Sodium Iodide

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John C Morris - One of the best experts on this subject based on the ideXlab platform.

  • the Sodium Iodide symporter nis novel applications for radionuclide imaging and treatment
    Endocrine-related Cancer, 2021
    Co-Authors: Christine Spitzweg, Peter J Nelson, Ernst Wagner, Peter Bartenstein, Wolfgang A Weber, M Schwaiger, John C Morris
    Abstract:

    Cloning of the Sodium Iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past 2 decades significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery, towards promising new applications in disseminated disease, in particular, through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

  • advanced radioiodine refractory differentiated thyroid cancer the Sodium Iodide symporter and other emerging therapeutic targets
    The Lancet Diabetes & Endocrinology, 2014
    Co-Authors: Christine Spitzweg, Keith C Bible, Lorenz C Hofbauer, John C Morris
    Abstract:

    Summary Approximately 30% of patients with advanced, metastatic differentiated thyroid cancer have radioiodine-refractory disease, based on decreased expression of the Sodium Iodide symporter SLC5A5 (NIS), diminished membrane targeting of NIS, or both. Patients with radioiodine-refractory disease, therefore, are not amenable to 131 I therapy, which is the initial systemic treatment of choice for non-refractory metastatic thyroid cancer. Patients with radioiodine-refractory cancer have historically had poor outcomes, partly because these cancers often respond poorly to cytotoxic chemotherapy. In the past decade, however, considerable progress has been made in delineating the molecular pathogenesis of radioiodine-refractory thyroid cancer. As a result of the identification of key genetic and epigenetic alterations and dysregulated signalling pathways, multiple biologically targeted drugs, in particular tyrosine-kinase inhibitors, have been evaluated in clinical trials with promising results and have begun to meaningfully impact clinical practice. In this Review, we summarise the current knowledge of the molecular pathogenesis of advanced differentiated thyroid cancer and discuss findings from clinical trials of targeted drugs in patients with radioiodine-refractory disease. Additionally, we focus on the molecular basis of loss of NIS expression, function, or both in refractory disease, and discuss preclinical and clinical data on restoration of radioiodine uptake.

  • The Sodium Iodide symporter (NIS) and potential regulators in normal, benign and malignant human breast tissue.
    PloS one, 2011
    Co-Authors: James Ryan, John C Morris, Catherine Curran, E. Hennessy, John Newell, Michael J. Kerin, Roisin M. Dwyer
    Abstract:

    Introduction The presence, relevance and regulation of the Sodium Iodide Symporter (NIS) in human mammary tissue remains poorly understood. This study aimed to quantify relative expression of NIS and putative regulators in human breast tissue, with relationships observed further investigated in vitro.

  • noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the Sodium Iodide symporter
    Molecular Therapy, 2009
    Co-Authors: John C Morris, Ileana Aderca, Pavlos Msaouel, Ianko D Iankov, Cory Allen, Mark J Federspiel, Donald J Tindall, Michael Koutsilieris, Stephen J. Russell
    Abstract:

    Prostate cancer cells overexpress the measles virus (MV) receptor CD46. Herein, we evaluated the antitumor activity of an oncolytic derivative of the MV Edmonston (MV-Edm) vaccine strain engineered to express the human Sodium Iodide symporter (NIS; MV-NIS virus). MV-NIS showed significant cytopathic effect (CPE) against prostate cancer cell lines in vitro. Infected cells effectively concentrated radioIodide isotopes as measured in vitro by Iodide-125 (125I) uptake assays. Virus localization and spread in vivo could be effectively followed by imaging of 123I uptake. In vivo administration of MV-NIS either locally or systemically (total dose of 9 × 106 TCID50) resulted in significant tumor regression (P < 0.05) and prolongation of survival (P < 0.01). Administration of 131I further enhanced the antitumor effect of MV-NIS virotherapy (P < 0.05). In conclusion, MV-NIS is an oncolytic vector with significant antitumor activity against prostate cancer, which can be further enhanced by 131I administration. The NIS transgene allows viral localization and monitoring by noninvasive imaging which can facilitate dose optimization in a clinical setting.

