saydam and N Saydam: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Virology, University of Zurich, Zurich, Switzerland

    O Saydam, D L Glauser, M Ackermann & C Fraefel

  2. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland

    N Saydam

  3. Department of Radiation Oncology, University of Zurich, Zurich, Switzerland

    M Pruschy & V Dinh-Van

  4. Institute of Veterinary Pathology, University of Zurich, Zurich, Switzerland

    M Hilbe

  5. Center for Molecular Medicine (CMMC) and Department of Neurology, Laboratory for Gene Therapy and Molecular Imaging, Max-Planck Institute for Neurological Research, University of Cologne, Cologne, Germany

    A H Jacobs

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  1. O Saydam
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Correspondence to C Fraefel.

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Saydam, O., Saydam, N., Glauser, D. et al. HSV-1 amplicon-mediated post-transcriptional inhibition of Rad51 sensitizes human glioma cells to ionizing radiation. Gene Ther 14, 1143–1151 (2007). https://doi.org/10.1038/sj.gt.3302967

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