RESUMEN
INTRODUCTION: High-resolution pre-clinical (131)I SPECT can facilitate development of new radioiodine therapies for cancer. To this end, it is important to limit resolution-degrading effects of pinhole edge penetration by the high-energy γ-photons of iodine. Here we introduce, optimize and validate (131)I SPECT performed with a dedicated high-energy clustered multi-pinhole collimator. METHODS: A SPECT-CT system (VECTor/CT) with stationary gamma-detectors was equipped with a tungsten collimator with clustered pinholes. Images were reconstructed with pixel-based OSEM, using a dedicated (131)I system matrix that models the distance- and energy-dependent resolution and sensitivity of each pinhole, as well as the intrinsic detector blurring and variable depth of interaction in the detector. The system performance was characterized with phantoms and in vivo static and dynamic (131)I-NaI scans of mice. RESULTS: Reconstructed image resolution reached 0.6mm, while quantitative accuracy measured with a (131)I filled syringe reaches an accuracy of +3.6±3.5% of the gold standard value. In vivo mice scans illustrated a clear shape of the thyroid and biodistribution of (131)I within the animal. Pharmacokinetics of (131)I was assessed with 15-s time frames from the sequence of dynamic images and time-activity curves of (131)I-NaI. CONCLUSIONS: High-resolution quantitative and fast dynamic (131)I SPECT in mice is possible by means of a high-energy collimator and optimized system modeling. This enables analysis of (131)I uptake even within small organs in mice, which can be highly valuable for development and optimization of targeted cancer therapies.
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Radioisótopos de Yodo , Relación Señal-Ruido , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único/métodos , Animales , Procesamiento de Imagen Asistido por Computador , Ratones , Ratones Endogámicos C57BL , Fantasmas de Imagen , Yoduro de Sodio/farmacocinética , Distribución TisularRESUMEN
BACKGROUND: Although radioactive iodine (RAI) imaging/therapy is one of the earliest applications of theranostics, there remain a number of unresolved clinical questions as to the optimization of diagnostic techniques/protocols and improvements in patient-specific treatment planning strategies. The objectives of this study were to determine the imaging characteristics and clinical feasibility of (124)I positron emission tomography/computed tomography (PET/CT) for the determination of extent of disease and evaluation of RAI kinetics in its physiologic and neoplastic distribution in patients with differentiated thyroid cancer (DTC). METHODS: The study was designed as a prospective phase II diagnostic trial of patients with confirmed DTC. Following adequate preparation, patients received 2 mCi (124)I in liquid form and sequential whole-body PET/CT imaging was performed at five time points (2-4 h, 24 ± 6 h, 48 ± 6 h, 72 ± 6 h, and 96 ± 6 h post-administration). All patients who had (124)I imaging subsequently underwent RAI treatment with (131)I, with administered activities ranging from 100 to 300 mCi. Post-treatment scans were obtained 5-7 days after RAI treatment. A by-patient and by-lesion analysis of the (124)I images was performed and compared with the post-treatment (131)I scans as well as F-18 FDG PET/CT images. Quantitative image analysis was also performed to determine the total functional volume (mL), activity per functional volume (µCi/mL), and cumulated activity (µCi/h) for remnants, salivary glands, and nodal metastases. RESULTS: Fifteen patients (6 women; Mage = 57 years; range 29-91 years) were enrolled into the study. Forty-six distinct lesions were identified in these 15 patients on (124)I PET/CT images, with a sensitivity of 92.5%. In addition, (124)I identified 22.5% more foci of RAI-avid lesions compared with the planar (131)I post-treatment scans. This study demonstrates different kinetic profiles for normal thyroid remnants (peaked at 24 h with mono-exponential clearance), salivary glands (peaked at 4 h with bi-exponential clearance), and metastatic lesions (protracted retention), as well as individual variations in functional volumes and thus cumulated activities. CONCLUSIONS: (124)I PET/CT is a valuable clinical imaging tool/agent, both in determining the extent of disease in the setting of metastatic DTC and in the functional volumetric and kinetic evaluation of target lesions.
