RESUMO
PURPOSE: The present study analyzed different protocols of administration of boronophenylalanine (BPA) and sodium butyrate (NaB) to increase the BNCT efficacy for poorly differentiated thyroid cancer (PDTC). MATERIALS AND METHODS: Nude mice implanted with human PDTC cells (WRO) were distributed into four protocols: 1) BPA; 2) BPA + ip NaB; 3) BPA + oral NaB; 4) Control. Biodistribution and histologic studies were performed. LAT (BPA transporter) isoforms gene expression was assessed by RT-PCR. RESULTS: Tumor growth delay was observed in animals of the Protocol #3 (p < 0.05). NaB (Protocol #2) increased tumor boron uptake 2-h post BPA injection (p < 0.05). On the other hand, NaB upregulated the expression of all the isoforms of the LAT transporter in vitro. Histologic studies showed a significant decrease of mitotic activity and an increase of vacuoles in tumors of Protocol #3. Neutrons alone or combined with NaB caused some tumor growth delay (p < 0.05), while in the BNCT and BNCT + NaB groups, there was a halt in tumor growth in 70 and 80% of the animals, respectively. CONCLUSIONS: Intraperitoneally administration of NaB increased boron uptake while oral administration for a longer period of time induced tumor growth delay previous to BPA administration. The use of NaB via ip would optimize the irradiation results.
Assuntos
Terapia por Captura de Nêutron de Boro/métodos , Ácido Butírico/uso terapêutico , Inibidores de Histona Desacetilases/uso terapêutico , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/radioterapia , Animais , Ácido Butírico/farmacocinética , Diferenciação Celular , Linhagem Celular Tumoral , Terapia Combinada , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Camundongos , Neoplasias da Glândula Tireoide/patologia , Distribuição Tecidual , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The quantification and analysis of the tracks forming the autoradiography image of a tissue section is essential for the measurement of particle emitter concentration and distribution (e.g. (10)B) in the sample. Conventional counting techniques cannot be used when track density is high because of track overlapping. A densitometry supported by image analysis method suitable for these cases has been developed. Optical density measurements obtained for boron solutions of known concentrations showed a linear behavior in the range of concentrations under consideration.
RESUMO
The aim of these studies was to evaluate the possibility of treating differentiated thyroid cancer by BNCT. These carcinomas are well controlled with surgery followed by therapy with (131)I; however, some patients do not respond to this treatment. BPA uptake was analyzed both in vitro and in nude mice implanted with cell lines of differentiated thyroid carcinoma. The boron intracellular concentration in the different cell lines and the biodistribution studies showed the selectivity of the BPA uptake by this kind of tumor.
Assuntos
Terapia por Captura de Nêutron de Boro , Neoplasias da Glândula Tireoide/radioterapia , Animais , Compostos de Boro/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Fenilalanina/análogos & derivados , Fenilalanina/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
The amount of (10)B in tissue samples may be determined by measuring the track density in the autoradiography image produced on a nuclear track detector. Different systems were evaluated as reference standards to be used for a quantitative evaluation of boron concentration. The obtained calibration curves were applied to evaluate the concentration of (10)B in melanoma tumour of NIH nude mice after a biodistribution study. The histological features observed in the tissue sections were accurately reproduced by the autoradiography images.
Assuntos
Autorradiografia/métodos , Boro/farmacocinética , Modelos Animais de Doenças , Melanoma Experimental/metabolismo , Animais , Calibragem , Feminino , Camundongos , Camundongos Nus , Distribuição TecidualRESUMO
The aim of this study was to report 2 novel clinical cases of reactive lesions of the peri-implant mucosa associated with titanium dental implants where metal-like particles were observed histologically. In both cases, the lesions were diagnosed as epulis, based on clinical evidence. Extirpation biopsies were carried out. Case 1 was diagnosed as pyogenic granuloma and case 2 as peripheral giant cell granuloma. The presence of metal-like particles in the tissues suggests that the etiology of the lesions might be related to the corrosion process of the metal structure. This is the first case of pyogenic granuloma to be reported in association with dental implants. All clinical cases of soft tissue lesions associated with implants should be reported to contribute to the understanding of the etiology and pathogeny of these lesions.
