RESUMO
Tissue factor (TF), a blood coagulation protein, plays an important role in tumor growth, invasion, and metastasis. Ixolaris, a tick-derived non-immunogenic molecule that binds to TF, has demonstrated in vivo inhibitory effect on murine models of melanoma, including primary growth and metastasis. This work aimed to: I) develop an efficient and stable labeling technique of ixolaris with Iodine-131(131I); II) compare the biodistribution of 131I and 131I-ixolaris in tumor-free and melanoma-bearing mice; III) evaluate whether 131I-ixolaris could serve as an antimetastatic agent. Ixolaris radioiodination was performed using iodogen, followed by liquid paper chromatography. Labeling stability and anticoagulant activity were measured. Imaging studies were performed after intravenous administration of free 131I or 131I-ixolaris in a murine melanoma model employing the B16-F10 cell line. Animals were divided in three experimental groups: the first experimental group, D0, received a single-dose of 9.25 MBq of 131I-ixolaris at the same day the animals were inoculated with melanoma cells. In the second group, D15, a single-dose of 9.25 MBq of 131I-ixolaris or free 131I was applied into mice on the fifteenth day after the tumor induction. The third group, D1-D15, received two therapeutic doses of 9.25 MBq of 131I-ixolaris or 131I. In vitro studies demonstrated that 131I-ixolaris is stable for up to 24 h and retains its inhibitory activity on blood coagulation. Biodistribution analysis and metastasis assays showed that all treatment regimens with 131I-ixolaris were effective, being the double-treatment (D1/D15) the most effective one. Remarkably, treatment with free 131I showed no anti-metastatic effect. 131I-ixolaris is a promising theranostic agent for metastatic melanoma.
Assuntos
Anticoagulantes/farmacologia , Coagulação Sanguínea/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Medicina de Precisão/métodos , Proteínas e Peptídeos Salivares/farmacologia , Tromboplastina/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Radioisótopos do Iodo/farmacologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas e Peptídeos Salivares/metabolismo , Proteínas e Peptídeos Salivares/farmacocinéticaRESUMO
Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-κB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFκB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-κB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-κB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up-regulating B-cell translocation gene 2-mediated activation of JNK/NF-κB pathways.
Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Radioisótopos do Iodo/uso terapêutico , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Humanos , Radioisótopos do Iodo/farmacologia , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
Iodine-131 (131I) is widely used for the treatment of thyroid-related diseases. This study aimed to investigate the expression of p53 and BTG2 genes following 131I therapy in thyroid cancer cell line SW579 and the possible underlying mechanism. SW579 human thyroid squamous carcinoma cells were cultured and treated with 131I. They were then assessed for 131I uptake, cell viability, apoptosis, cell cycle arrest, p53 expression, and BTG2 gene expression. SW579 cells were transfected with BTG2 siRNA, p53 siRNA and siNC and were then examined for the same aforementioned parameters. When treated with a JNK inhibitor of SP600125 and 131I or with a NF-κB inhibitor of BMS-345541 and 131I, non-transfected SW579 cells were assessed in JNK/NFκB pathways. It was observed that 131I significantly inhibited cell proliferation, promoted cell apoptosis and cell cycle arrest. Both BTG2 and p53 expression were enhanced in a dose-dependent manner. An increase in cell viability by up-regulation in Bcl2 gene, a decrease in apoptosis by enhanced CDK2 gene expression and a decrease in cell cycle arrest at G0/G1 phase were also observed in SW579 cell lines transfected with silenced BTG2 gene. When treated with SP600125 and 131I, the non-transfected SW579 cell lines significantly inhibited JNK pathway, NF-κB pathway and the expression of BTG2. However, when treated with BMS-345541 and 131I, only the NF-κB pathway was suppressed. 131I suppressed cell proliferation, induced cell apoptosis, and promoted cell cycle arrest of thyroid cancer cells by up-regulating B-cell translocation gene 2-mediated activation of JNK/NF-κB pathways.