  • construction of an muc 1 promoter driven conditionally replicating adenovirus that expresses the Sodium Iodide symporter for gene therapy of breast cancer
    Breast Cancer Research, 2009
    Co-Authors: Miguel A. Trujillo, E R Bergert, Michael J. Oneal, Julia Davydova, Masato Yamamoto, John C Morris
    Abstract:

    Introduction The Sodium Iodide symporter (NIS) directs the uptake and concentration of Iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the Sodium-Iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo and in vitro by using nonreplicating adenoviral vectors. Methods To improve virotherapy efficiency, we developed a conditionally replicating adenovirus (CRAd) in which the transcriptional cassette RSV promoter-human NIScDNA-bGH polyA was also inserted at the E3 region. The E1a gene is driven by the tumor-specific promoter MUC-1 in the CRAd Ad5AMUCH_RSV-NIS. Results In vitro infection of the MUC-1-positive breast cell line T47D resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the MUC-1-negative breast cancer cell line MDA-MB-231 was refractory to the viral cytopathic effect and did not support viral replication. The data indicate that Ad5AMUCH_RSV-NIS activity is stringently restricted to MUC-1-positive cancer cells. Radioiodine uptake was readily measurable in T47 cells infected with Ad5AMUCH_RSV-NIS 24 hours after infection, thus confirming NIS expression before viral-induced cell death. Conclusions This construct may allow multimodal therapy, combining virotherapy with radioiodine therapy to be developed as a novel treatment for breast and other MUC1-overexpressing cancers.

Christine Spitzweg - One of the best experts on this subject based on the ideXlab platform.

  • the Sodium Iodide symporter nis novel applications for radionuclide imaging and treatment
    Endocrine-related Cancer, 2021
    Co-Authors: Christine Spitzweg, Peter J Nelson, Ernst Wagner, Peter Bartenstein, Wolfgang A Weber, M Schwaiger, John C Morris
    Abstract:

    Cloning of the Sodium Iodide symporter (NIS) 25 years ago has opened an exciting chapter in molecular thyroidology with the characterization of NIS as one of the most powerful theranostic genes and the development of a promising gene therapy strategy based on image-guided selective NIS gene transfer in non-thyroidal tumors followed by application of 131I or alternative radionuclides, such as 188Re and 211At. Over the past 2 decades significant progress has been made in the development of the NIS gene therapy concept, from local NIS gene delivery, towards promising new applications in disseminated disease, in particular, through the use of oncolytic viruses, non-viral polyplexes, and genetically engineered MSCs as highly effective, highly selective and flexible gene delivery vehicles. In addition to allowing the robust therapeutic application of radioiodine in non-thyroid cancer settings, these studies have also been able to take advantage of NIS as a sensitive reporter gene that allows temporal and spatial monitoring of vector biodistribution, replication, and elimination - critically important issues for preclinical development and clinical translation.

  • advanced radioiodine refractory differentiated thyroid cancer the Sodium Iodide symporter and other emerging therapeutic targets
    The Lancet Diabetes & Endocrinology, 2014
    Co-Authors: Christine Spitzweg, Keith C Bible, Lorenz C Hofbauer, John C Morris
    Abstract:

    Summary Approximately 30% of patients with advanced, metastatic differentiated thyroid cancer have radioiodine-refractory disease, based on decreased expression of the Sodium Iodide symporter SLC5A5 (NIS), diminished membrane targeting of NIS, or both. Patients with radioiodine-refractory disease, therefore, are not amenable to 131 I therapy, which is the initial systemic treatment of choice for non-refractory metastatic thyroid cancer. Patients with radioiodine-refractory cancer have historically had poor outcomes, partly because these cancers often respond poorly to cytotoxic chemotherapy. In the past decade, however, considerable progress has been made in delineating the molecular pathogenesis of radioiodine-refractory thyroid cancer. As a result of the identification of key genetic and epigenetic alterations and dysregulated signalling pathways, multiple biologically targeted drugs, in particular tyrosine-kinase inhibitors, have been evaluated in clinical trials with promising results and have begun to meaningfully impact clinical practice. In this Review, we summarise the current knowledge of the molecular pathogenesis of advanced differentiated thyroid cancer and discuss findings from clinical trials of targeted drugs in patients with radioiodine-refractory disease. Additionally, we focus on the molecular basis of loss of NIS expression, function, or both in refractory disease, and discuss preclinical and clinical data on restoration of radioiodine uptake.

