Der Natrium-Iodid-Symporter (NIS): Bedeutung für die Bildgebung und therapeutische Optionen

Zusammenfassung

Der Natrium-Iodid-Symporter (NIS) vermittelt als intrinsisches Membranprotein den aktiven Transport von Iodid in die Schilddrüse sowie eine Reihe extrathyreoidaler Organe, insbesondere die laktierende Brustdrüse. Neben seiner Schlüsselrolle in der Schilddrüsenphysiologie bildet NIS die Grundlage der diagnostischen Schilddrüsenszintigrafie sowie der therapeutischen Anwendung von Radioiod bei der Behandlung benigner und maligner Schilddrüsenerkrankungen, und stellt damit eines der ältesten Targets molekularer Bildgebung und Therapie dar. In Anlehnung an die seit mehr als 60 Jahren mit großem Erfolg beim Schilddrüsenkarzinom eingesetzten Radioiodtherapie, ermöglicht die Klonierung und Charakterisierung des NIS-Gens die Entwicklung eines neuen, zytoreduktiven Gentherapieansatzes auf dem Boden der gezielten NIS-Expression in thyreoidalen und extrathyreoidalen Tumoren gefolgt von der therapeutischen Applikation von ¹³¹I oder alternativer Radionuklide, wie ¹⁸⁸Re oder ²¹¹At. Darüber hinaus erlaubt die Möglichkeit des direkten, nicht-invasiven Imagings funktioneller NIS-Expression mittels ¹²³I- und ^99mTc-Szintigrafie oder ¹²⁴I-PET-Imaging den Einsatz von NIS als neuem Reportergen. Zusammenfassend eröffnet die Doppelfunktion von NIS als diagnostisches und therapeutisches Gen sowie der Nachweis extrathyreoidaler endogener NIS-Expression in Mammakarzinomen viel versprechende Perspektiven in der Nuklearmedizin und molekularen Onkologie für die diagnostische und therapeutische Applikation von NIS auch außerhalb der Schilddrüse.

Abstract

The sodium iodide symporter (NIS) is an intrinsic plasma membrane glycoprotein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as therapeutic radioiodine application in benign and malignant thyroid disease. NIS therefore represents one of the oldest targets for molecular imaging and therapy. Based on the effective administration of radioiodine that has been used for over 60 years in the management of follicular cell-derived thyroid cancer, cloning and characterization of the NIS gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on targeted NIS expression in thyroidal and nonthyroidal cancer cells followed by therapeutic application of ¹³¹I or alternative radionuclides, including ¹⁸⁸Re and ²¹¹At. In addition, the possibility of direct and non-invasive imaging of functional NIS expression by ¹²³I- and ^99mTc-scintigraphy or ¹²⁴I-PET-imaging allows the application of NIS as a novel reporter gene. In conclusion, the dual role of NIS as diagnostic and therapeutic gene and the detection of extrathyroidal endogenous NIS expression in breast cancer open promising perspectives in nuclear medicine and molecular oncology for diagnostic and therapeutic application of NIS outside the thyroid gland.