Assuntos
Humanos , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Radioisótopos do Iodo/uso terapêutico , Sistema de Sinalização das MAP Quinases , Proteínas de Neoplasias/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Linhagem Celular Tumoral , Radioisótopos do Iodo/farmacologia , Proteínas de Neoplasias/metabolismo , Reação em Cadeia da Polimerase , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
The radioisotope iodine-131 [(131)I] can damage DNA. One way to prevent this is to increase the amount of antioxidants via dietary consumption. The goal of this study was to evaluate the radioprotective effect of fresh acerola pulp and synthetic beta-carotene in Rattus norvegicus hepatoma cells (HTC) in response to [(131)I] exposure in vitro. Cellular DNA damage was subsequently assessed using a cytokinesis block micronucleus assay. The mutagenic and cytotoxic activities of doses of [(131)I] (0.1, 0.5, 1, 5, and 10 µCi), acerola (0.025, 0.125, and 0.25 g acerola pulp/mL), and beta-carotene (0.2, 1, and 2 µM) were evaluated. Radioprotective tests were performed by simultaneous treatment with acerola (0.25 g/mL) plus [(131)I] (10 µCi) and beta-carotene (0.2 µM) plus [(131)I] (10 µCi). Acerola, beta-carotene, and low concentrations of [(131)I] did not induce micronucleus formation in HTC cells; in contrast, high concentrations of [(131)I] (10 µCi) were mutagenic and induced DNA damage. Moreover, neither acerola nor beta-carotene treatment was cytotoxic. However, acerola reduced the percentage of [(131)I]-induced damage, although beta-carotene did not show a similar effect. Thus, our results suggest that acerola diet supplementation may benefit patients who are exposed to [(131)I] during thyroid diagnostics and therapy.
Assuntos
Dano ao DNA/efeitos da radiação , Radioisótopos do Iodo/toxicidade , Malpighiaceae/metabolismo , Protetores contra Radiação/farmacologia , beta Caroteno/farmacologia , Animais , Antocianinas/análise , Antioxidantes/farmacologia , Ácido Ascórbico/análise , Carcinoma Hepatocelular , Carotenoides/análise , DNA/efeitos da radiação , Suplementos Nutricionais , Flavonoides/análise , Radioisótopos do Iodo/farmacologia , Neoplasias Hepáticas , Mutação/efeitos da radiação , Preparações de Plantas/efeitos adversos , Preparações de Plantas/farmacologia , Ratos , Ratos Wistar , Células Tumorais Cultivadas , beta Caroteno/efeitos adversosRESUMO
BACKGROUND: In patients with differentiated thyroid carcinoma considered to be free of the disease after initial therapy, the appropriate timing or necessity of subsequent stimulated thyroglobulin (Tg) testing is uncertain. The objective of this study was to determine the value of a repeat stimulated Tg in patients considered to be free of disease 6-12 months after thyroid ablation, and also who continued to have serum Tg <1 ng/mL while on thyrotropin suppressive doses of thyroxine (T4) (Tg/T4), negative anti-Tg antibodies (TgAb), and a normal clinical examination 5 years after their initial therapy. METHODS: The study participants were 203 patients who had total thyroidectomy followed by ablation with (131)I, who were considered to be free of disease 6-12 months after ablation (stimulated Tg <2 ng/mL in the absence of TgAb and negative diagnostic whole-body scanning), who had no recurrence, and who continued to have serum Tg/T4 of <1 ng/mL, negative TgAb and a normal clinical examination 5 years after initial therapy. These patients were evaluated with repeat stimulated Tg testing after 4 weeks of T4 withdrawal. RESULTS: Repeat stimulated Tg values after 5 years were <2 ng/mL in 192 (94.6%) patients of whom 188 were <1 ng/mL. Subsequent follow-up after a mean of 102 months did not detect new cases of tumor recurrence in this subgroup. Eleven patients (5.4%) had stimulated Tg levels of >2 ng/mL. Neck ultrasonography (US) revealed metastases in three and other imaging methods detected metastases in five patients with negative US. In the other three patients, no metastases were detected initially or during follow-up. Gender, age, and tumor stage were not predictors of recurrence or elevated Tg upon repeat testing after 5 years. CONCLUSIONS: The present results favor repeating stimulated Tg 5 years after ablation in patients who were initially considered to be free of disease and who continued to have Tg/T4 values of <1 ng/mL and negative TgAb tests. A negative predictive value of 100% was obtained for patients who continued to have low stimulated Tg values.