Assuntos
Implantes Dentários/efeitos adversos , Granuloma de Corpo Estranho/etiologia , Doenças Maxilares/etiologia , Idoso , Corrosão , Feminino , Granuloma de Corpo Estranho/patologia , Granuloma de Corpo Estranho/cirurgia , Granuloma de Células Gigantes/etiologia , Granuloma de Células Gigantes/patologia , Granuloma de Células Gigantes/cirurgia , Granuloma Piogênico/etiologia , Granuloma Piogênico/patologia , Granuloma Piogênico/cirurgia , Humanos , Doenças Maxilares/patologia , Doenças Maxilares/cirurgia , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Titânio/efeitos adversosRESUMO
The aim of this study was to evaluate histologically the biological effect of pitting corrosion and to contribute clinically relevant data on the permanence of titanium metal structures used in osteosynthesis in the body. Commercially pure titanium laminar implants (control) and commercially pure titanium laminar implants with pitting corrosion (experimental) were implanted in the tibiae of rats. At 14 days post-implantation the animals were killed. The tibiae were resected, fixed, radiographed and processed for embedding in methyl methacrylate. Percentage of bone-implant contact and peri-implant bone volume were evaluated. The histological study of the titanium implants submitted to pitting corrosion showed scarce bone-implant contact, it was only present in the areas with no pitting and/or surface alterations. There was a statistically significant lower percentage of bone-implant contact in the experimental group (6%+/-4) than in the control group (26%+/-6) (p<0.001). Products of corrosion in the peri-implant bed, especially around the blood vessels and areas of bone marrow in the metal-tissue interface, were observed. The microchemical analysis of corrosion products revealed the presence of titanium. The adverse local effects caused by pitting corrosion suggest that titanium plates and grids should be used with caution as permanent fixation structures.
Assuntos
Implantes Dentários/efeitos adversos , Materiais Dentários/efeitos adversos , Osseointegração/efeitos dos fármacos , Tíbia/ultraestrutura , Titânio/efeitos adversos , Animais , Regeneração Óssea/efeitos dos fármacos , Corrosão , Materiais Dentários/química , Masculino , Ratos , Ratos Wistar , Propriedades de Superfície , Tíbia/cirurgia , Titânio/químicaRESUMO
Exposure to uranium is an occupational hazard to workers who continually handle uranium and an environmental risk to the population at large. Since the cellular and molecular pathways of uranium toxicity in osteoblast cells are still unknown, the aim of the present work was to evaluate the adverse effects of uranyl nitrate (UN) on osteoblasts both in vivo and in vitro. Herein we studied the osteoblastic ultrastructural changes induced by UN in vivo and analyzed cell proliferation, generation of reactive oxygen species (ROS), apoptosis, and alkaline phosphatase (APh) activity in osteoblasts exposed to various UN concentrations (0.1, 1, 10, and 100 microM) in vitro. Cell proliferation was quantified by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, ROS was determined using the nitro blue tetrazolium test, apoptosis was morphologically determined using Hoechst 3332 and APh activity was assayed spectrophotometrically. Electron microscopy revealed that the ultrastructure of active and inactive osteoblasts exposed to uranium presented cytoplasmic and nuclear alterations. In vitro, 1-100 microM UN failed to modify cell proliferation ratio and to induce apoptosis. ROS generation increased in a dose-dependent manner in all tested doses. APh activity was found to decrease in 1-100 microM UN-treated cells vs. controls. Our results show that UN modifies osteoblast cell metabolism by increasing ROS generation and reducing APh activity, suggesting that ROS may play a more complex role in cell physiology than simply causing oxidative damage.
Assuntos
Osteoblastos/efeitos dos fármacos , Osteoblastos/ultraestrutura , Nitrato de Uranil/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Retículo Endoplasmático Rugoso/ultraestrutura , Feminino , Pesquisa Fetal , Humanos , Injeções Intraperitoneais , Masculino , Microscopia Eletrônica , Osteoblastos/metabolismo , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Acetato de Tetradecanoilforbol/administração & dosagem , Acetato de Tetradecanoilforbol/farmacologia , Acetato de Tetradecanoilforbol/toxicidade , Tíbia/citologia , Tíbia/metabolismo , Tíbia/ultraestrutura , Fatores de Tempo , Nitrato de Uranil/administração & dosagem , Nitrato de Uranil/toxicidadeRESUMO
BACKGROUND: The hamster cheek-pouch carcinogenesis model is a well-known animal system that closely mimics the development of premalignant and malignant lesions in human oral cancer. Our aim was to numerically characterize the premalignant and malignant lesions and expressions of field cancerization in this model using ploidy as the end-point. METHODS: To study the DNA content and proliferation status of the cells in this model we assessed the Feulgen reaction and the immunohistochemical reaction for 5-bromo-2-deoxiuridine (BrdU) in different histological areas of serial tissue sections of the cheek pouches of animals injected with BrdU. RESULTS: Ploidy values were higher in cancerized epithelia with no unusual microscopic features (NUMF), in preneoplastic and tumor areas than in control epithelia. The aneuploidy index was higher in NUMF areas than in control and differed significantly from control in preneoplastic areas and carcinoma. CONCLUSIONS: The unexpected alteration in DNA content observed in NUMF epithelia is of great relevance as a biomarker of field cancerized areas.
