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Radioiodine Therapy of Hepatoma Using Targeted Transfer of the Human Sodium/Iodide Symporter Gene

¹ Department of Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China; ² Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany; ³ Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany; and ⁴ Division of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China

Correspondence: For correspondence or reprints contact: Uwe Haberkorn, MD, Department of Nuclear Medicine, University of Heidelberg, Im Neuenheimer Feld 400, Germany 69120, Heidelberg. E-mail: uwe_haberkorn{at}med.uni-heidelberg.de

We investigated the feasibility of radioiodine therapy targeting hepatoma cells (MH3924A) by tissue-specific expression of the human sodium/iodide symporter (hNIS) gene directed by the murine albumin enhancer and promoter (mAlb). Methods: The cell-specific transcriptional activity of mAlb was examined by a luciferase assay in several transiently transfected cell lines. MH3924A cells were stably transfected with the recombinant retroviral vector, in which hNIS complementary DNA expression was driven by mAlb and coupled to hygromycin resistance gene using an internal ribosomal entry site (IRES). Functional hNIS expression in hepatoma cells was confirmed by an iodide uptake assay. In imaging studies, the tumor-bearing ACI rats were intravenously injected with ¹³¹I and imaged with a -camera. Biodistribution was studied at 30 min and at 1, 3, 6, and 25 h after injection of ¹³¹I. Toxic effects of ¹³¹I on hepatoma cells were studied in vitro and in vivo. Results: Stably transfected MH3924A cells concentrated ¹²⁵I up to 240-fold higher than the wild-type cells. The iodide uptake in stably transfected cells was inhibited by ouabain and sodium perchlorate but increased by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. An in vitro clonogenic assay revealed an 86% decrease in colony number in stably transfected cells after exposure to 3.7 MBq/mL of ¹³¹I and only about 8% in hNIS-negative control cells. Furthermore, the in vivo study showed intense tracer accumulation in hNIS-expressing tumors after administration of ¹³¹I. At 3 h after intraperitoneal injection, the transfected tumors accumulated ¹³¹I 19.2-fold higher than the parental tumors in a biodistribution study. Moreover, administration of a therapeutic dose of ¹³¹I resulted in an inhibition of hNIS-expressing tumor growth, whereas control tumors continued to increase in size. Conclusion: A therapeutic effect of ¹³¹I on hepatoma cells in vitro and in vivo has been demonstrated after tumor-specific iodide uptake induced by mAlb-directed hNIS gene expression. Because a stable transformed cell line has been used in these experiments, the clinical potential of this strategy must be evaluated after in vivo transfection of hepatoma cells.

Key Words: sodium/iodide symporter • radionuclide gene therapy • hepatoma • tissue-specific expression

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