Schlüsselwörter

Natrium-Iodid-Symporter - Radioiodtherapie - molekulare Bildgebung - molekulare Therapie - NIS-Gentherapie - NIS-Reportergen - Mammakarzinom - Radionuklidtherapie

Key words

sodium iodide symporter (NIS) - radioiodine therapy - molecular imaging - molecular therapy - NIS gene therapy - NIS reporter gene - mammary cancer - radionuclide therapy

Literatur

• 1 Spitzweg C, Joba W, Eisenmenger W, Heufelder A E. Analysis of human sodium iodide symporter gene expression in extrathyroidal tissues and cloning of its complementary deoxyribonucleic acids from salivary gland, mammary gland, and gastric mucosa.  J Clin Endocrinol Metab. 1998;  83 1746-1751
• 2 Spitzweg C, Joba W, Schriever K, Goellner J R, Morris J C, Heufelder A E. Analysis of human sodium iodide symporter immunoreactivity in human exocrine glands.  J Clin Endocrinol Metab. 1999;  84 4178-4184
• 3 Jhiang S M, Cho J-Y, Ryu K-Y, De Young B R, Smanik P A, McGaughy V R, Fischer A H, Mazzaferri E L. An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues.  Endocrinology. 1998;  139 4416-4419
• 4 Tazebay U H, Wapnir I L, Levy O, Dohan O, Zuckier L S, Zhao Q H, Deng H F, Amenta P S, Fineberg S, Pestell R G, Carrasco N. The mammary gland iodide transporter is expressed during lactation and in breast cancer.  Nat Med. 2000;  6 871-878
• 5 Spitzweg C, Dutton C M, Castro M R, Bergert E R, Goellner J R, Heufelder A E, Morris J C. Expression of the sodium iodide symporter in human kidney.  Kidney Int. 2001;  59 1013-1023
• 6 Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter.  Nature. 1996;  379 458-460
• 7 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. 1996;  226 339-345
• 8 Spitzweg C, Morris J C. The sodium iodide symporter: its pathophysiological and therapeutic implications.  Clin Endocrinol. 2002;  57 559-574
• 9 Van Sande J, Massart C, Beauwens R, Schoutens A, Costagliola S, Dumonat J E, Wolff J. Anion selectivity by the sodium iodide symporter.  Endocrinology. 2003;  144 247-252
• 10 Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter C S, Carrasco N. The sodium/Iodide symporter (NIS): Characterization, regulation, and medical significance.  Endocrine Rev. 2003;  24 48-77
• 11 Kogai T, Endo T, Saito T, Miyazaki A, Kawaguchi A, Onaya T. Regulation of thyroid-stimulating hormone of sodium/iodide symporter gene expression and protein levels in FRTL-5 cells.  Endocrinology. 1997;  138 2227-2232
• 12 Saito T, Endo T, Kawaguchi A, Ikeda M, Nakazato M, Kogai T, Onaya T. Increased expression of the Na⁺/I^- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves' thyroid tissue.  J Clin Endocrinol Metab. 1997;  82 3331-3336
• 13 Spitzweg C, Heufelder A E, Morris J C. Thyroid iodine transport.  Thyroid. 2000;  10 321-330
• 14 Spitzweg C, Joba W, Morris J C, Heufelder A E. Regulation of sodium-iodide symporter gene expression in FRTL-5 rat thyroid cells.  Thyroid. 1999;  9 821-830
• 15 Wolff J, Chaikoff I L. Plasma inorganic iodide as a homeostatic regulator of thyroid function.  J Biol Chem. 1948;  174 555-564
• 16 Castro M R, Bergert E R, Beito T G, McIver B D, Goellner J R, Morris J C. Development of monoclonal antibodies against the human sodium iodide symporter: Immunohistochemical characterization of this protein in thyroid cells.  J Clin Endocrinol Metab. 1999;  84 2957-2962
• 17 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. 1998;  83 4102-4106