Assuntos
Transformação Celular Neoplásica/genética , Mucosa Bucal/patologia , Neoplasias Bucais/genética , Ploidias , Lesões Pré-Cancerosas/genética , 9,10-Dimetil-1,2-benzantraceno/efeitos adversos , Aneuploidia , Animais , Biomarcadores Tumorais/análise , Carcinógenos/efeitos adversos , Carcinoma/genética , Carcinoma/patologia , Carcinoma in Situ/genética , Carcinoma in Situ/patologia , Proliferação de Células , Transformação Celular Neoplásica/patologia , Cricetinae , DNA de Neoplasias/análise , Modelos Animais de Doenças , Epitélio/patologia , Feminino , Hiperplasia , Masculino , Mesocricetus , Neoplasias Bucais/patologia , Lesões Pré-Cancerosas/patologiaRESUMO
A 350 mg/kg body weight (b.w.) oral dose of uranyl nitrate (UN) caused 100% mortality in mice three days after administration, due to resulting kidney lesions. Mortality decreased 50% after an oral (o) or subcutaneous (sc) dose of bisodic etidronate (EHBP). Given that bone is also a target organ for uranium (U) in acute intoxication, the aim of this work was to study the effect of exposure to a lethal oral dose of UN on endochondral ossification, and the latter's response to EHBP treatment. One hundred male Balb/c mice weighing 25 g were assigned to one of ten groups. Group I served as control. Group II received a lethal 350 mg/kg b.w. oral dose of UN by gavage. Groups III, IV, VII, and VIII received an equal dose of UN immediately followed by a single 500 mg/kg oral dose of EHBP in groups III and VII and a single 50 mg/kg subcutaneous dose of EHBP in groups IV and VIII. Groups V and IX only received a single 500 mg/kg oral dose of EHBP, and groups VI and X received a single 50 mg/kg subcutaneous dose of EHBP. The animals in groups II, III, IV, V, and VI were sacrificed 48 h after the onset of the experiment, whereas those in groups VII, VIII, IX, and X were killed at 14 days. Histologic and histomorphometric studies were performed on the femurs to determine growth cartilage width, bone volume, and metaphyseal bone activity. Our results showed that all growth cartilage and metaphyseal bone histomorphometric parameters were significantly lower in animals exposed to UN at 48 h than in controls. EHPB administration was found to prevent this condition at 48 h reaching similar values to those of controls. Although histomorphometric values did not reach control values at 14 days, they were higher than those of animals exposed to UN at 48 h not treated with EHBP. It is noteworthy that these values also decreased in animals only receiving EHBP at 14 days. Our results show that EHBP effectively ameliorates the adverse effects of a lethal dose of UN on endochondral ossification.
Assuntos
Condrogênese/efeitos dos fármacos , Difosfonatos/farmacologia , Fêmur/efeitos dos fármacos , Lâmina de Crescimento/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Nitrato de Uranil/toxicidade , Administração Oral , Animais , Relação Dose-Resposta a Droga , Interações Medicamentosas , Fêmur/patologia , Lâmina de Crescimento/patologia , Injeções Subcutâneas , Longevidade/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Human undifferentiated thyroid carcinoma (UTC) is a very aggressive tumor which lacks an adequate treatment. The UTC human cell line ARO has a selective uptake of BPA in vitro and after transplanting into nude mice. Applications of boron neutron capture therapy (BNCT) to mice showed a 100% control of growth and a 50% histological cure of tumors with an initial volume of 50 mm(3) or less. As a further step towards the potential application in humans we have performed the present studies. Four dogs with diagnosis of spontaneous UTC were studied. A BPA-fructose solution was infused during 60 min and dogs were submitted to thyroidectomy. Samples of blood and from different areas of the tumors (and in one dog from normal thyroid) were obtained and the boron was determined by ICP-OES. Selective BPA uptake by the tumor was found in all animals, the tumor/blood ratios ranged between 2.02 and 3.76, while the tumor/normal thyroid ratio was 6.78. Individual samples had tumor/blood ratios between 8.36 and 0.33. These ratios were related to the two histological patterns observed: homogeneous and heterogeneous tumors. We confirm the selective uptake of BPA by spontaneous UTC in dogs and plan to apply BNCT in the future.