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Diferenciación Celular , Radioisótopos de Yodo/farmacocinética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Yoduro de Sodio/farmacocinética , Neoplasias de la Tiroides/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Factibilidad , Femenino , Humanos , Radioisótopos de Yodo/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Radiofármacos/administración & dosificación , Yoduro de Sodio/administración & dosificación , Neoplasias de la Tiroides/metabolismo , Neoplasias de la Tiroides/patología , Distribución TisularAsunto(s)
Carcinoma Papilar Folicular/diagnóstico por imagen , Carcinoma Papilar Folicular/secundario , Carcinoma Papilar/diagnóstico por imagen , Carcinoma Papilar/secundario , Radioisótopos de Yodo/uso terapéutico , Enfermedades Renales Poliquísticas/diagnóstico por imagen , Radiofármacos/uso terapéutico , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Yoduro de Sodio/uso terapéutico , Neoplasias de la Tiroides/patología , Imagen de Cuerpo Entero , Anciano de 80 o más Años , Carcinoma Papilar/radioterapia , Carcinoma Papilar/cirugía , Carcinoma Papilar Folicular/radioterapia , Carcinoma Papilar Folicular/cirugía , Diagnóstico Diferencial , Reacciones Falso Positivas , Femenino , Humanos , Radioisótopos de Yodo/farmacocinética , Neoplasias Primarias Múltiples/cirugía , Radiofármacos/farmacocinética , Radioterapia Adyuvante , Yoduro de Sodio/farmacocinética , Hormonas Tiroideas/uso terapéutico , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Distribución Tisular , UltrasonografíaAsunto(s)
Medicina Basada en la Evidencia , Radioisótopos de Yodo/efectos adversos , Radiofármacos/efectos adversos , Yoduro de Sodio/efectos adversos , Enfermedades de la Tiroides/radioterapia , Glándula Tiroides/efectos de la radiación , Centers for Disease Control and Prevention, U.S. , Relación Dosis-Respuesta en la Radiación , Interacciones Farmacológicas , Medicina Basada en la Evidencia/métodos , Interacciones Alimento-Droga , Humanos , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/farmacocinética , Radioisótopos de Yodo/uso terapéutico , Cintigrafía , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Radiofármacos/uso terapéutico , Yoduro de Sodio/administración & dosificación , Yoduro de Sodio/farmacocinética , Yoduro de Sodio/uso terapéutico , Enfermedades de la Tiroides/diagnóstico por imagen , Enfermedades de la Tiroides/metabolismo , Enfermedades de la Tiroides/fisiopatología , Glándula Tiroides/diagnóstico por imagen , Glándula Tiroides/metabolismo , Glándula Tiroides/fisiopatología , Tirotropina/sangre , Distribución Tisular , Toxicología/métodos , Estados UnidosRESUMEN
OBJECTIVE: Radioiodide is commonly used to diagnose and treat hyperthyroidism and thyroid carcinoma. However, we could not find any experimental data that strictly compared the biodistribution and thyroid uptake of radioactive iodide between the oral and intravenous (iv) routes with time. This prompted us to compare (123)I biodistribution and thyroid uptake to clarify the differences between oral and iv bolus administration in rats. METHODS: The rats were divided into two groups, A and B (n = 5, each). In the first imaging experiment, Na(123)I solution (35 MBq/200 µL) was administered as a bolus to the rats orally in group A and intravenously in group B. Two weeks later, the second imaging experiment was performed as a crossover experiment. (123)I biodistribution was evaluated visually and quantitatively with a gamma camera at 10 min, 3, 6, 12, 24, and 48 h after (123)I administration. Thyroid uptake was compared between oral and iv groups. Correlation of (123)I thyroid uptake and whole-body excretion was evaluated. The area under the curve (AUC) of thyroid uptake was also calculated. RESULTS: (123)I biodistribution differed visually during 6 h between the two groups. (123)I thyroid uptake was significantly higher in the iv group at 10 min (P < 0.05) and in the oral group at 6 or more hour time points (P < 0.005-P < 0.0001) and peaked at 12 h in both groups (oral: 24.4 ± 2.8 %ID, iv: 15.2 ± 2.8 %ID). (123)I thyroid uptake showed significant inverse correlations with whole-body excretion from 6 h (r = -0.799, P < 0.0001), and thereafter [12 h (r = -0.957, P < 0.0001), 24 h (r = -0.905, P < 0.0001) and 48 h (r = -0.893, P < 0.0001)], respectively. (123)I whole-body excretion was significantly higher in the iv group at each time point (P < 0.0001). The AUC of (123)I thyroid uptake was 1.6 times higher in the oral group than the iv group. CONCLUSIONS: These results suggest that radioiodide accumulates in the rat thyroid more effectively by oral than iv administration probably due to slower and lower (123)I clearance from the body in the oral administration when administered in a bolus fashion.
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Radioisótopos de Yodo/administración & dosificación , Radiofármacos/administración & dosificación , Yoduro de Sodio/administración & dosificación , Glándula Tiroides/diagnóstico por imagen , Administración Oral , Animales , Área Bajo la Curva , Estudios Cruzados , Inyecciones Intravenosas , Radioisótopos de Yodo/farmacocinética , Masculino , Cintigrafía/instrumentación , Radiofármacos/farmacocinética , Distribución Aleatoria , Ratas Wistar , Yoduro de Sodio/farmacocinética , Estómago/diagnóstico por imagen , Factores de TiempoRESUMEN
Cartilage has a limited capacity for self-repair and focal damage can eventually lead to complete degradation of the tissue. Early diagnosis of degenerative changes in cartilage is therefore essential. Contrast agent-based computed tomography and magnetic resonance imaging provide promising tools for this purpose. However, the common assumption in clinical applications that contrast agents reach steady-state distributions within the tissue has been of questionable validity. Characterization of nonequilibrium diffusion of contrast agents rather than their equilibrium distributions may therefore be more effective for image-based cartilage assessment. Transport of contrast agent through the extracellular matrix of cartilage can be affected by tissue compression due to matrix structural and compositional changes including reduced pore size and fluid content. We therefore investigate the effects of static compression on diffusion of three common contrast agents: sodium iodide, sodium diatrizoate, and gadolinium diethylenetriamine-pentaacid (Gd-DTPA). Results showed that static compression was associated with significant decreases in diffusivities for sodium iodide and Gd-DTPA, with similar (but not significant) trends for sodium diatrizoate. Molecular mass of contrast agents affected diffusivities as the smallest one tested, sodium iodide, showed higher diffusivity than sodium diatrizoate and Gd-DTPA. Compression-associated cartilage matrix alterations such as glycosaminoglycan and fluid contents were found to correspond with variations in contrast agent diffusivities. Although decreased diffusivity was significantly correlated with increasing glycosaminoglycan content for sodium iodide and Gd-DTPA only, diffusivity significantly increased for all contrast agents by increasing fluid fraction. Because compounds based on iodine and gadolinium are commonly used for computed tomography and magnetic resonance imaging, present findings can be valuable for more accurate image-based assessment of variations in cartilage composition associated with focal injuries.
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Cartílago Articular/efectos de los fármacos , Medios de Contraste/farmacocinética , Diatrizoato/farmacocinética , Gadolinio DTPA/farmacocinética , Yoduro de Sodio/farmacocinética , Estrés Mecánico , Animales , Cartílago Articular/química , Bovinos , Difusión , Glicosaminoglicanos/química , PresiónRESUMEN
Current practice for radiation protection associated with (131)I therapy mainly focuses on external and internal exposure caused by physical contamination of the hospital staff, other patients and family members. However, if volatile (131)I is excreted by the treated patients, these individuals could also be exposed through inhalation of (131)I. This study quantifies the amount of volatile (131)I excreted by rats after intravenous administration of metaiodobenzylguanidine (MIBG)-(131)I or Na(131)I, the two most common forms of (131)I therapy. The results indicate that in 4 d following administration, the total excretion of volatile (131)I was 0.036 and 0.17 % of the administered activities of MIBG-(131)I and Na(131)I, respectively. As administered activities for (131)I therapy are typically of the order of 1-10 GBq, the overall excretion of volatile (131)I from a patient can be as high as 20 MBq. As a result, a family member can receive up to 0.07 mSv committed effective dose from inhaling the volatile (131)I excreted by the patient.
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3-Yodobencilguanidina/administración & dosificación , Radioisótopos de Yodo/análisis , Radioisótopos de Yodo/metabolismo , Yoduro de Sodio/administración & dosificación , 3-Yodobencilguanidina/farmacocinética , Animales , Masculino , Ratones , Ratones Pelados , Protección Radiológica , Radiometría , Radiofármacos/administración & dosificación , Radiofármacos/farmacocinética , Ratas , Yoduro de Sodio/farmacocinética , Distribución TisularRESUMEN
Methyl iodide (MeI) is a water soluble monohalomethane that is metabolized in vivo to release iodide (I-). A physiologically based pharmacokinetic (PBPK) model exists for iodide in adult rats, pregnant rats and fetuses, and lactating rats and neonates, but not for pregnant rabbits and fetuses, which have been used extensively for toxicity testing with MeI. Thus, this study was conducted to determine the blood and tissue distribution kinetics of radioiodide in pregnant rabbits and fetuses. Timed-pregnant New Zealand White rabbits received a single intravenous injection of the sodium salt of iodine-131 (Na131I) at either a high (10 mg/kg body weight) or low (0.75 mg/kg body weight) dose on gestation day 25. At various intervals ranging from 0.5 to 24h post- injection, blood and tissues (thyroid, stomach contents, and skin) were collected from each doe, and blood, stomach contents, thyroid, trachea, and amniotic fluid were collected from a random sampling of three fetuses per doe per time point. Radioiodide accumulated as expected in the thyroid of maternal animals, where concentrations were the highest of any maternal tissues measured in both dose groups. Radioiodide also accumulated in fetal blood and tissues; levels were consistently higher than maternal levels and, unlike maternal tissues, showed no evidence of clearance over the 24-h sampling period. In contrast to observations in the maternal animals, fetal stomach contents showed the highest accumulation of radioiodide for both dose groups by 1-2h after dosing, followed by the trachea and thyroid tissues, with the lowest concentrations of radioiodide in the amniotic fluid and blood. There was no evidence for preferential accumulation of radioiodide in fetal thyroid tissues.
