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SPITZWEG
Mammary radioiodine accumulation due to functional sodium iodide symporter expression in a benign fibroadenoma.Berger F, Unterholzner S, Diebold J, Knesewitsch P, Hahn K, Spitzweg C. Biochem Biophys Res Commun. 2006 Nov 3;349(4):1258-63. Epub 2006 Sep 7. [abstract only]
"The sodium iodide
symporter (NIS) has been characterized to mediate the active transport
of iodide not only in the thyroid gland but also in various
non-thyroidal tissues, including lactating mammary gland and the
majority of breast cancers, thereby offering the possibility of
diagnostic and therapeutic radioiodine application in breast cancer.
In this report, we present a 57-year-old patient with multifocal
papillary thyroid carcinoma, who showed focal radioiodine accumulation
in a lesion in the right breast on a posttherapy (131)I scan following
radioiodine therapy. CT and MR-mammography showed a focal solid lesion
in the right breast suggestive of a fibroadenoma, which was confirmed
by histological examination. Immunostaining of paraffin-embedded tumor
tissue sections using a human NIS antibody demonstrated NIS-specific
immunoreactivity confined to epithelial cells of mammary ducts. In
conclusion, in a thyroid cancer patient we identified a benign
fibroadenoma of the breast expressing high levels of functionally
active NIS protein as underlying cause of focal mammary radioiodine
accumulation on a posttherapy (131)I scan. These data show for the
first time that functional NIS expression is not restricted to
lactating mammary gland and malignant breast tissue, but can also be
detected in benign breast lesions, such as fibroadenomata of the
breast."
Dexamethasone stimulation of retinoic Acid-induced sodium iodide symporter expression and cytotoxicity of 131-I in breast cancer cells.Unterholzner S, Willhauck MJ, Cengic N, Schutz M, Goke B, Morris JC, Spitzweg C. J Clin Endocrinol Metab. 2006 Jan;91(1):69-78. Epub 2005 Oct 18. [abstract only]
"CONTEXT: The sodium iodide symporter (NIS) mediates the active iodide uptake in the thyroid gland as well as lactating breast tissue. Recently induction of functional NIS expression was reported in the estrogen receptor-positive human breast cancer cell line MCF-7 by all-trans retinoic acid (atRA) treatment in vitro and in vivo, which might offer the potential to treat breast cancer with radioiodine. OBJECTIVE: In the current study, we examined the effect of dexamethasone (Dex) on atRA-induced NIS expression and therapeutic efficacy of 131-I in MCF-7 cells. DESIGN: For this purpose, NIS mRNA and protein expression levels in MCF-7 cells were examined by Northern and Western blot analysis after incubation with Dex (10(-9) to 10(-7) m) in the presence of atRA (10(-6) m) as well as immunostaining using a mouse monoclonal human NIS-specific antibody. In addition, NIS functional activity was measured by iodide uptake and efflux assay, and in vitro cytotoxicity of 131-I was examined by in vitro clonogenic assay. RESULTS: After incubation with Dex in the presence of atRA, NIS mRNA levels in MCF-7 cells were stimulated up to 11-fold in a concentration-dependent manner, whereas NIS protein levels increased up to 16-fold and iodide accumulation was stimulated up to 3- to 4-fold. Furthermore, iodide efflux was modestly decreased after stimulation with Dex in the presence of atRA. Furthermore, in the in vitro clonogenic assay, selective cytotoxicity of 131-I was significantly increased from approximately 17% in MCF-7 cells treated with atRA alone to 80% in MCF-7 cells treated with Dex in the presence of atRA. CONCLUSION: Treatment with Dex in the presence of atRA significantly increases functional NIS expression levels in addition to inhibiting iodide efflux, resulting in an enhanced selective killing effect of 131-I in MCF-7 breast cancer cells."
A novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue-specific sodium iodide symporter gene expression.Cengic N, Baker CH, Schutz M, Goke B, Morris JC, Spitzweg C. J Clin Endocrinol Metab. 2005 Aug;90(8):4457-64.
Epub 2005 Jun 7. "CONTEXT: In contrast to papillary and follicular thyroid cancer, medullary thyroid cancer (MTC) remains difficult to treat due to its unresponsiveness to radioiodine therapy and its limited responsiveness to chemo- and radiotherapy. OBJECTIVE: To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of MTC after human sodium iodide symporter (hNIS) gene transfer using the calcitonin promoter to target hNIS gene expression to MTC cells (TT). DESIGN: TT cells were stably transfected with an expression vector, in which hNIS cDNA was coupled to the calcitonin promoter. Functional hNIS expression was confirmed by iodide accumulation assays, Northern and Western blot analysis, immunostaining, and in vitro clonogenic assay. RESULTS: hNIS-transfected TT cells showed perchlorate-sensitive iodide uptake, accumulating 125-I about 12-fold in vitro with organification of 4% of accumulated iodide resulting in a significant decrease in iodide efflux. NIS protein expression was confirmed by Western blot analysis using a monoclonal hNIS-specific antibody, which revealed a major band of a molecular mass of 80-90 kDa. In addition, immunostaining of hNIS-transfected TT cells revealed hNIS-specific immunoreactivity, which was primarily membrane associated. In an in vitro clonogenic assay, 84% of NIS-transfected TT cells were killed by exposure to 131-I, whereas only about 0.6% of control cells were killed. CONCLUSIONS: A therapeutic effect of 131-I has been demonstrated in MTC cells after induction of tissue-specific iodide uptake activity by calcitonin promoter-directed hNIS expression. This study demonstrates the potential of NIS as a therapeutic gene, allowing radioiodine therapy of MTC after tissue-specific NIS gene transfer.