• 18 Joba W, Spitzweg C, Schriever K, Heufelder A E. Analysis of human sodium/iodide symporter, thyroid transcription factor-1, and paired-box-protein-8 gene expression in benign thyroid diseases.  Thyroid. 1999;  9 455-466
• 19 Krohn K, Führer D, Bayer Y, Eszlinger M, Brauer V, Neumann S, Paschke R. Molecular pathogenesis of euthyroid and toxic multinodular goiter.  Endocrine Rev. 2005;  26 504-524
• 20 Russo D, Bulotta S, Bruno R, Arturi F, Giannasio P, Derwahl M, Bidart J-M, Schlumberger M, Filetti S. Sodium/iodide symporter (NIS) and pendrin are expressed differently in hot and cold nodules of thyroid toxic multinodular goiter.  Eur J Endocrinol. 2001;  145 591-597
• 21 Tonacchera M, Viacava P, Agretti P, De Marco G, Perri A, Di Cosmo C, De Servi M, Miccoli P, Lippi F, Naccarato A G, Pinchera A, Chiovato L, Vitti P. Benign nonfunctioning thyroid adenomas are characterized by a defective targeting to cell membrane or a reduced expression of the sodium iodide symporter protein.  J Clin Endocrinol Metab. 2001;  87 352-357
• 22 Mazzaferri E L. Carcinoma of follicular epithelium: Radioiodine and other treatments and outcomes. In: Braverman LE, Utiger RD (eds). The Thyroid: A Fundamental and Clinical Text. 7th ed. Lippincott-Raven, Philadelphia 1996; 922-945
• 23 Castro M R, Bergert E R, Beito T G, Roche P C, Ziesmer S C, Jhiang S M, Goellner J R, Morris J C. Monoclonal antibodies against the human sodium iodide symporter: Utility for immunocytochemistry of thyroid cancer.  J Endocrinol. 1999;  163 495-504
• 24 Castro M R, Bergert E R, Goellner J R, Hay I D, Morris J C. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: Correlation with ¹³¹I uptake.  J Clin Endocrinol Metab. 2001;  86 5627-5632
• 25 Dohan O, Baloch Z, Banrevi Z, Livolsi V, Carrasco N. Predominant intracellular overexpression of the Na+/I- symporter (NIS) in a large sampling of thyroid cancer cases.  J Clin Endocrinol Metab. 2001;  86 2697-2700
• 26 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. 1997;  240 832-838
• 27 Simon D, Körber C, Krausch M, Segering J, Groth P, Görges R, Grünwald F, Müller-Gärtner H W, Schmutzler C, Köhrle J, Röher H D, Reiners C. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: final results of a pilot study.  Eur J Nucl Med Mol Imaging. 2002;  29 775-782
• 28 Grüning T, Tiepolt C, Zöphel K, Bredow J, Kropp J, Franke W -G. Retinoic acid for redifferentiation of thyroid cancer - does it hold its promise.  Eur J Endocrinol. 2003;  148 395-402
• 29 Courbon F, Zerdoud S, Bastie D, Archambaud F, Hoff M, Eche N, Berry I, Caron P. Defective efficacy of retinoic acid treatment in patients with metastatic thyroid carcinoma.  Thyroid. 2006;  16 1025-1031
• 30 Spitzweg C, Harrington K J, Pinke L A, Vile R G, Morris J C. The sodium iodide symporter and its potential in cancer therapy.  J Clin Endocrinol Metab. 2001;  86 3327-3335
• 31 Eskin B A. Iodine and mammary cancer.  Adv Exp Med Biol. 1977;  91 293-304
• 32 Brown-Grant K. The iodide concentrating mechanism of the mammary gland.  J Physiol. 1957;  135 644-654
• 33 Cho J-Y, Leveille R, Kao R, Rousset B, Parlow A F, Burak W E, Mazzaferri E L, Jhiang S M. Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands.  J Clin Endocrinol Metab. 2000;  85 2936-2943
• 34 Rillema J A, Yu T X. Prolactin stimulation of iodide uptake into mouse mammary gland explants.  Am J Physiol. 1996;  271 E879-E882
