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    Keywords: CELLS ; EXPRESSION ; GROWTH ; IN-VITRO ; tumor ; TUMOR-CELLS ; Germany ; human ; IN-VIVO ; INHIBITION ; THERAPY ; VITRO ; VIVO ; imaging ; EXPOSURE ; SITE ; GENE ; GENE-EXPRESSION ; TUMORS ; LINES ; DNA ; RAT ; RATS ; CELL-LINES ; ENTRY ; gene expression ; TRANSCRIPTIONAL ACTIVITY ; ASSAY ; resistance ; VECTOR ; PROMOTER ; NUMBER ; PROSTATE-CANCER ; CELL-LINE ; LINE ; HEPATOMA ; BIODISTRIBUTION ; ESTABLISHMENT ; SODIUM/IODIDE SYMPORTER ; FEASIBILITY ; TISSUE-SPECIFIC EXPRESSION ; SODIUM-IODIDE SYMPORTER ; albumin ; ENHANCER ; TUMOR-GROWTH ; INCREASE ; TRANSFECTION ; TRANSPORTER ; HUMAN SODIUM/IODIDE SYMPORTER ; SIZE ; in vivo ; HUMAN HEPATOCELLULAR-CARCINOMA ; RADIONUCLIDE ; radionuclide gene therapy
    Abstract: 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 ACl rats were intravenously injected with I-131 and imaged with a gamma-camera. Biodistribution was studied at 30 min and at 1, 3, 6, and 25 h after injection of I-131. Toxic effects of I-131 on hepatoma cells were studied in vitro and in vivo. Results: Stably transfected MH3924A cells concentrated I-125 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 I-131 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 I-131. At 3 h after intraperitoneal injection, the transfected tumors accumulated I-131 19.2-fold higher than the parental tumors in a biodistribution study. Moreover, administration of a therapeutic dose of I-131 resulted in an inhibition of hNIS-expressing tumor growth, whereas control tumors continued to increase in size. Conclusion: A therapeutic effect of I-131 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
    Type of Publication: Journal article published
    PubMed ID: 16644756
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