Cardiac reporter gene imaging using the human sodium/iodide symporter gene.Miyagawa M, Beyer M, Wagner B, Anton M, Spitzweg C, Gansbacher B, Schwaiger M, Bengel FM. Cardiovasc Res. 2005 Jan 1;65(1):195-202. [abstract only]
"OBJECTIVE: Imaging of reporter gene expression holds promise for noninvasive monitoring of cardiovascular molecular therapy. We investigated the feasibility of myocardial gene expression imaging in living rats using the human sodium/iodide symporter gene (hNIS) and widely available scintigraphic techniques. METHODS: We injected adenovirus expressing hNIS under control of cytomegalovirus promoter (Ad(hNIS)) directly into left ventricular myocardium of Wistar rats. For detection of reporter gene expression, dynamic gamma-camera imaging was performed following intravenous injection of (123)Iodide or (99m)Technetium. RESULTS: For both radiotracers, focal cardiac accumulation was identified as early as 10 min, and remained detectable until 2 hrs after injection, while it was not present in animals injected with LacZ control virus. Intensity of tracer accumulation gradually decreased when decreasing titers of Ad(hNIS) were applied. Treatment with sodium perchlorate (a blocker of hNIS) abolished cardiac tracer uptake after Ad(hNIS)-infection. Serial imaging after cardiac gene transfer demonstrated a peak of tracer signal between days 1 and 3, and a subsequent decrease until day 12. Postmortem analysis of hearts yielded significant correlation between in vivo radiotracer accumulation and ex vivo gamma-counting. Autoradiography demonstrated specific regional radioactivity in Ad(hNIS)-infected myocardial areas. CONCLUSIONS: hNIS offers a practical and reliable approach for myocardial gene expression imaging. Using suitable vectors, hNIS may be coexpressed with therapeutic genes or stably expressed in stem cells for future monitoring of cardiovascular molecular therapy."
Radioiodine therapy of colon cancer following tissue-specific sodium iodide symporter gene transfer.Scholz IV, Cengic N, Baker CH, Harrington KJ, Maletz K, Bergert ER, Vile R, Goke B, Morris JC, Spitzweg C. Gene Ther. 2005 Feb;12(3):272-80. [abstract only]
"We investigated the feasibility of using radioiodine therapy in colon carcinoma cells (HCT 116) following tumor-specific expression of the human sodium iodide symporter (hNIS) using the carcinoembryonic antigen (CEA) promoter. HCT 116 cells were stably transfected with an expression vector, in which hNIS cDNA has been coupled to a CEA promoter fragment. This promoter is responsible for tissue-specific expression of CEA in gastrointestinal tract epithelium, and has been shown to target therapeutic genes to colorectal cancer cells. Functional NIS expression was confirmed by iodide uptake assay, Western blot analysis, immunostaining and in vitro clonogenic assay. The stably transfected HCT 116 cells concentrated (125)I about 10-fold in vitro without evidence of iodide organification. In contrast, transfection of control cancer cells without CEA expression did not result in iodide accumulation. Western blot analysis using a hNIS-specific antibody revealed a band of approximately 90 kDa. In addition, immunostaining of stably transfected HCT 116 cells revealed hNIS-specific membrane-associated immunoreactivity. In an in vitro clonogenic assay approximately 95% of stably transfected HCT 116 cells were killed by exposure to (131)I, while only about 5% of NIS-negative control cells were killed. Further, using an adenovirus carrying the NIS gene linked to the CEA promoter, high levels of tumor-specific radioiodide accumulation were induced in HCT 116 cells. In conclusion, a therapeutic effect of (131)I has been demonstrated in colon carcinoma cells following induction of tumor-specific iodide uptake activity by CEA promoter-directed NIS expression in vitro. This study demonstrates the potential of NIS as a therapeutic gene allowing radioiodine therapy of colon cancer following tumor-specific NIS gene transfer."
[The practical relevance of the sodium iodide symporter]Spitzweg C. Z Arztl Fortbild Qualitatssich. 2004 May;98 Suppl 5:25-32. Review. German. [abstract only]
"The sodium iodide
symporter (NIS) is an intrinsic plasma membrane protein mediating the
active transport of iodide in the thyroid gland and a number of
extrathyroidal tissues, in particular in the lactating mammary gland.
Because of its crucial role for the ability of thyroid follicular
cells to trap iodide, cloning of NIS opened up an exciting and
extensive new field of thyroid-related research. Cloning and molecular
characterisation of NIS allows investigation of its expression and
regulation in thyroidal and non-thyroidal tissues and its potential
pathophysiological and therapeutic implications in benign and
malignant thyroid disease. In addition to its key function in thyroid
physiology, NIS-mediated iodide accumulation allows both diagnostic
thyroid scintigraphy and the effective therapeutic application of
radioiodine in benign and malignant thyroid disease. Characterisation
and application of NIS as a novel therapeutic gene for cytoreductive
gene therapy of extra-thyroidal tumours and the presence of high
endogenous NIS expression in the majority of breast cancers further
suggest a promising role of NIS in the diagnosis and treatment of
cancer outside the thyroid gland."
Dexamethasone enhances the cytotoxic effect of radioiodine therapy in prostate cancer cells expressing the sodium iodide symporter.Scholz IV, Cengic N, Goke B, Morris JC, Spitzweg C J Clin Endocrinol Metab. 2004 Mar;89(3):1108-16.
"Recently, we have reported the induction of prostate-specific radioiodine accumulation in prostate cancer cells (LNCaP) using a prostate-specific antigen (PSA)-promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. The aim of our current study was to examine the regulation of PSA-promoter-directed NIS expression in NIS-transfected LNCaP cells (NP-1) by dexamethasone (Dex). For this purpose, NIS mRNA and protein expression levels were examined in NP-1 cells by Northern and Western blot analysis, respectively, after incubation with Dex (10(-8)-10(-6) M) in the presence of 10(-9) M mibolerone. NIS functional activity was measured by iodide uptake assay. In addition, we examined regulation of in vitro cytotoxicity of 131-I by Dex in an in vitro clonogenic assay. After incubation with Dex, iodide accumulation in NP-1 cells increased up to 1.5-fold, whereas NIS mRNA and protein expression levels were increased up to 1.7-fold. This effect of Dex was blocked by the androgen receptor antagonist casodex (10(-6) M). The killing effect of 131-I in NP-1 cells was increased from 55% when incubated with mibolerone alone to 95% when treated with Dex (10(-7) M) plus mibolerone. Treatment of NP-1 cells with Dex resulted in an additional antiproliferative effect as measured by clonogenic assay and nonradioactive proliferation assay. In conclusion, in addition to an antiproliferative effect, treatment with Dex increases androgen-dependent NIS mRNA and protein expression as well as iodide accumulation, resulting in an increased cytotoxic effect of 131-I in prostate cancer cells stably expressing NIS under the control of the PSA-promoter."
