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Basic Science Investigations |
1 Department of Nuclear Medicine, University of Heidelberg, Heidelberg, Germany
2 Clinical Cooperation Unit Nuclear Medicine, Deutsche Krebsforschungszentrum, Heidelberg, Germany
3 Department of Anatomy and Cell Biology III, University of Heidelberg, Heidelberg, Germany
4 Department of Radiation Protection, Deutsche Krebsforschungszentrum, Heidelberg, Germany
5 Department of Radiochemistry and Radiopharmacology, Deutsche Krebsforschungszentrum, Heidelberg, Germany
Transfer of the human sodium iodide symporter (hNIS) has been proposed as a new principle of cancer gene therapy. This study evaluates the iodide kinetics and dosimetry of iodide in hNIS-expressing thyroid carcinoma cells under optimized conditions. Methods: Using a bicistronic retroviral vector for the transfer of the hNIS and the hygromycin resistance gene, hNIS-expressing rat thyroid carcinoma cell lines were generated. Afterward, Na125I uptake and efflux were determined in genetically modified and wild-type cells in the presence or absence of modulators of iodide transport. In addition, the 131I distribution in thyroid-ablated nude mice bearing wild-type and genetically modified thyroid carcinomas was monitored after intraperitoneal administration of 131I with and without coadministration of lithium carbonate. Results: hNIS-expressing cell lines accumulated up to 49 times more iodide than did noninfected cells, with a maximal iodide uptake after 30 min of incubation. However, a 90% efflux of the radioactivity occurred 20 min after replacement of the medium. In mice, the hNIS-expressing tumors accumulated up to 23 and 19.5 times more iodide than did the wild-type tumors in lithium-treated and control animals, respectively. However, efflux of the radioactivity was also observed in vivo: After 24 h, hNIS-expressing tumors lost 82.5% and 80.4% of the initial activity. Dosimetric calculations showed that 1,650 MBq of 131I per square meter resulted in 5.4 and 5.2 Gy in hNIS-expressing tumors and 0.24 and 0.26 in wild-type tumors. Conclusion: Transduction of the hNIS gene in rat thyroid carcinoma cells induces iodide transport, which is associated with rapid efflux. Application of 131I in clinically relevant amounts did not result in therapeutically useful absorbed doses in hNIS-expressing tumors in vivo, even under optimized conditions of thyroid ablation and treatment with lithium carbonate.
Key Words: sodium iodide symporter • gene therapy • lithium • thyroid carcinoma
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