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Hidrocarburos Yodados/farmacocinética , Radioisótopos de Yodo/farmacocinética , Modelos Biológicos , Yoduro de Sodio/farmacocinética , Animales , Femenino , Embarazo , Conejos , Distribución Tisular/efectos de los fármacos , Distribución Tisular/fisiologíaRESUMEN
INTRODUCTION: Noninvasive analysis of therapeutic transgene expression is important for the development of clinical translational gene therapy strategies against cancer. To image p53 and MnSOD gene transfer noninvasively, we used radiologically detectable dual-expressing adenoviral vectors with the human sodium iodide symporter (hNIS) as the reporter gene. METHODS: Dual-expressing adenoviral vectors were constructed with hNIS cloned into E3 region and therapeutic genes, either MnSOD or p53, recombined into the E1 region. Steady-state mRNA levels of hNIS were evaluated by real-time polymerase chain reaction. hNIS function was determined by iodide uptake assay and MnSOD, and p53 protein levels were assessed by Western blots. RESULTS: 125I- accumulation resulting from hNIS expression in both Ad-p53-hNIS- and Ad-MnSOD-hNIS-infected MDA-MB-435 cells could be visualized clearly on phosphorimaging autoradiograph. Iodide accumulation increased with increasing adenovirus titer, and there was a linear correlation between iodide uptake and dose. p53 and MnSOD protein levels increased as a function of adenovirus titer, and there was a direct positive correlation between p53 and MnSOD expression and hNIS function. P53 and MnSOD overexpression inhibited cell growth in the dual-expressing adenoviral vector-infected cells. CONCLUSIONS: Radiological detection of hNIS derived from dual-expressing adenoviral vectors is a highly effective method to monitor therapeutic gene transfer and expression in a noninvasive manner.
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Adenoviridae/genética , Neoplasias de la Mama/diagnóstico por imagen , Técnicas de Transferencia de Gen , Vectores Genéticos , Simportadores/genética , Neoplasias de la Mama/enzimología , Genes Reporteros , Humanos , Radioisótopos de Yodo , Técnicas de Sonda Molecular , Cintigrafía , Yoduro de Sodio/farmacocinética , Superóxido Dismutasa/metabolismo , Células Tumorales Cultivadas , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
UNLABELLED: Transfer of the human sodium iodide symporter (hNIS) has been proposed as a new principle of cancer gene therapy. This study evaluates the iodide kinetics and dosimetry of iodide in hNIS-expressing thyroid carcinoma cells under optimized conditions. METHODS: Using a bicistronic retroviral vector for the transfer of the hNIS and the hygromycin resistance gene, hNIS-expressing rat thyroid carcinoma cell lines were generated. Afterward, Na(125)I uptake and efflux were determined in genetically modified and wild-type cells in the presence or absence of modulators of iodide transport. In addition, the (131)I distribution in thyroid-ablated nude mice bearing wild-type and genetically modified thyroid carcinomas was monitored after intraperitoneal administration of (131)I with and without coadministration of lithium carbonate. RESULTS: hNIS-expressing cell lines accumulated up to 49 times more iodide than did noninfected cells, with a maximal iodide uptake after 30 min of incubation. However, a 90% efflux of the radioactivity occurred 20 min after replacement of the medium. In mice, the hNIS-expressing tumors accumulated up to 23 and 19.5 times more iodide than did the wild-type tumors in lithium-treated and control animals, respectively. However, efflux of the radioactivity was also observed in vivo: After 24 h, hNIS-expressing tumors lost 82.5% and 80.4% of the initial activity. Dosimetric calculations showed that 1,650 MBq of (131)I per square meter resulted in 5.4 and 5.2 Gy in hNIS-expressing tumors and 0.24 and 0.26 in wild-type tumors. CONCLUSION: Transduction of the hNIS gene in rat thyroid carcinoma cells induces iodide transport, which is associated with rapid efflux. Application of (131)I in clinically relevant amounts did not result in therapeutically useful absorbed doses in hNIS-expressing tumors in vivo, even under optimized conditions of thyroid ablation and treatment with lithium carbonate.