Gene therapy for thyroid cancer: current status and future prospects.Spitzweg C, Morris JC. Thyroid. 2004 Jun;14(6):424-34. Review. [abstract only]
"Despite multimodality
treatment for thyroid cancer, including surgical resection,
radioiodine therapy, thyrotropin (TSH)-suppressive thyroxine
treatment, and chemotherapy/radiotherapy, survival rates have not
improved over the last decades. Therefore, development and evaluation
of novel treatment strategies, including gene therapy, are urgently
needed. A variety of gene therapy approaches have been evaluated for
the treatment of follicular cell-derived and medullary thyroid cancer,
including corrective gene therapy (p53 restoration, expression of a
dominant negative RET mutant), cytoreductive gene therapy (suicide
gene/prodrug strategy herpes simplex virus-thymidine kinase [HSV-tk]/ganciclovir,
antiangiogenic therapy with endostatin) and immunomodulatory gene
therapy (expression of interleukin (IL)-2 and IL-12). Furthermore,
cloning of the sodium iodide symporter (NIS) gene has paved the way
for the development of a novel cytoreductive gene therapy strategy
based on NIS gene transfer followed by the application of radioiodine
therapy ((131)I). NIS gene delivery into medullary and follicular
cell-derived thyroid cancer cells has been shown to be capable of
establishing or restoring radioiodine accumulation and might therefore
represent an effective therapy for medullary and dedifferentiated
thyroid tumors that lack iodide accumulating activity. The data
summarized in this review article clearly demonstrate that the
currently available strategies represent potentially curative novel
therapeutic approaches for future gene therapy of thyroid cancer. The
combination of different therapeutic genes has been demonstrated to be
very useful to enhance therapeutic efficacy and seems to have a
promising role at least as part of a multimodality approach for
advanced thyroid cancer."
Probasin promoter (ARR(2)PB)-driven, prostate-specific expression of the human sodium iodide symporter (h-NIS) for targeted radioiodine therapy of prostate cancer.Kakinuma H, Bergert ER, Spitzweg C, Cheville JC, Lieber MM, Morris JC. Cancer Res. 2003 Nov 15;63(22):7840-4. Erratum in: Cancer Res. 2003 Dec 15;63(24):9057. Cancer Res. 2004 Feb 15;64(4):1559.
"Prostate cancer is one of the most promising candidates for sodium iodide symporter (NIS)-mediated gene therapy. Adenovirus-mediated expression of NIS that is driven by prostate-specific promoters induces generous radioiodine accumulation in prostate cancer cells that may be used for therapy with (131)I. We have recently developed a replication-deficient adenovirus carrying the human NIS cDNA linked to a composite probasin promoter, ARR(2)PB, aiming toward specific expression of the human NIS gene (h-NIS) in prostate tissue for targeted radioactive iodide therapy of prostate cancer (Ad-ARR(2)PB/hNIS). The ability of Ad-ARR(2)PB/hNIS to cause NIS expression in tumor cells was characterized by iodide uptake assay and compared with Ad-CMV/hNIS in which the h-NIS expression is driven by the cytomegalovirus (CMV) promoter. Androgen-dependent prostate cancer cell lines (LNCaP) and non-prostate origin tumor cell lines (SNU449, MCF-7, HCT116, OVCAR-3, and Panc-1) were infected with the viral constructs, and perchlorate-sensitive (125)I uptake and NIS protein expression were measured. Ad-ARR(2)PB/hNIS-infected LNCaP cells showed androgen-dependent and perchlorate-sensitive iodide uptake. Iodide accumulation in LNCaP cells infected with Ad-ARR(2)PB/hNIS, followed by incubation with synthetic androgen, was 5.3-fold increased compared with those coincubated with perchlorate (15,184 +/- 1,173 cpm versus 2,837 +/- 187 cpm). Ad-ARR(2)PB/hNIS-infected LNCaP cells revealed a 3.2-fold increase of iodide accumulation compared with those infected with Ad-CMV/hNIS (multiplicity of infection = 30). Iodide uptake in a panel of non-prostate tumor cell lines infected with Ad-ARR(2)PB/hNIS was no more than 2,500 cpm, demonstrating the tissue specificity of this construct. These results indicate that Ad-ARR(2)PB/hNIS can be used to achieve high-magnitude and tissue-specific expression of h-NIS in prostate tissue and is a promising candidate for cancer gene therapy of prostate cancer."
Retinoic acid-induced stimulation of sodium iodide symporter expression and cytotoxicity of radioiodine in prostate cancer cells.Spitzweg C, Scholz IV, Bergert ER, Tindall DJ, Young CY, Goke B, Morris JC. Endocrinology. 2003 Aug;144(8):3423-32.
"We reported recently the induction of androgen-dependent iodide uptake activity in the human prostatic adenocarcinoma cell line LNCaP using a prostate-specific antigen (PSA) promoter-directed expression of the sodium iodide symporter (NIS) gene. This offers the potential to treat prostate cancer with radioiodine. In the current study, we examined the regulation of PSA promoter-directed NIS expression and therapeutic effectiveness of (131)I in LNCaP cells by all-trans-retinoic acid (atRA). For this purpose, NIS mRNA and protein expression levels in the NIS-transfected LNCaP cell line NP-1 were examined by Northern and Western blot analysis following incubation with atRA (10 (-9) to 10(-6) M) in the presence of 10(-9) M mibolerone (mib). In addition, NIS functional activity was measured by iodide uptake assay, and in vitro cytotoxicity of (131)I was examined by in vitro clonogenic assay. Following incubation with atRA, NIS mRNA levels in NP-1 cells were stimulated 3-fold in a concentration-dependent manner, whereas NIS protein levels increased 2.3-fold and iodide accumulation was stimulated 1.45-fold. This stimulatory effect of atRA, which has been shown to be retinoic acid receptor mediated, was completely blocked by the pure androgen receptor antagonist casodex (10(-6) M), indicating that it is androgen receptor dependent. The selective killing effect of (131)I in NP-1 cells was 50% in NP-1 cells incubated with 10(-9) M mib. This was increased to 90% in NP-1 cells treated with atRA (10(-7) M) plus 10(-9) M mib. In conclusion, treatment with atRA increases NIS expression levels and selective killing effect of (131)I in prostate cancer cells stably expressing NIS under the control of the PSA promoter. Therefore atRA may be used to enhance the therapeutic response to radioiodine in prostate cancer cells following PSA promoter-directed NIS gene delivery."
