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Increased invasion of malignant gliomas after 15-LO-1 and HSV-tk/ganciclovir combination gene therapy

Cancer Gene Therapy volume 19, pages 870–874 (2012)Cite this article

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Abstract

Recent clinical trials for malignant glioma have drawn attention to the potential therapeutic efficacy of herpes simplex virus-thymidine kinase (HSV-tk) suicide gene therapy. Nevertheless, because of the nature of these tumors, it is believed that no single treatment alone is able to combat this fatal disease. Combination therapies may provide a solution to further improve therapies against malignant gliomas. We have recently demonstrated that 15-lipoxygenase-1 (15-LO-1) is able to inhibit tumor angiogenesis as well as enhance apoptosis in tumors. As a result, we studied the potential additive/synergistic effects of 15-LO-1 gene therapy when combined with HSV-tk gene therapy for the treatment of malignant gliomas. For that, BT4C malignant glioma cells were implanted into BDIX male rats. Fourteen days after tumor cell implantation, animals were transduced using adenoviral vectors either with HSV-tk alone or in combination with 15-LO-1. The results show that the combination gene therapy neither improved inhibition of tumor growth nor did it show any benefit on survival. Instead, a profound effect on the migratory properties of the tumor cells was found, resulting in decreased survival. Similar to conventional therapies, the combination of two therapeutic genes may result in unexpected side effects, not seen when given alone.

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Acknowledgements

This study was supported by grants from the Finnish Academy, Finnish Culture Foundation of Northern Savo, Ark Therapeutics Oy, EU 7th Framework Program, Sigrid Juselius Foundation and Antti Heikkonen grant from Kuopio University Foundation. We thank Ms S Järveläinen and Ms T Koponen for Adh15-LO-1 production, Ark Therapeutics Oy for a generous gift of AdHSV-tk as well as Anna Hyvärinen MD, PhD for critical comments. All animal experiments were approved by the Experimental Animal Committee, University of Eastern Finland. This study was supported by grants from the North Savo Cancer Foundation, Sigrid Juselius Foundation and Antti Heikkonen grant from the Kuopio University Foundation.

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  1. A Pacholska and T Wirth: These authors contributed equally to this paper.

Authors and Affiliations

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

    A Pacholska, T Wirth, H Samaranayake, J Pikkarainen, F Ahmad & S Ylä-Herttuala

  2. Ark Therapeutics Oy, Kuopio, Finland

    H Samaranayake & J Pikkarainen

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  1. A Pacholska
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Correspondence to T Wirth.

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Pacholska, A., Wirth, T., Samaranayake, H. et al. Increased invasion of malignant gliomas after 15-LO-1 and HSV-tk/ganciclovir combination gene therapy. Cancer Gene Ther 19, 870–874 (2012). https://doi.org/10.1038/cgt.2012.76

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