Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells

The characteristic feature of thyroid cells of taking up iodide enables ben ign thyroid diseases and differentiated thyroid carcinoma to be successfull y treated with radioiodide therapy. The transport of iodide across the cell membrane is mediated by the human NaI symporter (hNIS). We therefore inves tigated whether the accumulation of iodide may be induced by the retroviral transfer of the hNIS gene in nonthyroid tumor cells. Methods: With use of a bicistronic retroviral vector for the transfer of the hNIS coding sequenc e and the hygromycin resistance gene, rat Morris hepatoma (MH3924A) cells w ere infected with retroviral particles and 32 hNIS-expressing cell lines we re generated by hygromycin selection. After incubation of the genetically m odified and wild-type hepatoma cells and the rat thyroid cell line FRTL5 wi th (NaI)-I-125, the uptake and efflux of iodide were determined. In additio n, the iodide distribution in rats bearing wildtype and genetically modifie d hepatomas was monitored. Results: Genetically modified MH3924A cell lines accumulated up to 235 times more iodide than did noninfected hepatoma cell s. The maximal iodide uptake in the cells was observed after 60 min incubat ion time. Competition experiments in the presence of sodium perchlorate rev ealed a dose-dependent decrease of iodide uptake (87%-92%), Moreover, carbo nyl cyanide p-trifluoromethoxyphenylhydrazone led to a loss of accumulated I-(32%), whereas 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene increase d the I- uptake into the cells (22%). However, a rapid efflux of the radioa ctivity (80%) was observed during the first 10 min after I-125(-)-containin g medium had been replaced by nonradioactive medium. In rats, the hNIS-expr essing tumors accumulated six times more iodide than did the contralateral wild-type tumor as monitored by scintigraphy. The ex vivo quantitation of t he iodide content performed 1 h after tracer administration in 1g of tumor tissue revealed a 17-fold higher iodide accumulation in the genetically mod ified tumors. In accordance with the in vitro data, we also observed a rapi d efflux of radioactivity from the tumor in vivo. Conclusion: The transduct ion of the hNIS gene per se is sufficient to induce I-125-transport in Morr is hepatoma cells in vitro and in vivo. With regard to a therapeutic applic ation, however, additional conditions need to be defined that inhibit the i odide efflux from the tumor cells.