[The sodium-iodide symporter. Pathophysiologic, diagnostic and therapeutic significance]Spitzweg C. Internist (Berl). 2003 Apr;44(4):396-402, 404-8, 410-1. Review. German. [abstract only]
"The sodium iodide
symporter NIS) is an intrinsic plasma membrane protein that mediates
the active transport of iodide in the thyroid gland and a number of
extrathyrioidal tissues, in particular lactating mammary gland.
Because of its crucial role in the ability of thyroid follicular cells
to trap iodide of NIS opened an exciting and extensivenew field of
thyroid-related research. Cloning and molecular characterization of
NIS allowed investigation of its expression and regulation in
thyroidal and nonthyroidal tissues, and its potential
pathophysiological and therepeutic implications is benign and
malignant thyroid diseases. In addition, NIS-mediated iodide
accumulation allows diagnostic thyroid scintigraphy as well as
effective therapeutic application of radio-iodide in benign and
malignant thyroid disease. characterization and application of NIS as
a novel therapeutic gene for cytoreductive gene therapy of
extrathyroidal tumors, and the presence of high endogenous NIS
expression in the majority of breast cancers further suggest a
promising role of NIS in diagnosis and therapy of cancer outside the
thyroid gland."
The sodium iodide symporter: its pathophysiological and therapeutic implications.Spitzweg C, Morris JC. Clin Endocrinol (Oxf). 2002 Nov;57(5):559-74. Review. [abstract only] "The sodium iodide symporter (NIS) is an intrinsic plasma membrane protein that mediates the active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular lactating mammary gland. Because of its crucial role in the ability of thyroid follicular cells to trap iodide, cloning of NIS opened an exciting and extensive new field of thyroid-related research. Cloning and molecular characterization of NIS allowed investigation of its expression and regulation in thyroidal and nonthyroidal tissues, and its potential pathophysiological and therapeutic implications in benign and malignant thyroid disease. In addition to its key function in thyroid physiology, NIS-mediated iodide accumulation allows diagnostic thyroid scintigraphy as well as effective therapeutic application of radioiodine in benign and malignant thyroid disease. Characterization and application of NIS as a novel therapeutic gene and the presence of high native NIS expression in the majority of breast cancers further suggest a promising role of NIS in diagnosis and therapy of cancer outside the thyroid gland."
Clinical review 132: The sodium iodide symporter and its potential role in cancer therapy.Spitzweg C, Harrington KJ, Pinke LA, Vile RG, Morris JC. J Clin Endocrinol Metab. 2001 Jul;86(7):3327-35. Review.
"As the thyroidal membrane protein that mediates iodide transport into thyroid follicular cells, NIS plays a key role in thyroid pathophysiology and allows very effective use of radioiodine for diagnosis and therapy of thyroid cancer. Since NIS was cloned in 1996, most studies have demonstrated decreased NIS expression levels in thyroid carcinomas, which may account at least in part for the reduced iodide uptake activity generally observed in such tumors. Initial therapeutic strategies, including RA and demethylation treatment, have been explored with the aim of stimulating NIS expression and optimizing therapeutic responsiveness to 131I in thyroid cancer.
"Functional NIS expression has further been detected and characterized in lactating mammary gland, providing iodide to the newborn, as well as in breast cancer tissue in vitro and in vivo, suggesting that radioiodine may be a potential alternative diagnostic and therapeutic modality in breast cancer. Although a recent study using RA to stimulate functional NIS expression in breast cancer cells yielded a selective cytotoxic effect of 131I in vitro, in vivo studies are needed to confirm these findings.
"In addition, cloning and molecular analysis of the NIS gene offer the possibility of a novel cytoreductive gene therapy strategy based on targeted NIS gene transfer into nonthyroidal tumors, followed by radioiodine therapy. This novel form of gene therapy would extend the application of carrier-free radioiodine and the extensive experience with radioiodine in thyroid cancer management to the treatment of extrathyroidal tumors. If further in vivo studies using efficient and safe in vivo NIS gene delivery systems can confirm the promising preliminary results obtained in various in vitro and in vivo experiments, this approach is undoubtedly one of the most exciting chapters of NIS gene-based research since its cloning in 1996."
Cloning of the mouse sodium iodide symporter.Pinke LA, Dean DS, Bergert ER, Spitzweg C, Dutton CM, Morris JC. Thyroid. 2001 Oct;11(10):935-9. Erratum in: Thyroid 2001 Nov;11(11):1087. [abstract only]
"The iodide-concentrating
ability of the thyroid gland is essential to the production of thyroid
hormone. We report the nucleotide and amino acid sequence of the mouse
sodium iodide symporter (mNIS), which mediates this activity within
the thyroid gland. An open reading frame of 1,857 nucleotides codes
for a protein of 618 amino acids with 95% identity to rat NIS and 84%
identity to human NIS. Transient expression of the mNIS cDNA in
Chinese hamster ovary (CHO) cells, a nonthyroid cell line, resulted in
sodium-dependent, perchlorate-sensitive iodide uptake. Western blot
analysis of membrane preparations of CHO cells transiently transfected
with mNIS cDNA showed a band of 90 kd when probed with an antibody
directed against rat NIS. mNIS will serve as an important reagent in
determining the role of NIS in experimental thyroid diseases and for
monitoring the immune response to in animal models of NIS-mediated
gene therapy."
In vivo sodium iodide symporter gene therapy of prostate cancer.Spitzweg C, Dietz AB, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. Gene Ther. 2001 Oct;8(20):1524-31. [abstract only]
"Radioiodine therapy, the most effective form of systemic radiotherapy available, is currently useful only for thyroid cancer because of thyroid-specific expression of the sodium iodide symporter (NIS). Here we explore the efficacy of a novel form of gene therapy using adenovirus-mediated in vivo NIS gene transfer followed by (131)I administration for treatment of prostate cancer. Prostate cancer xenografts in nude mice injected with an adenovirus carrying the NIS gene linked to the cytomegalovirus (CMV) promoter revealed highly active uptake of radioiodine. Following administration of 3 mCi of (131)I, we observed an average tumor volume reduction of 84 +/- 12%. These results show for the first time that in vivo NIS gene delivery into non-thyroidal tumors is capable of inducing accumulation of therapeutically effective radioiodine doses and might therefore represent an effective and potentially curative therapy for prostate cancer."