Assuntos
Tireoglobulina/química , Neoplasias da Glândula Tireoide/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Intervalo Livre de Doença , Feminino , Humanos , Radioisótopos do Iodo/farmacologia , Masculino , Oncologia/métodos , Pessoa de Meia-Idade , Recidiva , Risco , Tireoglobulina/sangue , Glândula Tireoide/cirurgia , Tireoidectomia , Tiroxina/sangue , Tiroxina/imunologia , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia/métodosRESUMO
Center for Genetic Engineering and Biotechnology (CIGB)-M3 is a trivalent recombinant single-chain Fv antibody fragment specific for carcinoembryonic antigen (CEA). Preclinical studies with radiolabeled CIGB-M3 have showed that the antibody fragment accumulates in human colon tumor xenografts growing in nude mice. A Phase I clinical trial was carried out to determine safety, biodistribution, and pharmacokinetics of the radiolabeled CIGB-M3 in two groups of patients with CEA+ colorectal cancers. Group I (10 patients) received a single intravenous injection of 0.3 mg of (131)I-CIGB-M3 (16.7-23.3 mCi/mg). Group II (7 patients) received 1 mg (5-7 mCi/mg). No adverse events related to the injected product were recorded, and no immunology response was detected up to 6 months after the injection. Tumors were detected in 15 of the 17 studied cases. The pharmacokinetic profile showed beta half-times of 14.1 and 6.3 hours for Groups I and II, respectively. Seventy-two (72) hours after the administration of the product, 85% of the total injected activity was excreted in urine in the form of free (131)I. The kidneys were identified as the organs that can limit the maximum tolerated dose. The (131)I-CIGB-M3 was safe in patients with colorectal cancer. The biodistribution and pharmacokinetic data suggest that the product can be further tested for molecular radiotherapy of CEA+tumors.
Assuntos
Anticorpos/química , Antígeno Carcinoembrionário/metabolismo , Radioisótopos do Iodo/farmacologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Fragmentos de Imunoglobulinas/metabolismo , Rim/metabolismo , Fígado/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Radioimunoterapia/métodos , Radiometria , Anticorpos de Cadeia Única/química , Fatores de TempoRESUMO
We report a novel material for use in (125)I brachytherapy that consists of amorphous carbon films grown by ion-beam-assisted deposition and doped with Xe (5 at%) by implantation. Samples of these films grown on Si substrates were irradiated with neutrons in a TRIGA-I nuclear reactor for the production (125)Xe, and latter characterized by gamma spectroscopy. The results indicate that the (124)Xe was efficiently converted into (125)Xe, the precursor of (125)I, and support the activity calculations for a model brachytherapy seed.
Assuntos
Braquiterapia/métodos , Carbono/química , Radioisótopos do Iodo/química , Isótopos de Xenônio/química , Humanos , Radioisótopos do Iodo/farmacologia , Espectrometria gamaRESUMO
BACKGROUND: Recombinant human thyroid stimulating hormone (rhTSH) is a valuable tool in the management of thyroid diseases. It is useful for radioiodine ablation in patients with differentiated thyroid carcinoma (DTC), for their follow-up, and for treatment of selected patients with metastatic or recurrent DTC. More recently, it has been suggested that rhTSH is useful for treatment of multinodular goiter and amiodarone-induced thyrotoxicosis, as well as for diagnosis of congenital hypothyroidism. OBJECTIVE: To provide an outline of literature regarding the uses of rhTSH in thyroid diseases. METHODS: We performed a literature search for relevant articles in the PubMed database. CONCLUSION: rhTSH has important roles in management of thyroid diseases, and some are still controversial. For patients with DTC, it avoids the need for thyroid hormone withdrawal, without being detrimental to short-term outcomes. Further studies are warranted to assess its effects on long-term outcomes.