  • the biology of the Sodium Iodide symporter and its potential for targeted gene delivery
    Current Cancer Drug Targets, 2010
    Co-Authors: Mohan Hingorani, Christine Spitzweg, Richard G. Vile, Georges Vassaux, Kate Newbold, Alan Melcher, Hardev Pandha, Kevin J. Harrington
    Abstract:

    The Sodium Iodide symporter (NIS) is responsible for thyroidal, salivary, gastric, intestinal and mammary Iodide uptake. It was first cloned from the rat in 1996 and shortly thereafter from human and mouse tissue. In the intervening years, we have learned a great deal about the biology of NIS. Detailed knowledge of its genomic structure, transcriptional and post-transcriptional regulation and pharmacological modulation has underpinned the selection of NIS as an exciting approach for targeted gene delivery. A number of in vitro and in vivo studies have demonstrated the potential of using NIS gene therapy as a means of delivering highly conformal radiation doses selectively to tumours. This strategy is particularly attractive because it can be used with both diagnostic (99mTc, 125I, 124I) and therapeutic (131I, 186Re, 188Re, 211At) radioisotopes and it lends itself to incorporation with standard treatment modalities, such as radiotherapy or chemoradiotherapy. In this article, we review the biology of NIS and discuss its development for gene therapy.

  • functional Sodium Iodide symporter expression in breast cancer xenografts in vivo after systemic treatment with retinoic acid and dexamethasone
    Breast Cancer Research and Treatment, 2008
    Co-Authors: Michael J. Willhauck, John C Morris, Burkhard Göke, Bibi Sharifsamani, Reingard Senekowitschschmidtke, Nathalie Wunderlich, Christine Spitzweg
    Abstract:

    Context The Sodium Iodide symporter (NIS) mediates Iodide uptake in the thyroid gland as well as in lactating breast, and is also expressed in the majority of breast cancers. Recently, we have reported stimulation of all-trans retinoic acid (atRA)-induced NIS expression in the human breast cancer cell line MCF-7 by dexamethasone (Dex), resulting in an enhanced therapeutic effect of 131I in vitro.

  • application of 188rhenium as an alternative radionuclide for treatment of prostate cancer after tumor specific Sodium Iodide symporter gene expression
    The Journal of Clinical Endocrinology and Metabolism, 2007
    Co-Authors: Michael J. Willhauck, John C Morris, Burkhard Göke, Reingard Senekowitschschmidtke, Franzjosef Gildehaus, Ingo Wolf, Bibi Rana Sharif Samani, Hans Jurgen Stark, Christine Spitzweg
    Abstract:

    Context: We reported recently the induction of Iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed Sodium Iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid Iodide efflux due to a lack of Iodide organification. Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I. Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biologic...

E R Bergert - One of the best experts on this subject based on the ideXlab platform.

  • construction of an muc 1 promoter driven conditionally replicating adenovirus that expresses the Sodium Iodide symporter for gene therapy of breast cancer
    Breast Cancer Research, 2009
    Co-Authors: Miguel A. Trujillo, E R Bergert, Michael J. Oneal, Julia Davydova, Masato Yamamoto, John C Morris
    Abstract:

