Subscribe to RSS
DOI: 10.1055/s-2001-11010
© Johann Ambrosius Barth
Gene therapy with sodium/iodide symporter in hepatocarcinoma
Publication History
Publication Date:
31 December 2001 (online)
![](https://www.thieme-connect.de/media/eced/200101/lookinside/thumbnails/10.1055-s-2001-11010-1.jpg)
Summary:
The ability of thyroid cells to accumulate iodide is a prerequisite for successfull 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 resistence 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rapid efflux of the radioactivity (80%) was observed during the first 10 minutes after the 125I- containing medium had been replaced by non-radioactive medium.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.
Key words:
Sodium/iodide symporter (NIS) - gene therapy - hepatocarcinoma
References
- 1 Arturi F, Russo D, Schlumberger M, du Villard J A, Caillou B, Vigneri P, Wicker R, Chiefari E, Suarez H G, Filetti S. Iodide symporter gene expression in human thyroid tumors. J Clin Endocrinol Metab. 83 2493-2496 1998;
- 2 Caillou B, Troalen F, Baudin E, Talbot M, Filetti S, Schlumberger M, Bidart J M. Na+/I- symporter distribution in human thyroid tissues: an immunohistochemical study. J Clin Endocrinol Metab. 83 4102-4106 1998;
- 3 Cho J Y, Sagartz J E, Capen C C, Mazzaferri E L, Jhiang S M. Early cellular abnormalities induced by RET/PTC1 oncogene in thyroid-targeted transgenic mice. Oncogene. 18 3659-3665 1999;
- 4 Haberkorn U, Henze M, Altmann A, Jiang S, Morr I, Mahmut M, Peschke P, Debus J, Eisenhut M. Transfer of the human sodium iodide symporter gene enhances iodide uptake in hepatoma cells. J Nucl Med. in press, 2/2001;
- 5 Kaminsky S M, Levy O, Salvador C, Dai G, Carrasco N. Na+I- symport activity is present in membrane vesicles from thyrotropin-deprived non-I- transporting cultured thyroid cells. Proc Natl Acad Sci USA. 91 3789-3793 1994;
- 6 Lazar V, Bidart J M, Caillou B, Mahe C, Lacroix L, Filetti S, Schlumberger M. Expression of the Na+/I- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab. 84 3228-3234 1999;
- 7 Mandell R B, Mandell L Z, Link C J. Radioisotope concentrator gene therapy using the sodium/iodide symporter gene. Cancer Res. 59 661-668 1999;
- 8 Marcocci C, Cohen J L, Grollman E F. Effect of actinomycin D on iodide transport in FRTL-5 thyroid cells. Endocrinology. 115 2123-2132 1984;
- 9 Maruca J, Santner S, Miller K, Santen R J. Prolonged iodine clearance with a depletion regimen for thyroid carcinoma. J Nucl Med. 25 1089-1093 1984;
- 10 Nakamura Y, Ohtaki S, Yamazaki I. Molecular mechanism of iodide transport by thyroid plasmalemmal vesicles: cooperative sodium activation and asymmetrical affinities for the ions on the outside and inside of the vesicles. J Biochem. 104 544-549 1988;
- 11 Nakamura Y, Kotani T, Ohtaki S. Transcellular ioide transport and iodination on the apical plasma membrane by monolayer porcine thyroid cells cultured on collagen-coated fibers. J Endocrinol. 126 275-281 1990;
- 12 Paire A, Bernier-Valentin F, Selmi-Ruby S, Rousset B. Characterization of the rat thyroid iodide transporter using anti-peptide antibodies. J Biol Chem. 272 18245-18249 1997;
- 13 Ryu K Y, Senokozlieff M E, Smanik P A, Wong M G, Siperstein A E, Duh Q Y, Clark O H, Mazzaferri E L, Jhiang S M. Development of reverse transcription-competitive polymerase chain reaction method to quantitate the expression levels of human sodium iodide symporter. Thyroid. 9 405-409 1999;
- 14 Schmutzler C, Winzer R, Meissner-Weigl J, Kohrle J. Retinoic acid increases sodium/iodide symporter mRNA levels in human thyroid cancer cell lines and suppresses expression of functional symporter in nontransformed FRTL-5 rat thyroid cells. Biochem Biophys Res Commun. 240 832-838 1997;
- 15 Shimura H, Haraguchi K, Miyazaki A, Endo T, Onaya T. Iodide uptake and experimental 131J therapy in transplanted undifferentiated thyroid cancer cells expressing the Na+/I- symporter gene. Endocrinology. 138 4493-4496 1997;
- 16 Smanik P A, Liu Q, Furminger T L, Ryu K, Xing S, Mazzaferri E L, Jhiang S M. Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun. 226 339-345 1996;
- 17 Venkataraman G M, Yatin M, Ain K B. Cloning of the human sodium-iodide symporter promoter and characterization in a differentiated human thyroid cell line, KAT-50. Thyroid. 8 63-69 1998;
- 18 Venkataraman G M, Yatin M, Marcinek R, Ain K B. Restoration of iodide uptake in dedifferentiated thyroid carcinoma: relationship to human Na+/I- symporter gene methylation status. J Clin Endocrinol Metab. 84 2449-2457 1999;
- 19 Weiss S J, Philp N J, Grollman E F. Iodide transport in a continuous line of cultured cells from rat thyroid. Endocrinology. 114 1090-1098 1984;
Prof. Dr. Uwe Haberkorn
Department of Nuclear Medicine
University of Heidelberg
Im Neuenheimer Feld 400
D-69120 Heidelberg
Germany
Phone: +49-6221-567731
Fax: +49-6221-567473
Email: Uwe_Haberkorn@med.uni-heidelberg.de