RESUMO
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.
Assuntos
Radioisótopos do Iodo , Razão Sinal-Ruído , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Processamento de Imagem Assistida por Computador , Camundongos , Camundongos Endogâmicos C57BL , Imagens de Fantasmas , Iodeto de Sódio/farmacocinética , Distribuição TecidualRESUMO
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.
Assuntos
Diferenciação Celular , Radioisótopos do Iodo/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/farmacocinética , Iodeto de Sódio/farmacocinética , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Viabilidade , Feminino , Humanos , Radioisótopos do Iodo/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Compostos Radiofarmacêuticos/administração & dosagem , Iodeto de Sódio/administração & dosagem , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Distribuição TecidualAssuntos
Carcinoma Papilar, Variante Folicular/diagnóstico por imagem , Carcinoma Papilar, Variante Folicular/secundário , Carcinoma Papilar/diagnóstico por imagem , Carcinoma Papilar/secundário , Radioisótopos do Iodo/uso terapêutico , Doenças Renais Policísticas/diagnóstico por imagem , Compostos Radiofarmacêuticos/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Iodeto de Sódio/uso terapêutico , Neoplasias da Glândula Tireoide/patologia , Imagem Corporal Total , Idoso de 80 Anos ou mais , Carcinoma Papilar/radioterapia , Carcinoma Papilar/cirurgia , Carcinoma Papilar, Variante Folicular/radioterapia , Carcinoma Papilar, Variante Folicular/cirurgia , Diagnóstico Diferencial , Reações Falso-Positivas , Feminino , Humanos , Radioisótopos do Iodo/farmacocinética , Neoplasias Primárias Múltiplas/cirurgia , Compostos Radiofarmacêuticos/farmacocinética , Radioterapia Adjuvante , Iodeto de Sódio/farmacocinética , Hormônios Tireóideos/uso terapêutico , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Distribuição Tecidual , UltrassonografiaAssuntos
Medicina Baseada em Evidências , Radioisótopos do Iodo/efeitos adversos , Compostos Radiofarmacêuticos/efeitos adversos , Iodeto de Sódio/efeitos adversos , Doenças da Glândula Tireoide/radioterapia , Glândula Tireoide/efeitos da radiação , Centers for Disease Control and Prevention, U.S. , Relação Dose-Resposta à Radiação , Interações Medicamentosas , Medicina Baseada em Evidências/métodos , Interações Alimento-Droga , Humanos , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/farmacocinética , Radioisótopos do Iodo/uso terapêutico , Cintilografia , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/uso terapêutico , Iodeto de Sódio/administração & dosagem , Iodeto de Sódio/farmacocinética , Iodeto de Sódio/uso terapêutico , Doenças da Glândula Tireoide/diagnóstico por imagem , Doenças da Glândula Tireoide/metabolismo , Doenças da Glândula Tireoide/fisiopatologia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/metabolismo , Glândula Tireoide/fisiopatologia , Tireotropina/sangue , Distribuição Tecidual , Toxicologia/métodos , Estados UnidosRESUMO
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.
Assuntos
Radioisótopos do Iodo/administração & dosagem , Compostos Radiofarmacêuticos/administração & dosagem , Iodeto de Sódio/administração & dosagem , Glândula Tireoide/diagnóstico por imagem , Administração Oral , Animais , Área Sob a Curva , Estudos Cross-Over , Injeções Intravenosas , Radioisótopos do Iodo/farmacocinética , Masculino , Cintilografia/instrumentação , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Aleatória , Ratos Wistar , Iodeto de Sódio/farmacocinética , Estômago/diagnóstico por imagem , Fatores de TempoRESUMO
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.
Assuntos
3-Iodobenzilguanidina/administração & dosagem , Radioisótopos do Iodo/análise , Radioisótopos do Iodo/metabolismo , Iodeto de Sódio/administração & dosagem , 3-Iodobenzilguanidina/farmacocinética , Animais , Masculino , Camundongos , Camundongos Pelados , Proteção Radiológica , Radiometria , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Iodeto de Sódio/farmacocinética , Distribuição TecidualRESUMO
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.
