Radioiodine therapy of hepatoma using targeted transfer of the human sodium/iodide symporter gene.
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 (131)I and imaged with a gamma-camera. Biodistribution was studied at 30 min and at 1, 3, 6, and 25 h after injection of (131)I. Toxic effects of (131)I on hepatoma cells were studied in vitro and in vivo.


RESULTS
Stably transfected MH3924A cells concentrated (125)I 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 (131)I 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 (131)I. At 3 h after intraperitoneal injection, the transfected tumors accumulated (131)I 19.2-fold higher than the parental tumors in a biodistribution study. Moreover, administration of a therapeutic dose of (131)I resulted in an inhibition of hNIS-expressing tumor growth, whereas control tumors continued to increase in size.


CONCLUSIONS
A therapeutic effect of (131)I 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.
Chen
Libo
L
Department of Nuclear Medicine, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University, Shanghai, China.
Altmann
Annette
A
Mier
Walter
W
Eskerski
Helmut
H
Leotta
Karin
K
Guo
Lihe
L
Zhu
Ruisen
R
Haberkorn
Uwe
U
D000418:Albumins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000532:radiotherapy*; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000532:radiotherapy*; D011401:Promoter Regions, Genetic; D051381:Rats; D027981:Symporters / Q000235:genetics*; D013997:Time Factors; D014018:Tissue Distribution; D000099209:Sodium-Iodide Symporters
D000418:Albumins; D000970:Antineoplastic Agents; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters