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Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice

Gene Therapy volume 10, pages 51–58 (2003)Cite this article

Abstract

The application of adeno-associated virus (AAV) vectors to cancers is limited by their low transduction efficiency. Previously, we reported that γ-ray enhanced the second-strand synthesis, leading to the improvement of the transgene expression, and cytocidal effect of the herpes simplex virus type-1 thymidine kinase (HSVtk) and ganciclovir (GCV) system. In this study, we extended this in vitro findings to in vivo. First, the laryngeal cancer cell line (HEp-2) and HeLa were treated with AAVtk/GCV, the number of surviving cells was reduced as the concentration of GCV increased. Furthermore, the 4 Gy irradiation enhanced the killing effects of AAVtk/GCV by four-fold on HeLa cells and 15-fold on HEp-2 cells. Following the in vitro experiments, we evaluated the transgene expression and the antitumor activity of the AAV vectors in combination with γ-ray in nude mice inoculated with HEp-2 subcutaneously. The LacZ expression was observed in the xenografted tumors and significantly increased by γ-ray. The AAVtk/GCV system suppressed the tumors growth, and γ-ray augmented the antitumor activity by five-fold. These findings suggest that the combination of AAVtk/GCV system with radiotherapy is significantly effective in the treatment of cancers and may lead to reduction of the potential toxicity of both AAVtk/GCV and γ-ray.

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Acknowledgements

We thank Dr M Nakazawa (Department of Radiology, Jichi Medical School) for technical advice and helpful discussion. We also thank Avigen Inc., for providing the plasmids, pAAVLacZ, pW1909 and plAd, and the Cell Resource Center for Biomedical Research, Tohoku University for providing the HEp-2 cells.

This work was supported in part by grants from the Ministry of Health, Labor and Welfare of Japan, Grants-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, CREST (Core Research for Evolutional Science and Technology), and Special Coordination Funds for promoting Science and Technology of the Science and Technology Agency of Japanese Government.

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Authors and Affiliations

  1. Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan

    T Kanazawa, H Mizukami, T Okada, Y Hanazono, A Kume & K Ozawa

  2. Department of Otolaryngology, Jichi Medical School, Tochigi, Japan

    T Kanazawa, H Nishino & K Ichimura

  3. CREST, Japan Science and Technology Corporation (JST), Tochigi, Japan

    T Kanazawa, H Mizukami, T Okada, Y Hanazono, A Kume & K Ozawa

  4. Department of Anatomy, Jichi Medical School, Tochigi, Japan

    K Takeuchi

  5. Department of Otolaryngology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan

    K Kitamura

  6. Department of Hematology, Jichi Medical School, Tochigi, Japan

    K Ozawa

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Kanazawa, T., Mizukami, H., Okada, T. et al. Suicide gene therapy using AAV-HSVtk/ganciclovir in combination with irradiation results in regression of human head and neck cancer xenografts in nude mice. Gene Ther 10, 51–58 (2003). https://doi.org/10.1038/sj.gt.3301837

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