Assuntos
Adenoviridae/genética , Neoplasias da Mama/diagnóstico por imagem , Técnicas de Transferência de Genes , Vetores Genéticos , Simportadores/genética , Neoplasias da Mama/enzimologia , Genes Reporter , Humanos , Radioisótopos do Iodo , Técnicas de Sonda Molecular , Cintilografia , Iodeto de Sódio/farmacocinética , Superóxido Dismutase/metabolismo , Células Tumorais Cultivadas , Proteína Supressora de Tumor p53/metabolismoRESUMO
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.
Assuntos
Carcinoma Papilar/radioterapia , Iodetos/metabolismo , Radioisótopos do Iodo/uso terapêutico , Simportadores/genética , Neoplasias da Glândula Tireoide/radioterapia , Animais , Carcinoma Papilar/terapia , Farmacorresistência Fúngica/genética , Terapia Genética , Vetores Genéticos , Humanos , Higromicina B/farmacologia , Carbonato de Lítio/farmacologia , Camundongos , Camundongos Nus , Doses de Radiação , Ratos , Retroviridae , Iodeto de Sódio/administração & dosagem , Iodeto de Sódio/farmacocinética , Iodeto de Sódio/farmacologia , Neoplasias da Glândula Tireoide/terapia , Células Tumorais CultivadasRESUMO
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.
Assuntos
Proteína de Ligação a Androgênios/genética , Terapia Genética/métodos , Radioisótopos do Iodo/uso terapêutico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/radioterapia , Iodeto de Sódio/farmacocinética , Simportadores/biossíntese , Adenovírus Humanos/genética , Western Blotting , Linhagem Celular Tumoral , Humanos , Radioisótopos do Iodo/farmacocinética , Masculino , Regiões Promotoras Genéticas , Neoplasias da Próstata/genética , Simportadores/genética , Simportadores/metabolismoRESUMO
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.
Assuntos
Adenoviridae/genética , Expressão Gênica , Iodeto de Sódio/farmacocinética , Simportadores/genética , Neoplasias da Glândula Tireoide/metabolismo , DNA Recombinante , Vírus Defeituosos , Humanos , Iodeto Peroxidase/genética , Iodeto Peroxidase/metabolismo , Radioisótopos do Iodo/farmacocinética , Cinética , RNA Mensageiro/análise , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Simportadores/metabolismo , Transfecção , Células Tumorais CultivadasRESUMO
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.
Assuntos
Receptores da Tireotropina/fisiologia , Simportadores/biossíntese , Hormônios Tireóideos/biossíntese , Tireotropina/fisiologia , Inibidores de Adenilil Ciclases , Adenilil Ciclases/fisiologia , Animais , Bovinos , Colforsina/farmacologia , AMP Cíclico/fisiologia , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica , Marcação de Genes , Genes Letais , Genes Reporter , Terapia de Reposição Hormonal , Hipotireoidismo/genética , Hipotireoidismo/metabolismo , Transporte de Íons , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores da Tireotropina/deficiência , Receptores da Tireotropina/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Iodeto de Sódio/farmacocinética , Simportadores/deficiência , Simportadores/genética , Tireoglobulina/biossíntese , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Hormônios Tireóideos/administração & dosagem , Tireotropina/sangue , Tireotropina/farmacologia , Extratos de Tecidos/uso terapêuticoRESUMO
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.
Assuntos
Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Iodeto de Sódio/farmacocinética , Simportadores , Neoplasias da Glândula Tireoide , Adulto , Animais , Modelos Animais de Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Técnicas In Vitro , Radioisótopos do Iodo/farmacocinética , Masculino , Camundongos , Camundongos Nus , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Células Tumorais CultivadasRESUMO
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.
