Gene therapy with sodium/iodide symporter in hepatocarcinoma.
The ability of thyroid cells to accumulate iodide is a prerequisite for successful radioiodide therapy of benign thyroid diseases and differentiated thyroid carcinoma. The transport of iodide across the cell membrane is mediated by the sodium iodide symporter (hNIS). Employing a bicistronic retroviral vector for the transfer of the hNIS coding sequence and the hygromycin resistance gene stable hNIS expressing rat Morris hepatoma (MH3924A) cell lines were generated by hygromycin selection. Genetically modified MH3924A cell lines accumulated up to 235 times more iodide when compared to non-infected hepatoma cells with a maximal iodide uptake after 60 minutes incubation. Competition experiments in the presence of sodium perchlorate revealed a dose dependent decrease of the iodide uptake, FCCP led to a loss of accumulated I(-), whereas DIDS increased the I(-) uptake into the cells. However, a rapid efflux of the radioactivity (80%) was observed during the first 10 minutes after the 125I(-) containing medium had been replaced by non-radioactive medium. In rats, the hNIS-expressing tumors accumulated six times more iodide as compared to the contralateral wild type tumor as monitored by scintigraphy. An ex vivo quantitation of the iodide content performed 1 hour after tracer administration in 1g tumor tissue revealed a 17-fold higher iodide accumulation in the genetically modified tumors. In vivo also a rapid efflux of the radioactivity out of the tumor was observed. Therefore, the transduction of the hNIS gene per se is sufficient to induce 125I(-) transport in Morris hepatoma cells in vitro and in vivo. For a therapeutic application of the hNIS gene, however, additional conditions need to be defined which inhibit the iodide efflux.
Haberkorn
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Department of Nuclear Medicine, University of Heidelberg and Clinical Cooperation Unit Radiation Therapy, German Cancer Research Center, Heidelberg, Germany. Uwe_Haberkorn@med.uni-heidelberg.de
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D019175:DNA Methylation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006207:Half-Life; D007454:Iodides / Q000378:metabolism; D007455:Iodine / Q000378:metabolism*; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000628:therapy*; D009368:Neoplasm Transplantation; D051381:Rats; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D007454:Iodides; D007455:Iodine; D007457:Iodine Radioisotopes; D027981:Symporters; D000099209:Sodium-Iodide Symporters