• 35 Rillema J A, Yu T X, Jhiang S M. Effect of prolactin on sodium iodide symporter expression in mouse mammary gland explants.  Am J Physiol Endocrinol Metab. 2000;  279 E769-E772
• 36 Knostman K A, Cho J -Y, Ryu K-Y, Lin X, McCubrey J A, Hla T, Liu C H, Di Carlo E, Keri R, Zhang M, Hwang D Y, Kisseberth W C, Capen C C, Jhiang S M. Signaling through 3′5′-cyclic adenosine monophosphate and phosphoinositide-3 kinase induces sodium/iodide symporter expression in breast cancer.  J Clin Endocrinol Metab. 2004;  89 5196-5203
• 37 Rudnicka L, Sinczak A, Szybinski P, Huszno B, Stachura J. Expression of the Na(+)/I(-) symporter in invasive ductal breast cancer.  Folia Histochem Cytobiol. 2003;  41 37-40
• 38 Moon D H, Lee S J, Park K Y, Park K K, Ahn S H, Pai M S, Chang H, Lee H K, Ahn I-M. Correlation between ^99mTc-pertechnetate uptakes and expression of human sodium iodide symporter gene in breast tumor tissues.  Nucl Med Biol. 2001;  28 829-834
• 39 Eskin B A, Parker J A, Bassett J G, George D L. Human breast uptake of radioactive iodine.  Obstet Gynecol. 1974;  44 398-402
• 40 Cancroft E T, Goldsmith S J. ^99mTc-pertechnetate scintigraphy as an aid in the diagnosis of breast masses.  Radiology. 1973;  106 441-444
• 41 Wapnir I L, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, Carrasco N. The Na+/I- symporter mediates iodide uptake in breast cancer metastases and can be selectively down-regulated in the thyroid.  Clin Cancer Res. 2004;  10 4294-4302
• 42 Dadachova E, Nguyen A, Lin E Y, Gnatovskiy L, Lu P, Pollard J W. Treatment with rhenium-188-perrhenate and iodine-131 of NIS-expressing mammary cancer in a mouse model remarkably inhibited tumor growth.  Nucl Med Biol. 2005;  32 695-700
• 43 Kogai T, Schultz J, Johnson L, Huang M, Brent G. Retinoic acid induces sodium/iodide symporter gene expression and radioiodine uptake in the MCF-7 breast cancer cell line.  Proc Natl Acad Sci, USA. 2000;  97 8519-8524
• 44 Kogai T, Kanamoto Y, Che L H, Taki K, Moatamed F, Schultz J J, Brent G A. Systemic retinoic acid treatment induces sodium/iodide symporter expression and radioiodine uptake in mouse breast cancer models.  Cancer Res. 2004;  64 415-422
• 45 Unterholzner S, Willhauck M J, Cengic N, Schütz M, Göke B, Morris J C, Spitzweg C. Dexamethasone stimulation of retinoic acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells.  J Clin Endocrinol and Metab. 2006;  91 69-78
• 46 Kogai T, Kanamoto Y, Li A I, Che L H, Ohashi E, Taki K, Chandraratna R A, Saito T, Brent G A. Differential regulation of sodium/iodide symporter gene expression by nuclear receptor ligands in MCF-7 breast cancer cells.  Endocrinology. 2005;  146 3059-3069
• 47 Dohan O, De la Vieja A, Carrasco N. Hydrocortisone and purinergic signaling stimulate NIS-mediated iodide transport in breast cancer cells.  Mol Endocrinol. 2006;  20 1121-1137
• 48 Berger F, Unterholzner S, Diebold J, Knesewitsch P, Hahn K, Spitzweg C. Mammary radioiodine accumulation due to functional sodium iodide symporter expression in a benign fibroadenoma.  Biochem Biophys Res Commun. 2006;  349 1258-1263
• 49 Shimura H, Haraguchi K, Myazaki A, Endo T, Onaya T. Iodide uptake and experimental ¹³¹I therapy in transplanted undifferentiated thyroid cancer cells expressing the Na⁺/I^- symporter gene.  Endocrinology. 1997;  138 4493-4496
• 50 Smit J W, Schroder-Van der Elst J P, Karperien M, Que I, Stokkel M, van der Heide D, Romijn J A. Iodide kinetics and experimental ⁽¹³¹⁾I therapy in a xenotransplanted human sodium-iodide symporter-transfected human follicular thyroid carcinoma cell line.  J Clin Endocrinol Metab. 2002;  87 1247-1253