    Introduction The Sodium Iodide symporter (NIS) directs the uptake and concentration of Iodide in thyroid cells. This in turn allows radioiodine imaging and therapy for thyroid cancer. To extend the use of NIS-mediated radioiodine therapy to other types of cancer, we successfully transferred and expressed the Sodium-Iodide symporter (NIS) gene in prostate, colon, and breast cancer cells both in vivo and in vitro by using nonreplicating adenoviral vectors. Methods To improve virotherapy efficiency, we developed a conditionally replicating adenovirus (CRAd) in which the transcriptional cassette RSV promoter-human NIScDNA-bGH polyA was also inserted at the E3 region. The E1a gene is driven by the tumor-specific promoter MUC-1 in the CRAd Ad5AMUCH_RSV-NIS. Results In vitro infection of the MUC-1-positive breast cell line T47D resulted in virus replication, cytolysis, and release of infective viral particles. Conversely, the MUC-1-negative breast cancer cell line MDA-MB-231 was refractory to the viral cytopathic effect and did not support viral replication. The data indicate that Ad5AMUCH_RSV-NIS activity is stringently restricted to MUC-1-positive cancer cells. Radioiodine uptake was readily measurable in T47 cells infected with Ad5AMUCH_RSV-NIS 24 hours after infection, thus confirming NIS expression before viral-induced cell death. Conclusions This construct may allow multimodal therapy, combining virotherapy with radioiodine therapy to be developed as a novel treatment for breast and other MUC1-overexpressing cancers.

  • adenovirus mediated and targeted expression of the Sodium Iodide symporter permits in vivo radioIodide imaging and therapy of pancreatic tumors
    Human Gene Therapy, 2006
    Co-Authors: Roisin M. Dwyer, E R Bergert, Michael K Oconnor, Sandra J Gendler, John C Morris
    Abstract:

    Pancreatic cancer is the fourth leading cause of cancer death in the United States. It is highly aggressive with no uniformly effective chemotherapy available for metastatic disease. The Sodium–Iodide symporter (NIS) is a transmembrane protein responsible for uptake of Iodide into cells. The presence of NIS in thyroid cells permits diagnostic imaging and therapy of thyroid tumors, using radioIodide. Previous studies from this laboratory reported mucin-1 (MUC1)-driven expression of NIS in cancer cells. MUC1 overexpression has also been reported in 90% of pancreatic tumors. In this study Ad5/MUC1/NIS was used to infect pancreatic cancer cells both in vitro and in vivo, to investigate the potential for radioIodide imaging and ablation of this disease. In vitro studies revealed a 43-fold increase in Iodide uptake in NIS-transduced cells compared with controls. In vivo imaging revealed effective Iodide uptake and retention at the site of NIS-transduced tumors, with optimal uptake (13% of injected dose) observe...

  • Sodium Iodide symporter mediated radioIodide imaging and therapy of ovarian tumor xenografts in mice
    Gene Therapy, 2006
    Co-Authors: Roisin M. Dwyer, E R Bergert, Michael K Oconnor, Sandra J Gendler, John C Morris
    Abstract:

    Ovarian cancer represents the fifth leading cause of cancer death among women in the United States, with >16 000 deaths expected this year. This study was carried out to investigate the potential of Sodium Iodide symporter (NIS)-mediated radioIodide therapy as a novel approach for ovarian cancer treatment. RadioIodide is routinely and effectively used for the treatment of benign and malignant thyroid disease as a result of native thyroidal expression of NIS, which mediates Iodide uptake. In vitro gene transfer studies in ovarian cancer cells revealed a 12- and five-fold increase in Iodide uptake when transduced with Ad/CMV/NIS or Ad/MUC1/NIS, respectively. Western blot/immunohistochemistry confirmed NIS protein expression. In vivo ovarian tumor xenografts were infected with the adenoviral constructs. 123I imaging revealed a clear image of the CMV/NIS-transduced tumor, with a less intense image apparent following infection with MUC1/NIS. Therapeutic doses of 131I following CMV/NIS infection caused a mean 53% reduction in tumor volume (P<0.0001). MUC1/NIS-transduced tumors did not regress, although at 8 weeks following therapy, tumor volume was significantly less that of control animals (166 versus 332%, respectively, P<0.05). This study represents a promising first step investigating the potential for NIS-mediated radioIodide imaging and therapy of ovarian tumors.

  • radioiodine therapy of colon cancer following tissue specific Sodium Iodide symporter gene transfer
    Gene Therapy, 2005
    Co-Authors: I V Scholz, John C Morris, Burkhard Göke, E R Bergert, Kevin J. Harrington, Richard G. Vile, Neziha Cengic, Claire H Baker, K Maletz, Christine Spitzweg
    Abstract:

    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 125I 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 131I, 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 131I 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.

