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α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma

Gene Therapy volume 15, pages 214–223 (2008)Cite this article

Abstract

Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human sodium iodide symporter (NIS) gene transfer using a mouse α-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1–6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1–6 cell line showed a 10-fold increase in iodide accumulation, while HepG2 cells accumulated 125I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1–6 and 93% of HepG2 cells were killed by 131I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total 123I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq−1 131I. After administration of a therapeutic 131I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of 131I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.

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Acknowledgements

We are grateful to Dr SM Jhiang, Ohio State University, Columbus, OH, USA, for supplying the full-length human NIS cDNA. This study was supported by grants to C Spitzweg (Sp/581/3-2, Sp 581/4-1, Sp 581/4-2 (DFG-Forschergruppe ‘Radionuklidtherapie’ FOR-411) from the German Research Council (Deutsche Forschungsgemeinschaft, Bonn, Germany), by the FöFoLe-Program of the Ludwig-Maximilians-University Munich to MJ Willhauck (FöFoLe Reg. Nr. 442), and by the Mayo Foundation Prostate Cancer SPORE grant (CA91956) to JC Morris.

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Authors and Affiliations

  1. Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany

    M J Willhauck, B R Sharif Samani, K Klutz, N Cengic, B Göke & C Spitzweg

  2. Department of Nuclear Medicine, Technical University, Munich, Germany

    I Wolf & R Senekowitsch-Schmidtke

  3. Department of Internal Medicine II, Albert-Ludwigs-University Freiburg, Germany

    L Mohr & M Geissler

  4. Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN, USA

    J C Morris

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  1. M J Willhauck
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Correspondence to C Spitzweg.

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Willhauck, M., Sharif Samani, B., Klutz, K. et al. α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. Gene Ther 15, 214–223 (2008). https://doi.org/10.1038/sj.gt.3303057

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