Assuntos
Carcinoma Papilar, Variante Folicular/radioterapia , Falência Renal Crônica/complicações , Diálise Peritoneal Ambulatorial Contínua , Neoplasias da Glândula Tireoide/radioterapia , Adulto , Medula Óssea/metabolismo , Carcinoma Papilar, Variante Folicular/complicações , Creatinina/sangue , Feminino , Meia-Vida , Humanos , Iodo/sangue , Iodo/urina , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/uso terapêutico , Masculino , Pessoa de Meia-Idade , Radiometria , Iodeto de Sódio/administração & dosagem , Iodeto de Sódio/farmacocinética , Neoplasias da Glândula Tireoide/complicações , TireoidectomiaRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/genética , Proteínas de Membrana/genética , Iodeto de Sódio/farmacocinética , Simportadores , Tretinoína/farmacologia , Alitretinoína , Animais , Neoplasias da Mama , Proteínas de Transporte/biossíntese , Linhagem Celular , Colforsina/farmacologia , Regulação para Baixo/efeitos dos fármacos , Feminino , Humanos , Iodetos/metabolismo , Radioisótopos do Iodo/farmacocinética , Cinética , Proteínas de Membrana/biossíntese , Ocitocina/farmacologia , Prolactina/farmacologia , Ratos , Transcrição Gênica/efeitos dos fármacos , Células Tumorais CultivadasRESUMO
Radiolabelled meta-iodobenzylguanidine (MIBG) is selectively taken up by tumours of neuroendocrine origin, where its cellular localization is believed to be cytoplasmic. The radiopharmaceutical [131I]MIBG is now widely used in the treatment of neuroblastoma, but other radioconjugates of benzylguanidine have been little studied. We have investigated the cytotoxic efficacy of beta, alpha and Auger electron-emitting radioconjugates in treating neuroblastoma cells grown in monolayer or spheroid culture. Using a no-carrier-added synthesis route, we produced 123I-, 125I-, 131I- and 211At-labelled benzylguanidines and compared their in vitro toxicity to the neuroblastoma cell line SK-N-BE(2c) grown in monolayer and spheroid culture. The Auger electron-emitting conjugates ([123I]MIBG and [125I]MIBG) and the alpha-emitting conjugate ([211At]MABG) were highly toxic to monolayers and small spheroids, whereas the beta-emitting conjugate [131I]MIBG was relatively ineffective. The Auger emitters were more effective than expected if the cellular localization of MIBG is cytoplasmic. As dosimetrically predicted however, [211At]MABG was found to be extremely potent in terms of both concentration of radioactivity and number of atoms ml(-1) administered. In contrast, the Auger electron emitters were ineffective in the treatment of larger spheroids, while the beta emitter showed greater efficacy. These findings suggest that short-range emitters would be well suited to the treatment of circulating tumour cells or small clumps, whereas beta emitters would be superior in the treatment of subclinical metastases or macroscopic tumours. These experimental results provide support for a clinical strategy of combinations ('cocktails') of radioconjugates in targeted radiotherapy.
Assuntos
3-Iodobenzilguanidina/farmacologia , Antineoplásicos/farmacologia , Astato/uso terapêutico , Guanidinas/farmacologia , Radioisótopos do Iodo/uso terapêutico , Neuroblastoma/tratamento farmacológico , Neuroblastoma/radioterapia , 3-Iodobenzilguanidina/farmacocinética , Antineoplásicos/farmacocinética , Terapia Combinada , Guanidinas/farmacocinética , Humanos , Neuroblastoma/metabolismo , Iodeto de Sódio/farmacocinética , Esferoides Celulares , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
UNLABELLED: This study evaluates breast milk secretion of 131I following therapeutic administration of 4000 MBq of 131I-iodide during lactation. METHODS: Breast milk 131I activity concentration was measured over a 32-day period. Dosimetry calculations were undertaken to estimate the period for discontinuation of breast feeding and the equivalent dose to the breasts. RESULTS: To achieve an infant effective dose < 1 mSv and an infant thyroid dose < 10 mSv, breast feeding would need to be discontinued for at least 52 days. The estimated equivalent dose to the breasts was 1.6 Gy. CONCLUSION: It is suggested that 131I-iodide administration is not undertaken during lactation and that breast feeding is discontinued several days prior to administration.