Approaches to gene therapy with sodium/iodide symporter.Spitzweg C, Morris JC. Exp Clin Endocrinol Diabetes. 2001;109(1):56-9. Review. [abstract only]
"Since cloning and
characterization of the sodium iodide symporter (NIS) gene, several
investigators explored the possibility of a novel cytoreductive gene
therapy strategy based on NIS gene transfer into non-thyroidal tumor
cells followed by radioiodine therapy. NIS gene transfer has been
shown to be capable of inducing radioiodine accumulation in vitro and
in vivo in several non-thyroidal cancer cell lines. Following PSA
promoter-mediated NIS gene delivery we were able to demonstrate
prostate-specific iodide accumulation in prostate cancer cells that
was high enough to elicit a therapeutic response of 131-I in vitro and
in vivo. This study clearly demonstrates the potential of NIS as a
novel therapeutic gene for non-thyroidal cancers, in particular
prostate cancer."
Gene therapy for prostate cancer: current status and future prospects.Harrington KJ, Spitzweg C, Bateman AR, Morris JC, Vile RG. J Urol. 2001 Oct;166(4):1220-33. Review. [abstract only]
"PURPOSE: Locally advanced,
relapsed and metastatic prostate cancer has a dismal prognosis with
conventional therapies offering no more than palliation. In recent
years advances achieved in understanding the molecular biology of
cancer have afforded clinicians and scientists the opportunity to
develop a range of novel genetic therapies for this disease. MATERIALS
AND METHODS: We performed a detailed review of published reports of
gene therapy for prostate cancer. Particular emphasis was placed on
recent developments in the arena of nonviral (plasmid DNA, DNA coated
gold particles, liposomes and polymer DNA complexes) and viral
(adenovirus, retrovirus, adeno-associated virus, herpes virus and pox
virus) vectors. Therapeutic strategies were categorized as corrective,
cytoreductive and immunomodulatory gene therapy for the purpose of
data analysis and comparison. RESULTS: Locoregional administration of
nonviral and viral vectors can yield impressive local gene expression
and therapeutic effects but to our knowledge no efficient systemically
delivered vector is available to date. Corrective gene therapy to
restore normal patterns of tumor suppressor gene (p53, Rb, p21 and
p16) expression or negate the effect of mutated tumor promoting
oncogenes (ras, myc, erbB2 and bcl-2) have efficacy in animal models
but this approach suffers from the fact that each cancer cell must be
targeted. A wide variety of cytoreductive strategies are under
development, including suicide, anti-angiogenic, radioisotopic and
pro-apoptotic gene therapies. Each approach has strengths and
weaknesses, and may best be suited for use in combination.
Immunomodulatory gene therapy seeks to generate an effective local
immune response that translates to systemic antitumor activity.
Currently most studies involve immunostimulatory cytokine genes, such
as granulocyte-macrophage colony-stimulating factor, or interleukin-2
or 12. CONCLUSIONS: Various therapeutic genes have proved activity
against prostate cancer in vitro and in vivo. However, the chief
challenge facing clinical gene therapy strategies is the lack of
efficient gene delivery by local and systemic routes. For the
foreseeable future vector development may remain a major focus of
ongoing research. Despite this caveat it is anticipated that gene
therapy approaches may significantly contribute to the management of
prostate cancer in the future."
Expression of the sodium iodide symporter in human kidney.Spitzweg C, Dutton CM, Castro MR, Bergert ER, Goellner JR, Heufelder AE, Morris JC. Kidney Int. 2001 Mar;59(3):1013-23.
"BACKGROUND: The human sodium iodide symporter (hNIS) is a transmembrane protein that mediates the active transport of iodide in the thyroid gland. Following cloning of NIS, NIS expression has been detected in a broad range of nonthyroidal tissues, suggesting that iodide transport in these tissues is conferred by the expression of functional NIS protein.
METHODS: The aim of this study was to examine functional hNIS expression in kidney by reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), immunohistochemistry, and Western blot analysis accompanied by iodide accumulation studies in kidney cells.
RESULTS: Using a pair of full-length hNIS-specific oligonucleotide primers, RT-PCR followed by Southern hybridization revealed hNIS mRNA expression in normal human kidney tissue. The PCR products were subjected to automated sequencing and revealed full identity with the published human thyroid-derived NIS cDNA sequence. Furthermore, positive protected bands indicating the presence of hNIS mRNA were apparent in RPA gel lanes corresponding to human kidney cells as well as Chinese hamster ovary (CHO) cells stably transfected with hNIS cDNA and Graves' thyroid tissue. Immunohistochemical analysis of normal human kidney tissue using a mouse monoclonal hNIS-specific antibody showed marked hNIS-specific immunoreactivity confined to tubular cells, while no hNIS-specific immunoreactivity was detected in the glomeruli. NIS protein expression in human kidney cells was further confirmed by Western blot analysis. In addition, accumulation of (125)I was detected in human kidney cells in vitro and was shown to be sodium dependent and sensitive to perchlorate.
CONCLUSIONS: Functional hNIS expression was demonstrated
in the renal tubular system, suggesting that renal iodide transport
may be, at least in part, an active process driven by NIS."
The immune response to the iodide transporter.Spitzweg C, Morris JC. Endocrinol Metab Clin North Am. 2000 Jun;29(2):389-98, viii. Review. [abstract only]
"In addition to physiologic, diagnostic, and therapeutic implications, the recently cloned and characterized sodium iodide symporter (NIS) also may play an important role in the pathogenesis of autoimmune thyroid disease. Sodium iodide symporter expression patterns characteristically are changed in autoimmune thyroid disease, including Graves' disease and Hashimoto's thyroiditis, which may be caused, in part, by the regulation of sodium iodide symporter expression of cytokines involved in the pathogenesis of autoimmune thyroid disease. Further, there is increasing evidence that NIS-directed antibodies are present in sera from patients with autoimmune thyroid disease, and these antibodies also may affect NIS functional activity."
Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter.Spitzweg C, O'Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC. Cancer Res. 2000 Nov 15;60(22):6526-30.
"Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) by targeted NIS gene transfer might offer the possibility of radioiodine therapy of prostate cancer. Therefore, we investigated radioiodine accumulation and therapeutic effectiveness of 131I in NIS-transfected prostate cancer cells in vitro and in vivo. The human prostatic adenocarcinoma cell line LNCaP was stably transfected with NIS cDNA under the control of the prostate-specific antigen promoter. The stably transfected LNCaP cell line NP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in vitro that resulted in selective killing of these cells by 131I in an in vitro clonogenic assay. Xenografts were established in athymic nude mice and imaged using a gamma camera after i.p. injection of 500 microCi of 123I. In contrast to the NIS-negative control tumors (P-1) which showed no in vivo uptake of 123I, NP-1 tumors accumulated 25-30% of the total 123I administered with a biological half-life of 45 h. In addition, NIS protein expression in LNCaP cell xenografts was confirmed by Western blot analysis and immunohistochemistry. After a single i.p. application of a therapeutic 131I dose (3 mCi), significant tumor reduction was achieved in NP-1 tumors in the therapy group compared with P-1 tumors and tumors in the control group. In conclusion, a therapeutic effect of 131I has been demonstrated in prostate cancer cells after induction of tissue-specific iodide uptake activity by prostate-specific antigen promoter-directed NIS expression in vitro and in vivo. This study demonstrates the potential of NIS as a novel therapeutic gene for nonthyroidal cancers, in particular prostate cancer."
Thyroid iodine transport.Spitzweg C, Heufelder AE, Morris JC. Thyroid. 2000 Apr;10(4):321-30. Review. No abstract available. [citation only]
Analysis of human sodium iodide symporter immunoreactivity in human exocrine glands.Spitzweg C, Joba W, Schriever K, Goellner JR, Morris JC, Heufelder AE. J Clin Endocrinol Metab. 1999 Nov;84(11):4178-84.
"The human sodium iodide
symporter (hNIS) is an intrinsic transmembrane protein that mediates
the active transport of iodide across the basolateral membrane of
thyroid follicular cells. In addition to normally functioning thyroid
tissue, various extrathyroidal tissues, including salivary gland,
lacrimal gland, gastric mucosa, choroid plexus, and lactating mammary
gland, have been demonstrated to accumulate iodide. After cloning and
molecular characterization of the sodium iodide symporter, expression
of hNIS messenger ribonucleic acid has been detected in a broad range
of extrathyroidal tissues using Northern blot analysis and RT-PCR. In
this study we used both monoclonal and polyclonal antibodies directed
against different portions of hNIS protein together with a highly
sensitive immunostaining technique to assess hNIS protein expression
in tissue sections derived from normal human salivary and lacrimal
glands, pancreas, as well as gastric and colonic mucosa.
Immunohistochemical analysis of normal human salivary and lacrimal
glands revealed marked hNIS immunoreactivity in ductal cells and less
intense staining of acinar cells. Further, immunostaining of gastric
and colonic mucosa showed marked hNIS immunoreactivity confined to
chief and parietal cells in gastric mucosa and to epithelial cells
lining mucosal crypts in colonic mucosa. In normal human pancreas,
hNIS immunoreactivity was located in ductal cells, exocrine
parenchymal cells, and Langerhans islet cells. In conclusion, our
study demonstrates the expression of hNIS protein by several human
exocrine glands, suggesting that iodide transport in these glands is a
specific property conferred by the expression of hNIS protein, which
may serve important functions by concentrating iodine in glandular
secretions."
[Sodium-iodine symporter of the thyroid gland. Discovery, characterization, clinical relevance and prospects]Spitzweg C, Heufelder AE. [citation only]
Regulation of sodium iodide symporter gene expression in FRTL-5 rat thyroid cells.Spitzweg C, Joba W, Morris JC, Heufelder AE. Thyroid. 1999 Aug;9(8):821-30. [abstract only]
"The sodium iodide symporter (NIS), first identified in FRTL-5 cells, plays a critical role in iodide transport in the thyroid gland and in the production of the iodine-containing thyroid hormones. The aim of our study was to examine the regulation of NIS RNA steady-state levels and protein expression as well as functional activity in FRTL-5 cells. FRTL-5 cells cycling in media containing thyrotropin (TSH) were incubated for 48 hours with dexamethasone (10(-8)-10(-5) M), triiodothyronine (T3; 10(-9)-10(-6) M), methimazole (100 microM), propylthiouracil (PTU; 100 microM), perchlorate (10 microM) and potassium iodide (40 microM). In other experiments, cells were treated for 48 hours with various cytokines including interleukin-6 (IL-6) (100 U/mL), interferon-gamma (IFN-gamma) (100 U/mL), tumor necrosis factor-alpha (TNF-alpha) (10 ng/ml), IL-1alpha (100 U/mL), and IL-1beta (100 U/mL). Northern blot analysis using a 32P-labeled rat NIS-specific cDNA probe (nucleotides 1397-1937) revealed NIS mRNA as a single species of approximately 3 kb. When normalized for beta-actin mRNA signal intensities, NIS RNA steady-state levels in viable FRTL-5 cells were suppressed by approximately 80% after incubation with dexamethasone and T3 in a concentration-dependent manner. Iodide accumulation was decreased by up to 40% after incubation with dexamethasone and T3, respectively, in a concentration-dependent manner. Using a rabbit polyclonal rNIS-specific antibody, Western blot analysis of FRTL-5 cell membranes revealed a 60% and 70% suppression of NIS protein expression after treatment with T3 (0.1 microM) and dexamethasone (1 microM), respectively. In additon, NIS RNA steady-state levels were decreased by approximately 50% after treatment of monolayers with methimazole, PTU, and potassium iodide, respectively. Incubation with methimazole and PTU resulted in a 20% and 25% decrease of iodide accumulation, respectively, whereas potassium iodide suppressed iodide accumulation by approximately 50%. Treatment of FRTL-5 cells with IL-6 and IL-1beta resulted in a 30% decrease of NIS RNA steady-state levels. IL-6 did not alter NIS functional activity, but IL-1beta suppressed iodide accumulation by approximately 25%. IFN-gamma and perchlorate failed to alter NIS RNA steady-state levels. In contrast to IFN-gamma that had no effect on iodide accumulation, perchlorate almost completely suppressed iodide accumulation. TNF-alpha and IL-1alpha failed to alter NIS RNA steady-state levels in higher passage numbers of FRTL-5 cells, whereas treatment with TNF-alpha and IL-1alpha of early passages of FRTL-5 cells (<20 cell passages) resulted in a 70% and 40% decrease of NIS RNA steady-state levels, respectively, and in a 20% suppression of NIS functional activity. In conclusion, our data suggest that various agents known to affect iodide transport are capable of differentially altering NIS gene expression and function in cultured thyroid cells. Suppression of NIS gene expression and function by certain cytokines may be responsible, at least in part, for the impaired radioiodine uptake by thyroid tissue in certain forms of thyroiditis."