• 51 Cho J-Y, Xing S, Liu X, Buckwalter T LF, Hwa L, Sferra T J, Chiu I-M, Jhiang S M. Expression and activity of human Na+/I- symporter in human glioma cells by adenovirus-mediated gene delivery.  Gene Ther. 2000;  7 740-749
• 52 Cho J-Y, Shen D HY, Yang W, Williams B, Buckwalter T LF, La Perle K MD, Hinkle G, Pozderac R, Kloos R, Nagaraja H N, Barth R F, Jhiang S M. In vivo imaging and radioiodine therapy following sodium iodide symporter gene transfer in animal model of intracerebral gliomas.  Gene Ther. 2002;  9 1139-1145
• 53 Mandell R B, Mandell L Z, Link C J. Radioisotope concentrator gene therapy using the sodium/iodide symporter gene.  Cancer Res. 1999;  59 661-668
• 54 Boland A, Ricard M, Opolon P, Bidart J -M, Yeh P, Filetti S, Schlumberger M, Perricaudet M. Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy.  Cancer Res. 2000;  60 3484-3492
• 55 Carlin S, Cunningham S H, Boyd M, McCluskey A G, Mairs R J. Experimental targeted radioiodide therapy following transfection of the sodium iodide symporter gene: effect on clonogenicity in both two- and three-dimensional models.  Cancer Gene Ther. 2000;  7 1529-1536
• 56 Dingli D, Peng K-W, Harvey M E, Greipp P R, O'Connor M K, Cattaneo R, Morris J C, Russell S J. Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter.  Blood. 2004;  103 1641-1646
• 57 Faivre J, Clerc J, Gerolami R, Herve J, Longuet M, Liu B, Roux J, Moal F, Perrricaudet M, Brechot C. Long-term radioiodine retention and regression of liver cancer after sodium iodide symporter gene transfer in wistar rats.  Cancer Res. 2004;  64 8045-8051
• 58 Haberkorn U, Henze M, Altmann A, Jiang S, Morr I, Mahmut M, Peschke P, Kübler W, Debus J, Eisenhut M. Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells.  J Nucl Med. 2001;  42 317-325
• 59 Spitzweg C, Zhang S, Bergert E R, Castro M R, McIver B D, Tindall D J, Young C YF, Morris J C. Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.  Cancer Res. 1999;  59 2136-2141
• 60 Spitzweg C, O'Connor M K, Bergert E R, Tindall D J, Young C YF, Morris J C. Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter.  Cancer Res. 2000;  60 6526-6530
• 61 Spitzweg C, Scholz I V, Bergert E R, Tindall D J, Young C YF, Göke B, Morris J C. Retinoic acid-induced stimulation of sodium iodide symporter (NIS) expression and cytotoxicity of radioiodine in prostate cancer cells.  Endocrinology. 2003;  144 3423-3432
• 62 Scholz I V, Cengic N, Göke B, Morris J C, Spitzweg C. Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter (NIS).  J Clin Endocrinol Metab. 2004;  89 1108-1116
• 63 Spitzweg C, Dietz A B, O'Connor M K, Bergert E R, Tindall D J, Young C YF, Morris J C. In vivo sodium iodide symporter gene therapy of prostate cancer.  Gene Ther. 2001;  8 1524-1531
• 64 Kakinuma H, Bergert E R, Spitzweg C, Cheville J C, Lieber M M, Morris J C. Probasin Promoter (ARR2PB) driven, prostate specific expression of h-NIS for targeted radioiodine therapy of prostate cancer.  Cancer Res. 2003;  63 7840-7844
• 65 Dwyer R M, Schatz S M, Bergert E R, Myers R M, Harvey M E, Classic K L, Blanco M C, Frisk C S, Marler R J, Davis B J, O'Connor M K, Russell S J, Morris J C. A preclinical large animal model of adenovirus-mediated expression of the sodium-iodide symporter for radioiodide imaging and therapy of locally recurrent prostate cancer.  Mol Ther. 2005;  12 835-841