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Carcinoma Papilar/radioterapia , Yoduros/metabolismo , Radioisótopos de Yodo/uso terapéutico , Simportadores/genética , Neoplasias de la Tiroides/radioterapia , Animales , Carcinoma Papilar/terapia , Farmacorresistencia Fúngica/genética , Terapia Genética , Vectores Genéticos , Humanos , Higromicina B/farmacología , Carbonato de Litio/farmacología , Ratones , Ratones Desnudos , Dosis de Radiación , Ratas , Retroviridae , Yoduro de Sodio/administración & dosificación , Yoduro de Sodio/farmacocinética , Yoduro de Sodio/farmacología , Neoplasias de la Tiroides/terapia , Células Tumorales CultivadasRESUMEN
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.
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Proteína de Unión a Andrógenos/genética , Terapia Genética/métodos , Radioisótopos de Yodo/uso terapéutico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/radioterapia , Yoduro de Sodio/farmacocinética , Simportadores/biosíntesis , Adenovirus Humanos/genética , Western Blotting , Línea Celular Tumoral , Humanos , Radioisótopos de Yodo/farmacocinética , Masculino , Regiones Promotoras Genéticas , Neoplasias de la Próstata/genética , Simportadores/genética , Simportadores/metabolismoRESUMEN
We evaluated the potential of radioiodide therapy in human sodium iodide symporter (hNIS)-defective thyroid cancer cells via exogenous hNIS expression. Three human thyroid cancer cells (ARO, FRO and NPA) of different origin were transduced by a recombinant adenovirus encoding hNIS expression cassette (Rad-hNIS). The cells were efficiently transduced by a recombinant adenovirus in a virus dose-dependent manner. Consequently, the hNIS protein could be readily detected by Western blot analysis 48-h post-infection at 10 infectious virus particles per cell. These hNIS-transduced cells actively transported iodide into the cytoplasm at the level of 11635.3, 61571.6, and 19367.5 pmoles/10(6) cells in ARO, FRO, and NPA, respectively. However, a significant amount of iodide was eluted to an iodide-free media within 60 min in all the cell lines. RT-PCR analysis revealed that the expression of genes related to iodide trapping (Tg, TSHR and TPO) was dramatically downregulated in these cells. The present study indicates that functional hNIS can be efficiently expressed and is responsible for active transport of iodide in hNIS-negative human thyroid cancer cells by a recombinant adenovirus. However, the human thyroid cancer cells, along with downregulation of iodide metabolism-related gene expression, lose the ability to maintain iodide. Therefore, these kinetic characteristics of iodide uptake and efflux may limit the therapeutic potential of hNIS/radioiodide-based treatment following exogenous hNIS expression in human thyroid cancer.
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Adenoviridae/genética , Expresión Génica , Yoduro de Sodio/farmacocinética , Simportadores/genética , Neoplasias de la Tiroides/metabolismo , ADN Recombinante , Virus Defectuosos , Humanos , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Radioisótopos de Yodo/farmacocinética , Cinética , ARN Mensajero/análisis , Receptores de Tirotropina/genética , Receptores de Tirotropina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Simportadores/metabolismo , Transfección , Células Tumorales CultivadasRESUMEN
The thyrotropin (TSH) receptor (TSHR) is a member of the heterotrimeric G protein-coupled family of receptors whose main function is to regulate thyroid cell proliferation as well as thyroid hormone synthesis and release. In this study, we generated a TSHR knockout (TSHR-KO) mouse by homologous recombination for use as a model to study TSHR function. TSHR-KO mice presented with developmental and growth delays and were profoundly hypothyroid, with no detectable thyroid hormone and elevated TSH. Heterozygotes were apparently unaffected. Knockout mice died within 1 week of weaning unless fed a diet supplemented with thyroid powder. Mature mice were fertile on the thyroid-supplemented diet. Thyroid glands of TSHR-KO mice produced uniodinated thyroglobulin, but the ability to concentrate and organify iodide could be restored to TSHR-KO thyroids when cultured in the presence of the adenylate cyclase agonist forskolin. Consistent with this observation was the lack of detectable sodium-iodide symporter expression in TSHR-KO thyroid glands. Hence, by using the TSHR-KO mouse, we provided in vivo evidence, demonstrating that TSHR expression was required for expression of sodium-iodide symporter but was not required for thyroglobulin expression, suggesting that the thyroid hormone synthetic pathway of the mouse could be dissociated into TSHR-dependent and -independent steps.