Assuntos
Adenocarcinoma Folicular/radioterapia , Radioisótopos do Iodo/uso terapêutico , Leite Humano/química , Iodeto de Sódio/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Adenocarcinoma Folicular/cirurgia , Adulto , Mama/efeitos da radiação , Aleitamento Materno , Terapia Combinada , Feminino , Humanos , Lactente , Radioisótopos do Iodo/farmacocinética , Doses de Radiação , Dosagem Radioterapêutica , Fatores de Risco , Iodeto de Sódio/farmacocinética , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia , Fatores de TempoRESUMO
The efficacy of the modified compression immobilization technique in retarding spread of radio-labeled Russell's viper venom in 3 rhesus monkeys (Macaca mulata) and "mock venom" NaI131 in 14 human volunteers was studied. 0.1 microgram of Russell's viper venom having 10 microCi radioactivity in 0.2 ml normal saline containing 0.5% bovine serum albumin was injected subcutaneously at the lateral aspect of the right hind limb of a rhesus monkey. A hand-tight bandaging of a rubber pad measuring 55 x 28 x 16 mm over the injection site and splinting effectively retard spread of radio-labeled venom for the entire length of time applied, although complete immobilization was not achieved. In human volunteers, application of a pad measuring 60 x 50 x 17 mm over the subcutaneous injection site of 20 microCi or 12 microCi/0.2 ml NaI131 with a hand-tight bandaging (60 +/- 10 mmHg) and immobilization of limb was found to be effective in retarding the movement of radioactive NaI131. These results suggested that the compression pads tried in this study effectively retard the spread of radio-labeled Russell's viper venom (MW ranging from 20,000-90,000) and radioactive NaI131 (MW 150) from the site of injection. Thus, it is highly likely that the present compression pad will be useful as a first-aid measure in Russell's viper bite victims.
Assuntos
Iodeto de Sódio/farmacocinética , Venenos de Víboras/farmacocinética , Adulto , Animais , Bandagens , Primeiros Socorros , Humanos , Imobilização , Radioisótopos do Iodo , Macaca mulatta , Masculino , Pessoa de Meia-Idade , Pressão , Borracha , Iodeto de Sódio/administração & dosagem , Contenções , Fatores de Tempo , Venenos de Víboras/administração & dosagemRESUMO
Radioiodine labelled 17-iodo-heptadecanoic acid (IHA) is used for non-invasive study of myocardial metabolism in coronary heart disease and cardiomyopathy. Yet in the interpretation of in vivo myocardial tracer kinetics, it is controversial whether the intracellular degradation of IHA or the removal of iodide across cellular membranes is the rate-limiting step in iodide release from the myocardium. In five patients undergoing coronary sinus catheterization, a mixture of about 40 kBq of [123I] NaI was injected into the left coronary artery. During the following 15-min period, frequent blood samples were taken from the aorta and the coronary sinus. In the aqueous phase of the venous blood, 14CO2 and inorganic 131I appeared nearly in parallel, with a peak time of 4-5 min. Moreover, as shown by the AV difference, there was no significant back diffusion of IHA and no significant non-specific deiodination detectable over the period of observation. There was myocardial retention of inorganic iodide (123I) injected into the left coronary artery. The data strongly support the premise that lipid turnover through beta-oxidation is the rate-limiting step in the externally measured release of iodide after IHA injection, provided that recirculating inorganic radioactive iodide is corrected for. In addition, 15 volunteers were studied using [11C]palmitic acid and [123I]IHA using PET and dynamic planar camera scintigraphy with iodide correction. There was no significant difference between the mean values of the elimination half-times, and also no significant correlation between half-times of both fatty acids for single individuals.