  • immunohistochemical analysis of Sodium Iodide symporter expression in metastatic differentiated thyroid cancer correlation with radioiodine uptake
    The Journal of Clinical Endocrinology and Metabolism, 2001
    Co-Authors: Regina M Castro, John R Goellner, E R Bergert, Ian D Hay, John C Morris
    Abstract:

    The ability of thyroid cancers to concentrate radioiodine (RAI) is dependent, in part, upon the expression and functional integrity of the Sodium Iodide symporter (NIS). However, some differentiated thyroid carcinomas (DTCs) and most undifferentiated thyroid carcinomas lack the ability to concentrate Iodide and are thereby insensitive to 131I therapy. Variation of NIS protein expression may be an important factor in this behavior. We wished to determine whether NIS protein expression in primary DTC tumors correlated with the subsequent RAI uptake by metastatic lesions in the same patients. We obtained paraffin-embedded tissue specimens from 60 patients with metastatic thyroid cancer who had undergone total or near-total thyroidectomy at the Mayo Clinic for DTC and had known presence or absence of RAI uptake in their tumor deposits determined by total body scanning after thyroid hormone withdrawal. Tissue sections from the primary intrathyroidal tumors were subjected to immunostaining (IS) using a monoclon...

Burkhard Göke - One of the best experts on this subject based on the ideXlab platform.

  • functional Sodium Iodide symporter expression in breast cancer xenografts in vivo after systemic treatment with retinoic acid and dexamethasone
    Breast Cancer Research and Treatment, 2008
    Co-Authors: Michael J. Willhauck, John C Morris, Burkhard Göke, Bibi Sharifsamani, Reingard Senekowitschschmidtke, Nathalie Wunderlich, Christine Spitzweg
    Abstract:

    Context The Sodium Iodide symporter (NIS) mediates Iodide uptake in the thyroid gland as well as in lactating breast, and is also expressed in the majority of breast cancers. Recently, we have reported stimulation of all-trans retinoic acid (atRA)-induced NIS expression in the human breast cancer cell line MCF-7 by dexamethasone (Dex), resulting in an enhanced therapeutic effect of 131I in vitro.

  • α fetoprotein promoter targeted Sodium Iodide symporter gene therapy of hepatocellular carcinoma
    Gene Therapy, 2008
    Co-Authors: Michael J. Willhauck, Burkhard Göke, Reingard Senekowitschschmidtke, Kathrin Klutz, Neziha Cengic, B Sharif R Samani, Ingo Wolf, L Mohr, M Geissler, John C Morris
    Abstract:

    Due to limited treatment options the prognosis of patients with advanced hepatocellular cancer (HCC) has remained poor. To investigate an alternative therapeutic approach, we examined the feasibility of radioiodine therapy of HCC following human Sodium Iodide symporter (NIS) gene transfer using a mouse alpha-fetoprotein (AFP) promoter construct to target NIS expression to HCC cells. For this purpose, the murine Hepa 1-6 and the human HepG2 hepatoma cell lines were stably transfected with NIS cDNA under the control of the tumor-specific AFP promoter. The stably transfected Hepa 1-6 cell line showed a 10-fold increase in Iodide accumulation, while HepG2 cells accumulated (125)I approximately 60-fold. Tumor-specific NIS expression was confirmed on mRNA level by northern blot analysis, and on protein level by immunostaining, that revealed primarily membrane-associated NIS-specific immunoreactivity. In an in vitro clonogenic assay up to 78% of NIS-transfected Hepa 1-6 and 93% of HepG2 cells were killed by (131)I exposure, while up to 96% of control cells survived. In vivo NIS-transfected HepG2 xenografts accumulated 15% of the total (123)I administered per gram tumor with a biological half-life of 8.38 h, resulting in a tumor absorbed dose of 171 mGy MBq(-1) (131)I. After administration of a therapeutic (131)I dose (55.5 MBq) tumor growth of NIS expressing HepG2 xenografts was significantly inhibited. In conclusion, tumor-specific Iodide accumulation was induced in HCC cells by AFP promoter-directed NIS expression in vitro and in vivo, which was sufficiently high to allow a therapeutic effect of (131)I. This study demonstrates the potential of tumor-specific NIS gene therapy as an innovative treatment strategy for HCC.