Analysis of human sodium/iodide symporter, thyroid transcription factor-1, and paired-box-protein-8 gene expression in benign thyroid diseases.Joba W, Spitzweg C, Schriever K, Heufelder AE. Thyroid. 1999 May;9(5):455-66. [abstract only]
"The ability to concentrate iodide, a fundamental property of normally functioning thyroid tissue, is altered in various thyroid diseases. Given the critical role of the Na+/I- symporter (NIS) in controlling iodide access to the thyroid gland, altered expression of NIS may be responsible, at least in part, for an enhanced or diminished capacity to concentrate iodide. In this study, we used Northern blot analysis, a newly established quantitative polymerase chain reaction (PCR) assay and in addition hNIS-directed immunohistochemical analysis to assess the levels of hNIS mRNA and protein expression in various localized and diffuse benign thyroid abnormalities, including Graves' disease (GD), scintigraphically cold solitary benign thyroid nodule (CBTN), nontoxic multinodular goiter (NMNG), solitary autonomously functioning thyroid nodule (AFTN), and mild diffuse iodine deficiency goiter (IDG). In addition, in view of the recent identification of putative binding sites for the transcription factors thyroid transcription factor-1 (TTF-1) and human paired-box-protein-8 (Pax-8) in the human NIS gene promoter, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to assess in these same samples the levels of TTF-1 and Pax-8 gene expression. Northern blot analysis revealed high levels of hNIS gene expression in thyroid specimens derived from patients with GD and AFTN. In contrast, levels of hNIS mRNA expression were moderate in NMNG, low in diffuse IDG, and very low in CBTN. Quantitative RT-PCR analysis of hNIS mRNA transcripts revealed variable but generally low levels of hNIS gene expression in IDG and NMNG, and undetectable or very low levels of hNIS mRNA in all scintigraphically CBTN studied. In contrast, markedly elevated levels of hNIS mRNA transcripts were detected in active GD (up to 17-fold) and AFTN (up to 25-fold). Immunohistochemical analysis revealed abundant hNIS protein expression by thyroid follicular cells in GD, moderate and heterogeneous levels in NMNG, and very low levels in CBTN. hNIS mRNA levels were correlated with TTF-1 and Pax-8 gene expression in GD and, to a lesser degree, in AFTN, NMNG, and IDG, but not in CBTN. In general, hNIS gene expression was more closely correlated with TTF-1 as compared to Pax-8 gene expression. In conclusion, the abundance of hNIS mRNA and protein expression in a broad range of benign thyroid pathologies correlated well with their functional state as assessed by thyroid scintigraphy. In addition to TTF-1 and Pax-8, other transcription factors and enhancer elements may contribute to regulation of NIS gene promoter activity."
Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.Spitzweg C, Zhang S, Bergert ER, Castro MR, McIver B, Heufelder AE, Tindall DJ, Young CY, Morris JC. Cancer Res. 1999 May 1;59(9):2136-41.
"Currently, no curative therapy for metastatic prostate cancer exists. Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) would enable those cells to concentrate iodide from plasma and might offer the ability to treat prostate cancer with radioiodine. Therefore, the aim of our study was to achieve tissue-specific expression of full-length human NIS (hNIS) cDNA in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP and in subcell lines C4, C4-2, and C4-2b in vitro. For this purpose, an expression vector was generated in which full-length hNIS cDNA coupled to the prostate-specific antigen (PSA) promoter has been ligated into the pEGFP-1 vector (NIS/PSA-pEGFP-1). The PSA promoter is responsible for androgen-dependent expression of PSA in benign and malignant prostate cells and was therefore used to mediate androgen-dependent prostate-specific expression of NIS. In addition, two control vectors were designed, which consist of the pEGFP-1 vector containing the PSA promoter without NIS cDNA (PSA-pEGFP-1) and NIS cDNA without the PSA promoter (NIS-pEGFP-1). Prostate cancer cells were transiently transfected with each of the above-described expression vectors, incubated with or without androgen (mibolerone) for 48 h, and monitored for iodide uptake activity. In addition, stably transfected LNCaP cell lines were established for each vector. Prostate cells transfected with NIS/PSA-pEGFP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in a range comparable to that observed in control cell lines transfected with hNIS cDNA. Perchlorate-sensitive iodide uptake was not observed in cells transfected with NIS/PSA-pEGFP-1 and treated without androgen or in cells transfected with the control vectors. In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1. Western blotting of LNCaP and C4-2b cell membranes transfected with NIS/PSA-pEGFP-1 using a monoclonal antibody that recognizes the COOH-terminus of hNIS revealed a band with a molecular weight of 90,000 that was not detected in androgen-deprived cells or in cells transfected with the control vectors, as well as a minor band at Mr 150,000 in transiently transfected LNCaP cell membranes. In conclusion, tissue-specific androgen-dependent iodide uptake activity has been induced in prostate cancer cells by PSA promoter-directed NIS expression. This study represents an initial step toward therapy of prostate cancer with radioiodine."
Expression of thyroid-related genes in human thymus.Spitzweg C, Joba W, Heufelder AE. Thyroid. 1999 Feb;9(2):133-41. [abstract only]
"There are several thyroid
antigens including human sodium iodide symporter (hNIS), thyrotropin
receptor (TSH-R), thyroid peroxidase (TPO), and thyroglobulin (Tg)
that have been considered to be thyroid-specific proteins involved in
the pathogenesis of autoimmune thyroid diseases. We examined the
expression of these thyroid-tolerance related genes in normal human
thymus, the lymphoid organ responsible for the induction of central
T-cell self. Reverse transcription-polymerase chain reaction (RT-PCR)
amplifications were performed with 4 pairs of oligonucleotide primers
specific for the hNIS, TSH-R, TPO, and Tg genes, respectively.
Gene-specific transcripts were confirmed by Southern hybridization
using digoxigenin-labeled internal oligonucleotide probes. To monitor
cDNA integrity and quantity, all samples were coamplified with a pair
of intron-spanning human beta-actin-specific oligonucleotide primers.
