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Improved therapeutic effect on malignant glioma with adenoviral suicide gene therapy combined with temozolomide

Gene Therapy volume 20, pages 1165–1171 (2013)Cite this article

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Abstract

Malignant gliomas (MGs) are cancers with poor prognosis and limited therapeutic options. Herpes Simplex virus-1 thymidine kinase expressed from adenoviruses with prodrug ganciclovir (TK/GCV) is the best-characterized suicide gene therapy, whereas temozolomide (TMZ) is the first-line chemotherapy for MG. However, the potential of their combination has not been studied thoroughly. The aim of this study was to evaluate the therapeutic response of this combination and to study whether addition of valproic acid (VPA) could benefit the treatment outcome. Efficacies of different treatments were first studied in vitro in BT4C rat MG cells. Therapeutic assessment in vivo was done in an immunocompetent rat MG model for treatment efficacy and toxicity. In vitro, VPA was able to significantly enhance cytotoxicity and increase adenovirus-mediated transduction efficiency up to sevenfold. In vivo, rats receiving TK/GCV+TMZ had notably smaller tumors and enhanced survival (P<0.001) in comparison with control rats. However, VPA was not able to further enhance the treatment response in vivo. Leukocytopenia and thrombocytopenia were the major side effects. We conclude that careful optimization of the treatment schedules and doses of individual therapies are necessary to achieve an optimal therapeutic effect with TK/GCV+TMZ combination. No further in vivo benefit with VPA was observed.

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Acknowledgements

We thank Sari Järveläinen, Tiina Koponen, Riina Liikala, Joonas Malinen, Anne Martikainen, Anneli Miettinen, Mervi Nieminen and Seija Sahrio for their skillful technical assistance. Dr Johanna Närväinen (Biomedical NMR research group, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland) is acknowledged for her assistance in MRI issues. We also thank Ark Therapeutics Ltd. for providing Ad.HSV-TK virus for the study. This study was supported by grants from Cancer Foundation of Northern Savo, Duodecim, Finnish Academy, Kuopio University Hospital, University of Eastern Finland and Ark Therapeutics Ltd.

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Authors and Affiliations

  1. Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    H Stedt, H Samaranayake, J Pikkarainen, A M Määttä, L Alasaarela, K Airenne & S Ylä-Herttuala

  2. Movet Oy, Kuopio, Finland

    A M Määttä

  3. Research Unit, Kuopio University Hospital, Kuopio, Finland

    S Ylä-Herttuala

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

    S Ylä-Herttuala

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  1. H Stedt
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Correspondence to S Ylä-Herttuala.

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Haritha Samaranayake and Jere Pikkarainen were employees of Ark Therapeutics until end of 2012. The remaining authors declare no conflict of interest.

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Stedt, H., Samaranayake, H., Pikkarainen, J. et al. Improved therapeutic effect on malignant glioma with adenoviral suicide gene therapy combined with temozolomide. Gene Ther 20, 1165–1171 (2013). https://doi.org/10.1038/gt.2013.46

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