  • application of 188rhenium as an alternative radionuclide for treatment of prostate cancer after tumor specific Sodium Iodide symporter gene expression
    The Journal of Clinical Endocrinology and Metabolism, 2007
    Co-Authors: Michael J. Willhauck, John C Morris, Burkhard Göke, Reingard Senekowitschschmidtke, Franzjosef Gildehaus, Ingo Wolf, Bibi Rana Sharif Samani, Hans Jurgen Stark, Christine Spitzweg
    Abstract:

    Context: We reported recently the induction of Iodide accumulation in prostate cancer cells (LNCaP) by prostate-specific antigen promoter-directed Sodium Iodide symporter (NIS) expression that allowed a significant therapeutic effect of 131iodine (131I). These data demonstrated the potential of the NIS gene as a novel therapeutic gene, although in some extrathyroidal tumors, therapeutic efficacy may be limited by rapid Iodide efflux due to a lack of Iodide organification. Objective: In the current study, we therefore studied the potential of 188rhenium (188Re), as an alternative radionuclide, also transported by NIS, with a shorter half-life and higher energy β-particles than 131I. Results: NIS-transfected LNCaP cells (NP-1) concentrated 8% of the total applied activity of 188Re as compared with 16% of 125I, which was sufficient for a therapeutic effect in an in vitro clonogenic assay. γ-Camera imaging of NP-1 cell xenografts in nude mice revealed accumulation of 8–16% injected dose (ID)/g 188Re (biologic...

  • a novel therapeutic strategy for medullary thyroid cancer based on radioiodine therapy following tissue specific Sodium Iodide symporter gene expression
    The Journal of Clinical Endocrinology and Metabolism, 2005
    Co-Authors: Neziha Cengic, John C Morris, Burkhard Göke, Claire H Baker, Martin Schutz, Christine Spitzweg
    Abstract:

    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 w...

  • radioiodine therapy of colon cancer following tissue specific Sodium Iodide symporter gene transfer
    Gene Therapy, 2005
    Co-Authors: I V Scholz, John C Morris, Burkhard Göke, E R Bergert, Kevin J. Harrington, Richard G. Vile, Neziha Cengic, Claire H Baker, K Maletz, Christine Spitzweg
    Abstract:

    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 125I 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 131I, 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 131I 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.

Gregory A. Brent - One of the best experts on this subject based on the ideXlab platform.

  • the Sodium Iodide symporter nis regulation and approaches to targeting for cancer therapeutics
    Pharmacology & Therapeutics, 2012
    Co-Authors: Takahiko Kogai, Gregory A. Brent
    Abstract:

    Expression of the Sodium Iodide symporter (NIS) is required for efficient Iodide uptake in thyroid and lactating breast. Since most differentiated thyroid cancer expresses NIS, β-emitting radioactive Iodide is routinely utilized to target remnant thyroid cancer and metastasis after total thyroidectomy. Stimulation of NIS expression by high levels of thyroid-stimulating hormone is necessary to achieve radioIodide uptake into thyroid cancer that is sufficient for therapy. The majority of breast cancer also expresses NIS, but at a low level insufficient for radioiodine therapy. Retinoic acid is a potent NIS inducer in some breast cancer cells. NIS is also modestly expressed in some non-thyroidal tissues, including salivary glands, lacrimal glands and stomach. Selective induction of Iodide uptake is required to target tumors with radioIodide. Iodide uptake in mammalian cells is dependent on the level of NIS gene expression, but also successful translocation of NIS to the cell membrane and correct insertion. The regulatory mechanisms of NIS expression and membrane insertion are regulated by signal transduction pathways that differ by tissue. Differential regulation of NIS confers selective induction of functional NIS in thyroid cancer cells, as well as some breast cancer cells, leading to more efficient radioIodide therapy for thyroid cancer and a new strategy for breast cancer therapy. The potential for systemic radioIodide treatment of a range of other cancers, that do not express endogenous NIS, has been demonstrated in models with tumor-selective introduction of exogenous NIS.