Furthermore, using a highly sensitive immunostaining technique and
antibodies specific for these 4 antigens, we examined whether NIS-,
TSH-R-, TPO-, and Tg-specific immunoreactivity can be detected and
localized in normal human thymus. RT-PCR and Southern hybridization
revealed expression of each of these 4 thyroid-related genes in normal
human thymus. In addition, immunohistochemical analysis of frozen
tissue sections derived from normal human thymus showed marked
immunoreactivity for NIS, TSH-R, and Tg as well as weaker staining for
TPO. Control reactions using isotype matched nonimmune immunoglobulins
were consistently negative. Taken together, our results suggest that
NIS-, TSH-R-, TPO-, and Tg-RNA are present and actively processed to
immunoreactive NIS-, TSH-R-, TPO-, and Tg-like protein in human
thymus. These data support the concept that pre-T lymphocytes may be
educated to recognize thyroid-related epitopes expressed in thymus,
and, thus, to generate self-tolerance against these thyroid-related
antigens."
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.Spitzweg C, Joba W, Eisenmenger W, Heufelder AE. J Clin Endocrinol Metab. 1998 May;83(5):1746-51.
"The ability to concentrate iodide is a fundamental property of normally functioning thyroid tissue and represents the first step in the production of thyroid hormones. Iodide uptake has been demonstrated in various extrathyroidal tissues, including salivary gland, gastric mucosa, and lactating mammary gland. Recently, cloning and molecular characterization of the human sodium iodide symporter (hNIS) have been reported; however, the patterns of hNIS gene expression in human tissues have remained unidentified. To examine the profiles of human hNIS gene expression in various normal human tissues, we performed high-stringency Northern blot analysis using a 32P-labeled hNIS-specific complementary DNA (cDNA) probe (nucleotides 1184-1667). To detect rare hNIS transcripts in small tissue samples, RT-PCR was performed with a pair of hNIS-specific oligonucleotide primers designed to amplify a portion (nucleotides 1184-1667) of the hNIS gene. hNIS-specific transcripts were confirmed by Southern hybridization using a digoxigenin-labeled internal hNIS-specific oligonucleotide probe (nucleotides 1460-1477). To monitor cDNA integrity and quantity, and to rule out DNA contamination and illegitimate transcription, all samples were coamplified with two pairs of intron-spanning primers designed to amplify fragments of the human beta-actin and thyroglobulin genes, respectively. Using Northern blot analysis, hNIS transcripts of approximately 4 kb were detected in thyroid gland and parotid gland but not in a broad range of endocrine and nonendocrine tissues. RT-PCR and Southern hybridization revealed hNIS gene expression in thyroid gland, salivary gland, parotid gland, submandibular gland, pituitary gland, pancreas, testis, mammary gland, gastric mucosa, prostate and ovary, adrenal gland, heart, thymus, and lung. By contrast, hNIS transcripts were not detected in normal orbital fibroblasts, colon, and nasopharyngeal mucosa. To further analyze hNIS gene sequences in parotid gland, mammary gland, and gastric mucosa, the EXPAND High Fidelity PCR System and three sets of overlapping NIS oligonucleotide primers were used for amplification and cloning. The resulting PCR products were subcloned into pBluescript-SKII(-)vector, and at least two independent cDNA clones derived from each tissue were subjected to automated sequencing. The nucleotide sequences of hNIS cDNA derived from parotid gland, mammary gland, and gastric mucosa revealed full identity with the recently published human thyroid-derived NIS cDNA sequence. In conclusion, our results demonstrate markedly variable levels of hNIS gene expression in several extrathyroidal tissues. Although the physiological role of hNIS in these tissues awaits further study, our results suggest that the capacity to actively transport iodine may be a feature common to several secretory and endocrine tissues. The diminished capacity to transport and concentrate iodide in extrathyroidal tissues (such as parotid gland, mammary gland, and gastric mucosa), compared with thyroid gland, does not seem to be caused by an altered primary structure of the hNIS cDNA. Variability of NIS gene expression levels in normal extrathyroidal tissues may rather be caused by differences in NIS gene transcriptional activity. Further studies will address this hypothesis and examine the mechanisms of tissue-specific regulation of NIS gene expression."
The sodium iodide symporter: its emerging relevance to clinical thyroidology.Spitzweg C, Heufelder AE. Eur J Endocrinol. 1998 Apr;138(4):374-5. Review.
"Thus, in addition to other types of congenital hypothyroidism, such as PIT-1 (pituitary-specific factor-1) abnormalities, thyrotropin deficiency, thyroglobulin deficiency, thyroid peroxidase deficiency and thyroid hormone resistance, these data collectively suggest an essential role for NIS gene mutations in the pathogenesis of congenital hypothyroidism due to an iodide trapping defect. Congenital iodide transport defects, therefore, represent the first group of thyroid diseases that is conclusively caused by a disorder of NIS. But there is already some preliminary evidence suggesting a role for the symporter in autoimmune thyroid diseases and, possibly, hot and cold thyroid nodules, and thyroid cancer."
Update on the thyroid sodium iodide symporter: a novel thyroid antigen emerging on the horizon.Spitzweg C, Heufelder AE. Eur J Endocrinol. 1997 Jul;137(1):22-3. Review.
"There is thus now mounting evidence to conclude that sera of patients with autoimmune thyroid diseases, in particular Graves’ disease, contain antibodies that cross-react with rNIS, and that several of the extramembranous domains constitute major antigenic epitopes. Thus, if confirmed by studies using human NIS peptides or even whole protein, the list of established thyroid autoantigens (thyroid peroxidase, thyroglobulin, thyrotrophin receptor) will soon have to include the NIS as its latest, but perhaps not least important, member.
Selenium-induced thyroid dysfunction.Hofbauer LC, Spitzweg C, Magerstadt RA, Heufelder AE. Postgrad Med J. 1997 Feb;73(856):103-4. [abstract only]
"Administration of the anti-oxidative trace element selenium is currently being evaluated for its benefits in patients with inflammatory diseases. However, little is known about the risks of selenium. We report on a patient in whom, along with standard therapy, administration of large intravenous doses of selenite for sepsis secondary to pneumonia resulted in development of marked hypothyroidism. In addition, severe iodine deficiency was noted, and supplementation with iodine led to normalisation of thyroid function."
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