• 66 Scholz I V, Cengic N, Baker C H, Harrington K J, Maletz K, Bergert E R, Vile R, Göke B, Morris J C, Spitzweg C. Radioiodine therapy of colon cancer following tissue-specific sodium iodide symporter gene transfer.  Gene Ther. 2005;  12 272-280
• 67 Cengic N, Baker C H, Schutz M, Göke B, Morris J C, Spitzweg C. A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression.  J Clin Endocrinol Metab. 2005;  90 4457-4464
• 68 Willhauck M J, Sharif-Samani B, Cengic N, Mohr L, Geissler M, Göke B, Morris J C, Spitzweg C. Alpha fetoprotein promoter-targeted sodium iodide symporter gene therapy of hepatocellular carcinoma. 88th Annual Meeting of the Endocrine Society, Boston, USA, 2006
• 69 Chen L, Altmann A, Mier W, Eskerski H, Leotta K, Guo L, Zhu R, Haberkorn U. Radioiodine therapy of hepatoma using targeted transfer of the human sodium/iodide symporter gene.  J Nucl Med. 2006;  47 854-862
• 70 Schipper M L, Weber A, Behe M, Göke R, Joba W, Schmidt H, Bert T, Simon B, Arnold R, Heufelder A E, Behr T M. Radioiodide treatment after sodium iodide symporter gene transfer is a highly effective therapy in neuroendocrine tumor cells.  Cancer Res. 2003;  63 1333-1338
• 71 Dingli D, Diaz R M, Bergert E R, O'Connor M K, Morris J C, Russell S J. Genetically targeted radiotherapy for multiple myeloma.  Blood. 2003;  102 489-496
• 72 Dwyer R M, Bergert E R, O'Connor M K, Gendler S J, Morris J C. In vivo radioiodide imaging and treatment of breast cancer xenografts after MUC1-driven expression of the sodium iodide symporter.  Clin Cancer Res. 2005;  11 1483-1489
• 73 Dwyer R M, Bergert E R, O'Connor M K, Gendler S J, Morris J C. Sodium iodide symporter-mediated radioiodide imaging and therapy of ovarian tumor xenografts in mice.  Gene Ther. 2006;  13 60-66
• 74 Dwyer R M, Bergert E R, O'Connor M K, Gendler S J, Morris J C. Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors.  Hum Gene Ther. 2006;  17 661-668
• 75 Dingli D, Bergert E R, Bajzer Z, O'Connor M K, Russell S J, Morris J C. Dynamic iodide trapping by tumor cells expressing the thyroidal sodium iodide symporter.  Biochem Biophys Res Commun. 2004;  325 157-166
• 76 Boland A, Magnon C, Filetti S, Bidart J-M, Schlumberger M, Yeh P, Perricaudet M. Transposition of the thyroid iodide uptake and organification system in nonthyroid tumor cells by adenoviral vector-mediated gene transfers.  Thyroid. 2002;  12 19-26
• 77 Huang M, Batra R K, Kogai T, Lin Y Q, Hershman J M, Lichtenstein A, Sharma S, Zhu L X, Brent G A, Dubinett S M. Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non-small cell lung cancer.  Cancer Gene Ther. 2001;  8 612-618
• 78 Zhang L, Sharma S, Zhu L X, Kogai T, Hershman J M, Brent G A, Dubinett S M, Huang M. Nonradioactive iodide effectively induces apoptosis in genetically modified lung cancer cells.  Cancer Res. 2003;  63 5065-5072
• 79 Elisei R, Vivaldi A, Ciampi R, Faviana P, Basolo F, Santini F, Traino C, Pacini F, Pinchera A. Treatment with drugs able to reduce iodine efflux significantly inceases the intracellular retention time in thyroid cancer cells stably transfected with sodium iodide symporter (NIS) cDNA.  J Clin Endocrinol Metab. 2006;  91 2389-2395
• 80 Dadachova E, Bouzahzah B, Zuckier L S, Pestell R G. Rhenium-188 as an alternative to iodine-131 for treatment of breast tumors expressing the sodium/iodide symporter (NIS).  Nucl Med Biol. 2002;  29 13-18
