Abstract
In this study, we determined the in vitro and in vivo efficacy of sodium iodide symporter (NIS) gene transfer and the therapeutic potential of oncolytic virotherapy combined with radioiodine therapy using a conditionally replicating oncolytic adenovirus. For this purpose, we used a replication-selective adenovirus in which the E1a gene is driven by the mouse alpha-fetoprotein (AFP) promoter and the human NIS gene is inserted in the E3 region (Ad5-E1/AFP-E3/NIS). Human hepatocellular carcinoma cells (HuH7) infected with Ad5-E1/AFP-E3/NIS concentrated radioiodine at a level that was sufficiently high for a therapeutic effect in vitro. In vivo experiments demonstrated that 3 days after intratumoral (i.t.) injection of Ad5-E1/AFP-E3/NIS HuH7 xenograft tumors accumulated approximately 25% ID g−1 (percentage of the injected dose per gram tumor tissue) 123I as shown by 123I gamma camera imaging. A single i.t. injection of Ad5-E1/AFP-E3/NIS (virotherapy) resulted in a significant reduction of tumor growth and prolonged survival, as compared with injection of saline. Combination of oncolytic virotherapy with radioiodine treatment (radiovirotherapy) led to an additional reduction of tumor growth that resulted in markedly improved survival as compared with virotherapy alone. In conclusion, local in vivo NIS gene transfer using a replication-selective oncolytic adenovirus is able to induce a significant therapeutic effect, which can be enhanced by additional 131I application.
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Acknowledgements
We are grateful to SM Jhiang, Ohio State University, Columbus, OH, USA, for supplying the full-length human NIS complementary DNA; to M Geissler, Esslingen, Germany, for supplying the murine AFP promoter/enhancer fragment; and to JC Morris, Mayo Clinic, Rochester, MN, USA, for providing the NIS mouse monoclonal antibody. We also thank R Anderson, Viraquest, for the synthesis of the Ad5-E1/AFP-E3/NIS construct; K Mantwill, Technical University Munich, Germany for providing the qPCR primers and protocol as well as D Mayr, Ludwig-Maximilians University, Munich, Germany, for preparation of paraffin-embedded slides. This study was supported by grant SFB 824 (Sonderforschungsbereich 824) from the Deutsche Forschungsgemeinschaft, Bonn, Germany, and by a grant from the Wilhelm-Sander-Stiftung (2008.037.1) to C Spitzweg.
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Grünwald, G., Klutz, K., Willhauck, M. et al. Sodium iodide symporter (NIS)-mediated radiovirotherapy of hepatocellular cancer using a conditionally replicating adenovirus. Gene Ther 20, 625–633 (2013). https://doi.org/10.1038/gt.2012.79
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DOI: https://doi.org/10.1038/gt.2012.79
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