Assuntos
Proteínas Recombinantes/uso terapêutico , Doenças da Glândula Tireoide/tratamento farmacológico , Tireotropina/uso terapêutico , Amiodarona/farmacologia , Ensaios Clínicos como Assunto , Bócio/tratamento farmacológico , Humanos , Radioisótopos do Iodo/farmacologia , Metástase Neoplásica , Hormônios Tireóideos/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Tireotoxicose/tratamento farmacológico , Resultado do TratamentoRESUMO
The radiolabelled monoclonal antibody anti-CD20 has the property of binding to the CD20 antigen expressed on the cell surface of B-lymphocytes, thus making it a useful tool in the treatment of non-Hodgkin's lymphoma. In this work, the event-by-event Monte Carlo code NOREC is used to calculate the single-event distribution function f(1)(z) in the cell nucleus using the beta spectra of the (188)Re and (131)I radionuclides. The simulated geometry consists of two concentric spheres representing the nucleus and the cell surface embedded in a semi-infinite water medium. An isotropic point source was placed on the cell surface to simulate the binding of the anti-CD20 labelled with either (188)Re or (131)I. The simulations were carried out for two combinations of cell surface and nucleus radii. A method was devised that allows one to calculate the contribution of betas of energy greater than 1 MeV, which cannot be simulated by the NOREC code, to the single-event distribution function. It is shown that disregarding this contribution leads to an overestimation of the frequency-mean specific energy of the order of 9-12%. In general, the antibody radiolabelled with (131)I produces single-event distribution functions that yield higher frequency-mean specific energies.
Assuntos
Anticorpos Monoclonais/química , Antígenos CD20/química , Radiometria/métodos , Núcleo Celular/metabolismo , Dano ao DNA , Humanos , Radioisótopos do Iodo/farmacologia , Modelos Estatísticos , Método de Monte Carlo , Radioisótopos/farmacologia , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Rênio/farmacologiaRESUMO
Our aim was to assess testicular function in patients treated with high-dose radioiodine. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone levels were determined in 52 men with thyroid carcinoma before and 6, 12, and 18 months after radioiodine therapy (3.7-5.5 GBq (131)I; mean, 4.25 GBq (131)I) (group 1) and were also determined before and 18 months after the last radioiodine therapy in 22 patients who received high cumulative activities (13-27.7 GBq; mean, 20.3 GBq (131)I) (group 2). FSH levels were increased 6 months after therapy in all patients of group 1, while a decline was observed after 12 months, with 37 of 52 (71%) subjects presenting normal values. FSH values returned to normal after 18 months in all patients. In group 2, 12 of 22 (54.5%) patients presented elevated FSH and 8 (66%) of these individuals had oligospermia. Six months after radioiodine, increased LH levels were observed in only 5 of 52 (9.6%) patients of group 1, which returned to normal after 12 months, and in 5 of 22 (22%) of group 2. All patients showed normal testosterone levels. We conclude that 131I therapy may cause impairment of testicular function. A generally transient increase in FSH is highly common but is usually reversed within 18 months. Oligospermia was common (one third) after high cumulative (131)I activities. Becausee we did not perform a spermiogram before therapy, we cannot state that high cumulative (131)I activities cause permanent infertility. We recommend the routine use of sperm banks in the cases of men who still wish to have children and who will undergo therapy with (131)I activities of 14 GBq or more or in the case of patients with pelvic metastases.