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

Journal of Nuclear Medicine

Ruisen Zhu¹  Walter Mier¹  Lihe Guo¹  Annette Altmann¹  Uwe Haberkorn¹  Helmut Eskerski¹  Karin Leotta¹  Libo Chen¹ 

关键词: sodium/iodide symporter;    radionuclide gene therapy;    hepatoma;    tissue-specific expression;   

DOI  :  

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

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 γ-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.

【 授权许可】

Unknown