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Receptores de Tirotropina/fisiología , Simportadores/biosíntesis , Hormonas Tiroideas/biosíntesis , Tirotropina/fisiología , Inhibidores de Adenilato Ciclasa , Adenilil Ciclasas/fisiología , Animales , Bovinos , Colforsina/farmacología , AMP Cíclico/fisiología , Inhibidores Enzimáticos/farmacología , Regulación de la Expresión Génica , Marcación de Gen , Genes Letales , Genes Reporteros , Terapia de Reemplazo de Hormonas , Hipotiroidismo/genética , Hipotiroidismo/metabolismo , Transporte Iónico , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Tirotropina/deficiencia , Receptores de Tirotropina/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sistemas de Mensajero Secundario/efectos de los fármacos , Yoduro de Sodio/farmacocinética , Simportadores/deficiencia , Simportadores/genética , Tiroglobulina/biosíntesis , Glándula Tiroides/metabolismo , Glándula Tiroides/patología , Hormonas Tiroideas/administración & dosificación , Tirotropina/sangre , Tirotropina/farmacología , Extractos de Tejidos/uso terapéuticoRESUMEN
Application of a sensitive new detection method has revealed widespread perchlorate contamination of groundwater in the southwestern United States, typically at 0.005-0.020 mg/L (5-20 ppb). Perchlorate is a competitive inhibitor of the process by which iodide is actively transported from the bloodstream into the thyroid. This inhibitory action of perchlorate is the basis of its pharmaceutical use (in the treatment of hyperthyroidism) as well as its potential toxicity. To establish the dose response in humans for perchlorate inhibition of thyroidal iodide uptake and any short-term effects on thyroid hormones, we gave perchlorate in drinking water at 0.007, 0.02, 0.1, or 0.5 mg/kg-day to 37 male and female volunteers for 14 days. In 24 subjects we performed 8- and 24-hr measurements of thyroidal (123)I uptake (RAIU) before exposure, on exposure days 2 (E2) and 14 (E14), and 15 days postexposure (P15). In another 13 subjects we omitted both E2 studies and the 8-hr P15 study. We observed a strong correlation between the 8- and 24-hr RAIU over all dose groups and measurement days. We found no difference between E2 and E14 in the inhibition of RAIU produced by a given perchlorate dose. We also found no sex difference. On both E2 and E14, the dose response was a negative linear function of the logarithm of dose. Based on the dose response for inhibition of the 8- and 24-hr RAIU on E14 in all subjects, we derived estimates of the true no-effect level: 5.2 and 6.4 micro g/kg-day, respectively. Given default body weight and exposure assumptions, these doses would be ingested by an adult if the drinking-water supply contained perchlorate at concentrations of approximately 180 and 220 micro g/L (ppb), respectively. On P15, RAIU was not significantly different from baseline. In 24 subjects we measured serum levels of thyroxine (total and free), triiodothyronine, and thyrotropin in blood sampled 16 times throughout the study. Only the 0.5 mg/kg-day dose group showed any effect on serum hormones: a slight downward trend in thyrotropin levels in morning blood draws during perchlorate exposure, with recovery by P15.
Asunto(s)
Exposición a Riesgos Ambientales , Percloratos/efectos adversos , Compuestos de Sodio/efectos adversos , Yoduro de Sodio/farmacocinética , Glándula Tiroides/fisiología , Abastecimiento de Agua , Adolescente , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Radioisótopos de Yodo/farmacocinética , Masculino , Persona de Mediana Edad , Medición de Riesgo , Glándula Tiroides/efectos de los fármacos , Tirotropina/sangreRESUMEN
UNLABELLED: This investigation compared in vitro dissolution profiles from sodium iodide capsules with radioiodide thyroid uptake in patients with thyroid abnormalities, using sodium iodide capsules prepared with a formulation exhibiting complete release of radioiodide in vitro and a formulation exhibiting incomplete release. METHODS: In vitro dissolution profiles for radioactive sodium iodide capsules with 2 different formulations were determined using the U.S. Pharmacopeia (USP) XXIV dissolution test. The 2 formulations studied in vitro were sodium phosphate dibasic powder with 1% magnesium stearate and calcium phosphate dibasic powder with 3% magnesium stearate. The thyroid uptake of radioiodide from capsules exhibiting complete release or incomplete release of radioiodide was determined in patients with thyroid disorders. RESULTS: In the dissolution studies, by 20 min after initiation of the test, >95% of the radioactive iodide was released from capsules of sodium phosphate dibasic powder. The capsules of calcium phosphate dibasic powder reached 75% at 65 min, with no further release occurring thereafter. In the in vivo studies, the mean thyroid uptake at 1 h for sodium phosphate dibasic powder with 1% magnesium stearate (complete-release formulation) was 12.7%, compared with 9.3% for calcium phosphate dibasic powder with 3% magnesium stearate (incomplete-release formulation) (P < 0.05). At 24 h, the value was 56.6% for the complete-release formulation, compared with 50.3% for the incomplete-release formulation (P < 0.01, Wilcoxon signed rank test). At 1 h, the abdominal activity for the complete-release formulation was 3.4%, compared with 8.8% for the incomplete-release formulation (P < 0.01). At 24 h, the value was 0.4% for the complete-release formulation, compared with 1.0% for the incomplete-release formulation (P < 0.01). CONCLUSION: The data suggest that the incomplete dissolution profile observed in vitro may correlate with reduced bioavailability of radioiodide in vivo. The USP dissolution test can be applied to radioiodide sodium iodide capsules as a quality assurance procedure.
