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

M. J. Willhauck, B. R. Sharif Samani, K. Klutz, N. Cengic, I. Wolf, L. Mohr, M. Geissler, R. Senekowitsch-Schmidtke, B. Göke, J. C. Morris, C. Spitzweg

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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 8.38h, resulting in a tumor absorbed dose of 171mGyMBq-1 131I. After administration of a therapeutic 131I dose (55.5MBq) 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.

Original languageEnglish (US)
Pages (from-to)214-223
Number of pages10
JournalGene Therapy
Volume15
Issue number3
DOIs
StatePublished - Feb 2008

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Fetal Proteins
Genetic Therapy
Hepatocellular Carcinoma
Liver Neoplasms
Hep G2 Cells
Neoplasms
Iodides
Heterografts
Therapeutics
Cell Line
Therapeutic Uses
sodium-iodide symporter
Northern Blotting
Half-Life
Complementary DNA
Messenger RNA
Membranes
Growth

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Willhauck, M. J., Sharif Samani, B. R., Klutz, K., Cengic, N., Wolf, I., Mohr, L., ... Spitzweg, C. (2008). α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. Gene Therapy, 15(3), 214-223. https://doi.org/10.1038/sj.gt.3303057

α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. / Willhauck, M. J.; Sharif Samani, B. R.; Klutz, K.; Cengic, N.; Wolf, I.; Mohr, L.; Geissler, M.; Senekowitsch-Schmidtke, R.; Göke, B.; Morris, J. C.; Spitzweg, C.

In: Gene Therapy, Vol. 15, No. 3, 02.2008, p. 214-223.

Research output: Contribution to journalArticle

Willhauck, MJ, Sharif Samani, BR, Klutz, K, Cengic, N, Wolf, I, Mohr, L, Geissler, M, Senekowitsch-Schmidtke, R, Göke, B, Morris, JC & Spitzweg, C 2008, 'α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma', Gene Therapy, vol. 15, no. 3, pp. 214-223. https://doi.org/10.1038/sj.gt.3303057
Willhauck MJ, Sharif Samani BR, Klutz K, Cengic N, Wolf I, Mohr L et al. α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. Gene Therapy. 2008 Feb;15(3):214-223. https://doi.org/10.1038/sj.gt.3303057
Willhauck, M. J. ; Sharif Samani, B. R. ; Klutz, K. ; Cengic, N. ; Wolf, I. ; Mohr, L. ; Geissler, M. ; Senekowitsch-Schmidtke, R. ; Göke, B. ; Morris, J. C. ; Spitzweg, C. / α-Fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. In: Gene Therapy. 2008 ; Vol. 15, No. 3. pp. 214-223.
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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 8.38h, resulting in a tumor absorbed dose of 171mGyMBq-1 131I. After administration of a therapeutic 131I dose (55.5MBq) 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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AU - Wolf, I.

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