• 81 Petrich T, Helmeke H-J, Meyer G J, Knapp W H, Pötter E. Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter.  Eur J Nucl Med Mol Imaging. 2002;  29 842-854
• 82 Carlin S, Mairs R J, Welsh P, Zalutsky M R. Sodium-iodide symporter (NIS)-mediated accumulation of (²¹¹At)astatide in NIS-transfected human cancer cells.  Nucl Med Biol. 2002;  29 729-739
• 83 Carlin S, Akabani G, Zalutsky M R. In vitro cytotoxicity of ²¹¹At-Astatide and ¹³¹I-Iodide to glioma tumor cells expressing the sodium/iodide symporter.  J Nucl Med. 2003;  44 1827-1838
• 84 Petrich T, Quintanilla-Martinez L, Korkmaz Z, Samson E, Helmeke H J, Meyer G J, Knapp W H, Pötter E. Effective cancer therapy with the a-particle emitter [211-At]astatine in a mouse model of genetically modified sodium/iodide symporter-expressing tumors.  Clin Cancer Res. 2006;  12 1342-1348
• 85 Dingli D, Russell S J, Morris J C. In vivo imaging and tumor therapy with the sodium iodide symporter.  J Cell Biochem. 2003;  90 1079-1086
• 86 Marsee D K, Shen D HY, MacDonald L R, Vadysirisack D D, Lin X, Hinkle G, Kloos R T, Jhiang S M. Imaging of metastatic pulmonary tumors following NIS gene transfer using single photon emission computed tomography.  Cancer Gene Ther. 2004;  11 121-127
• 87 Groot-Wassink T, Aboagye E O, Wang Y, Lemoine N R, Reader A J, Vassaux G. Quantitative imaging of Na/I symporter transgene expression using positron emission tomography in the living animal.  Mol Ther. 2004;  9 436-442
• 88 Groot-Wassink T, Aboagye E O, Wang Y, Lemoine N R, Keith W N, Vassaux G. Noninvasive imaging of the transcriptional activities of human telomerase promoter fragments in mice.  Cancer Res. 2004;  64 4906-4911
• 89 Dingli D, Kemp B J, O'Connor M K, Morris J C, Russell S J, Lowe V J. Combined I-124 Positron Emission Tomography/Computed Tomography Imaging of NIS gene expression in animal models of stably transfected and intravenously transfected tumors.  Mol Imaging Biol. 2006;  8 16-23
• 90 Niu G, Anderson R G, Madsen M T, Graham M M, Oberley L W, Domann F E. Dual-expressing adenoviral vectors encoding the sodium iodide symporter for use in noninvasive radiological imaging of therapeutic gene transfer.  Nucl Med Biol. 2006;  33 391-398
• 91 Miyagawa M, Beyer M, Wagner B, Anton M, Spitzweg C, Gansbacher B, Schwaiger M, Benger F M. Cardiac reporter gene imaging using the human sodium/iodide symporter gene.  Cardiovasc Res. 2005;  65 195-202
• 92 Miyagawa M, Anton M, Wagner B, Haubner R, Souvatzoglou M, Gansbacher B, Schwaiger M, Bengel F M. Non-invasive imaging of cardiac transgene expression with PET: comparison of the human sodium/iodide symporter gene and HSV1-tk as the reporter gene.  Eur J Nucl Med Mol Imaging. 2005;  32 1108-1114
• 93 Niu G, Krager K J, Graham M M, Hichwa R D, Domann F E. Noninvasive radiological imaging of pulmonary gene transfer and expression using the human sodium iodide symporter.  Eur J Nucl Med Mol Imaging. 2005;  32 534-540
• 94 Yang H S, Lee H, Kim S J, Lee W W, Yang Y-J, Moon D H, Park S-W. Imaging of human sodium-iodide symporter gene expression mediated by recombinat adenovirus in skeletal muscle of living rats.  Eur J Nucl Med Mol Imaging. 2004;  31 1304-1311
• 95 Vadysirisack D D, Shen D H, Jhiang S M. Correlation of Na+/I- symporter expression and activity: implications of Na+/I- symporter as an imaging reporter gene.  J Nucl Med. 2006;  47 182-190