Asunto(s)
Radioisótopos de Yodo/farmacocinética , Yoduro de Sodio/farmacocinética , Glándula Tiroides/diagnóstico por imagen , Adulto , Anciano , Disponibilidad Biológica , Química Farmacéutica , Femenino , Humanos , Técnicas In Vitro , Masculino , Persona de Mediana Edad , Cintigrafía , Enfermedades de la Tiroides/diagnóstico por imagen , Glándula Tiroides/metabolismo , Factores de TiempoRESUMEN
Uptake of iodide is a prerequisite for radioiodine therapy in thyroid cancer. However, loss of iodide uptake is frequently observed in metastasized thyroid cancer, which may be explained by diminished expression of the human sodium iodide symporter (hNIS). Strategies to restore iodide uptake in thyroid cancer include the exploration of hNIS gene transfer into hNIS defective thyroid cancer. In this study, we report the stable transfection of a hNIS expression vector into the hNIS defective follicular thyroid carcinoma cell line FTC133. Stablely transfected colonies exhibited high uptake of Na125I, which could be blocked completely with sodiumperchlorate. hNIS mRNA expression corresponded with iodide uptake in semiquantitative polymerase chain reaction. Iodide uptake was maximal after 60 minutes, whereas iodide efflux was complete after 120 minutes. hNIS transfected FTC133 and control cell lines injected subcutaneously in nude mice formed tumors after 6 weeks. Iodide uptake in the hNIS transfected tumor was much higher than in the nontransfected tumor, which corresponded with hNIS mRNA expression in tumors.
Asunto(s)
Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Yoduro de Sodio/farmacocinética , Simportadores , Neoplasias de la Tiroides , Adulto , Animales , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Técnicas In Vitro , Radioisótopos de Yodo/farmacocinética , Masculino , Ratones , Ratones Desnudos , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Células Tumorales CultivadasRESUMEN
In patients with end-stage renal disease (ESRD), Na131I dosages for thyroid cancer may have to be reduced to avoid excess radiation doses to red marrow, because radioiodine is primarily excreted by kidneys. In ESRD patients receiving continuous ambulatory peritoneal dialysis (CAPD) therapy (three to five 2-L exchanges daily) creatinine clearance rates are very low (mean, 7 mL/min), and radioiodine clearance rates may be proportionately reduced. Thus, radioiodine kinetic studies were performed in two hypothyroid CAPD patients with thyroid cancer, in eight euthyroid CAPD patients, and in eight thyroid cancer patients with normal renal function. All received Na131I or Na123I orally, with serial blood, urine, and/or dialysate sampling for 24-70 h. Dosimetry calculations were performed using the MIRDOSE3 computer program. In CAPD patients, serum radioiodine half-times were 5 times longer, and radioiodine clearance rates by urine plus dialysate were 20% of those in patients with normal renal function. Na131I dosages for the two CAPD patients with thyroid cancer were reduced from 150 mCi [5.6 gigabecquerels (GBq)] to 26.6 mCi (0.98 GBq) and 29.9 mCi (1.11 GBq), respectively, resulting in radiation doses to red marrow and total body comparable to those in patients with normal renal function who received a mean of 148 mCi (5.5 GBq) Na131I. Thus, in patients receiving continuous ambulatory peritoneal dialysis therapy, 5-fold reductions in radioiodine clearance rates require 5-fold decreases in Na131I dosages to avoid excessive radiation doses to total body and red marrow.
