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The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice

Cancer Gene Therapy volume 9, pages 908–916 (2002)Cite this article

Abstract

Background and methods: Gene therapy may offer a new tool for the treatment of renal cell carcinoma (RCC). We have tested a combination of cytotoxic and antiangiogenic gene therapy for wild-type orthotopic human RCC xenografts in nude mice using intratumoral adenovirus-mediated herpes simplex virus thymidine kinase (HSV-tk) and endostatin (ES) gene therapy. In vivo magnetic resonance imaging, morphometry, immunocytochemistry, and survival were used to evaluate the treatment effect. Adenovirus-mediated marker gene transfers (GFP) were used as controls. Results: In vivo transduction efficiency, measured using GFP gene transfer, was 27±7%. The combination gene therapy with HSV-tk and ES adenoviruses resulted in a significant antitumor effect (P<.01) compared to single HSV-tk (n.s.) or ES (n.s.). In the survival study, all tumors with single gene therapy using HSV-tk, ES, and marker gene adenoviruses showed progression in magnetic resonance imaging. In contrast, the majority of the tumors in the combination treatment group remained dormant or were eradicated (57%). Survival of these mice equaled healthy nude mice, and was significantly prolonged (P<.0001) compared to HSV-tk (P<.028) and ES (n.s.) groups. Conclusions: It is concluded that the inhibition of angiogenesis using ES gene transfer together with the cytotoxic HSV-tk gene therapy results in a significantly improved treatment effect in RCC compared to the single gene treatments.

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Acknowledgements

We thank Markku Julkunen, MSc, for the statistical analysis, and Anne Martikainen, Mari Supinen, Mervi Nieminen, and Sisko Juutinen for skillful technical assistance. This study was supported by the Kuopio University Hospital (EVO Grant 5118), European Union Biomed program (BMH4-CT98-3469), Sigrid Juselius Foundation, Foundation for the Finnish Cancer Institute, Maud Kuistila Memorial Foundation, Ida Montin Foundation, and Cancer Society of Northern Savo.

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Authors and Affiliations

  1. Department of Molecular Medicine, AI Virtanen Institute, University of Kuopio, Kuopio, Finland

    Kalevi Juhani Pulkkanen, Johanna M Laukkanen, Jani M Kannasto & Seppo Yla-Herttuala

  2. Department of Oncology, Kuopio University Hospital, Kuopio, Finland

    Kalevi Juhani Pulkkanen

  3. Ludwig Institute for Cancer Research, Karolinska Institute, Stockholm, Sweden

    Jonas Fuxe & Ralf F Pettersson

  4. National BIO-NMR Facility, AI Virtanen Institute, University of Kuopio, Kuopio, Finland

    Mikko I Kettunen & Risto A Kauppinen

  5. Biocenter and Department of Medical Biochemistry, Collagen Research Unit, University of Oulu, Oulu, Finland

    Marko Rehn

  6. Animal Biotechnology Group, AI Virtanen Institute, University of Kuopio, Kuopio, Finland

    Jyrki J Parkkinen

  7. Department of Medicine, Kuopio University Hospital, Kuopio, Finland

    Seppo Yla-Herttuala

  8. Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

    Seppo Yla-Herttuala

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  1. Kalevi Juhani Pulkkanen
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  2. Johanna M Laukkanen
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Correspondence to Seppo Yla-Herttuala.

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Pulkkanen, K., Laukkanen, J., Fuxe, J. et al. The combination of HSV-tk and endostatin gene therapy eradicates orthotopic human renal cell carcinomas in nude mice. Cancer Gene Ther 9, 908–916 (2002). https://doi.org/10.1038/sj.cgt.7700519

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