  • enhancement of Sodium Iodide symporter expression in thyroid and breast cancer
    Endocrine-related Cancer, 2006
    Co-Authors: Takahiko Kogai, K Taki, Gregory A. Brent
    Abstract:

    The Sodium/Iodide symporter (NIS) mediates Iodide uptake in the thyroid gland and lactating breast. NIS mRNA and protein expression are detected in most thyroid cancer specimens, although functional Iodide uptake is usually reduced resulting in the characteristic finding of a ‘cold’ or non-functioning lesion on a radioiodine image. Iodide uptake after thyroid stimulating hormone (TSH) stimulation, however, is sufficient in most differentiated thyroid cancer to utilize b-emitting radioactive Iodide for the treatment of residual and metastatic disease. Elevated serum TSH, achieved by thyroid hormone withdrawal in athyreotic patients or after recombinant human thyrotropin administration, directly stimulates NIS gene expression and/or NIS trafficking to the plasma membrane, increasing radioIodide uptake. Approximately 10‐20% differentiated thyroid cancers, however, do not express the NIS gene despite TSH stimulation. These tumors are generally associated with a poor prognosis. Reduced NIS gene expression in thyroid cancer is likely due in part, to impaired trans-activation at the proximal promoter and/or the upstream enhancer. Basal NIS gene expression is detected in about 80% breast cancer specimens, but the fraction with functional Iodide transport is relatively low. Lactogenic hormones and various nuclear hormone receptor ligands increase Iodide uptake in breast cancer cells in vitro, but TSH has no effect. A wide range of ‘differentiation’ agents have been utilized to stimulate NIS expression in thyroid and breast cancer using in vitro and in vivo models, and a few have been used in clinical studies. Retinoic acid has been used to stimulate NIS expression in both thyroid and breast cancer. There are similarities and differences in NIS gene regulation and expression in thyroid and breast cancer. The various agents used to enhance NIS expression in thyroid and breast cancer will be reviewed with a focus on the mechanism of action. Agents that promote tumor differentiation, or directly stimulate NIS gene expression, may result in iodine concentration in ‘scan-negative’ thyroid cancer and some breast cancer. Endocrine-Related Cancer (2006) 13 797‐826

  • systemic retinoic acid treatment induces Sodium Iodide symporter expression and radioIodide uptake in mouse breast cancer models
    Cancer Research, 2004
    Co-Authors: Takahiko Kogai, Katsumi Taki, Yoko Kanamoto, Lisa H Che, Farhad Moatamed, James J Schultz, Gregory A. Brent
    Abstract:

    Lactating breast tissue and some breast cancers express the Sodium/Iodide symporter (NIS) and concentrate Iodide. We recently demonstrated that all-trans retinoic acid (tRA) induces both NIS gene expression and Iodide accumulation in vitro in well-differentiated human breast cancer cells (MCF-7). In the present study, we investigated the in vivo efficacy and specificity of tRA-stimulated Iodide accumulation in mouse breast cancer models. Immunodeficient mice with MCF-7 xenograft tumors were treated with systemic tRA for 5 days. Iodide accumulation in the xenograft tumors was markedly increased, approximately 15-fold greater than levels without treatment, and the effects were tRA dose dependent. Iodide accumulation in other organs was not significantly influenced by tRA treatment. Significant induction of NIS mRNA and protein in the xenograft tumors was observed after tRA treatment. Iodide accumulation and NIS mRNA expression were also selectively induced in breast cancer tissues in transgenic mice expressing the oncogene, polyoma virus middle T antigen. These data demonstrate selective induction of functional NIS in breast cancer by tRA. Treatment with short-term systemic retinoic acid, followed by radioIodide administration, is a potential tool in the diagnosis and treatment of some differentiated breast cancer.

  • 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 Therapy, 2001
    Co-Authors: Min Huang, Raj K. Batra, Takahiko Kogai, Ying Q. Lin, Alan Lichtenstein, Jerome M. Hershman, Sherven Sharma, Li X. Zhu, Gregory A. Brent, Steven M. Dubinett
    Abstract:

    Ectopic expression of the thyroperoxidase gene augments radioIodide uptake and retention mediated by the Sodium Iodide symporter in non–small cell lung cancer

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