Asunto(s)
Carcinoma Papilar Folicular/radioterapia , Fallo Renal Crónico/complicaciones , Diálisis Peritoneal Ambulatoria Continua , Neoplasias de la Tiroides/radioterapia , Adulto , Médula Ósea/metabolismo , Carcinoma Papilar Folicular/complicaciones , Creatinina/sangre , Femenino , Semivida , Humanos , Yodo/sangre , Yodo/orina , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/uso terapéutico , Masculino , Persona de Mediana Edad , Radiometría , Yoduro de Sodio/administración & dosificación , Yoduro de Sodio/farmacocinética , Neoplasias de la Tiroides/complicaciones , TiroidectomíaRESUMEN
The sodium/iodide symporter (NIS) stimulates iodide uptake in normal lactating breast, but is not known to be active in nonlactating breast or breast cancer. We studied NIS gene regulation and iodide uptake in MCF-7 cells, an estrogen receptor (ER)-positive human breast cancer cell line. All-trans retinoic acid (tRA) treatment stimulated iodide uptake in a time- and dose-dependent fashion up to approximately 9.4-fold above baseline. Stimulation with selective retinoid compounds indicated that the induction of iodide uptake was mediated by retinoic acid receptor. Treatment with tRA markedly stimulated NIS mRNA and immunoreactive protein ( approximately 68 kDa). tRA stimulated NIS gene transcription approximately 4-fold, as shown by nuclear run-on assay. No induction of iodide uptake was observed with RA treatment of an ER-negative human breast cancer cell line, MDA-MB 231, or a normal human breast cell line, MCF-12A. The iodide efflux rate of tRA-treated MCF-7 cells was slow (t(1/2) = 24 min), compared with that in FRTL-5 thyroid cells (t(1/2) = 3.9 min), favoring iodide retention in MCF-7 cells. An in vitro clonogenic assay demonstrated selective cytotoxicity with (131)I after tRA stimulation of MCF-7 cells. tRA up-regulates NIS gene expression and iodide uptake in an ER-positive breast cancer cell line. Stimulation of radioiodide uptake after systemic retinoid treatment may be useful for diagnosis and treatment of some differentiated breast cancers.
Asunto(s)
Antineoplásicos/farmacología , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Yoduro de Sodio/farmacocinética , Simportadores , Tretinoina/farmacología , Alitretinoína , Animales , Neoplasias de la Mama , Proteínas Portadoras/biosíntesis , Línea Celular , Colforsina/farmacología , Regulación hacia Abajo/efectos de los fármacos , Femenino , Humanos , Yoduros/metabolismo , Radioisótopos de Yodo/farmacocinética , Cinética , Proteínas de la Membrana/biosíntesis , Oxitocina/farmacología , Prolactina/farmacología , Ratas , Transcripción Genética/efectos de los fármacos , Células Tumorales CultivadasRESUMEN
Iodine-deficiency disorders are a major problem of public health in Morocco. To mitigate this deficiency, the iodination of all the salt intended for human consumption in a proportion of 80 +/- 10 mg/kg of salt has become obligatory since a decree published in 1995. We estimated that this rate of iodized salt issued risked inducing an iodine excess in the population. To check this hypothesis, we provided 7 families made up of 28 subjects, who at the start were consuming a non-iodized salt, with the decreed, iodized salt and we followed the evolution of their urinary iodine excretion over a period of 3 weeks. The mean values of urinary iodine excretion of the 28 subjects were 12.8 micrograms/dl before use of iodized salt and 26.8, 35.5 and 63.2 micrograms/dl, respectively, after 7, 14 and 21 days from the introduction of iodized salt into their diet. After 21 days of the use of iodized salt, 84.6 per cent of the subjects had an iodine excess. We conclude that prolonged use of this iodized salt exposes the population to the risk of thyroid disorders.
Asunto(s)
Cloruro de Sodio Dietético/administración & dosificación , Yoduro de Sodio/efectos adversos , Adolescente , Adulto , Niño , Preescolar , Conducta Alimentaria , Femenino , Humanos , Yodo/orina , Legislación Alimentaria , Masculino , Persona de Mediana Edad , Marruecos , Salud Pública , Riesgo , Cloruro de Sodio Dietético/análisis , Cloruro de Sodio Dietético/farmacocinética , Yoduro de Sodio/administración & dosificación , Yoduro de Sodio/análisis , Yoduro de Sodio/farmacocinética , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/epidemiologíaRESUMEN
Radioactivity after administration of 123I-sodium iodide was measured in breast milk samples obtained from a patient with postpartum thyroiditis. The breast milk was collected over 93 h during the infant's regular feeding times. The radioactivity in the breast milk was calculated with a 123I capsule of the same lot number as the standard source. 123I was excreted exponentially with an effective half-life of 5.5 h; 2.5% of the total radioactivity administered was excreted in the breast milk over the 93 h, 95% of which was excreted within the first 24 h, and 98.2% within 36 h. The first milk sample collected at 7 h after administration of the radiopharmaceutical contained 48.5% of the total radioactivity excreted. We estimated the potential absorption of radioactivity to an infant's thyroid in uninterrupted breast-feeding to be 30.3 mGy. With a 24-hour interruption, the absorbed radioactivity would be 1.25 mGy; with a 36-hour interruption, it would be 0.24 mGy. According to our calculations, breast feeding should be curtailed for 36 h to reduce the infant's exposure to 123I radioactivity. By using a correction factor based on maximum radioactivity from another 123I capsule of the same lot, we were able to ascertain the appropriate protocol for our patient and establish a measurement method that can be applied in similar clinical situations.