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Thyroid Physiology

Thyroid Disease

Cancer

Thyroid Cancer

• Abraham

• Carrasco

• Chow

• Feldt-Rasmussen

• Filetti, Arturi

• Franceschi

• Gartner

• Jeong, Kim

• Kogai

• Kristensen

• Maier, Krohn, Paschke

• Mastorakos

• Mutaku, Many

• Neumann, Paschke

• Park

• Ringel

• Schlumberger

• Skubis-Zegadlo

• Smit

• Son

• Spitzweg

• Venkataraman

• Verkooijen

• West

• Xing, Sidransky

• Zaichick

SPITZWEG 

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."

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."
 

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.^"

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