RESUMO
Differentiated thyroid cancer and hyperthyroidism are treated with radioiodine. However, when the radioisotope dose exceeds certain limits, the patient must be hospitalized to avoid contact with people that would otherwise be exposed to radiation. It would be desirable to obtain a similar therapeutic effect using lower radioiodine doses. Radiosensitizers can be utilized for this purpose. Nicotinamide (NA) increases thyroid radiosensitivity to 131I in both normal and goitrous glands. NA causes a significant increase in thyroid blood flow, which would increase tissue oxygenation and tissue damage via free radicals. Wistar rats were treated with either nicotinamide (NA), 131I or both. The expression of the three isoforms of nitric oxide synthase (NOS) in the thyroid (Western blot) and the activities of SOD, GPx, catalase and organic peroxides were determined. Treatment with NA or 131I increased the expression of eNOS and the generation of organic peroxides. When administered jointly, they showed a synergistic effect. No changes were observed in the other NOS isoforms or in the activities of catalase, glutathione peroxidase and superoxide dismutase. NA potentiates the effect of 131I by increasing eNOS, which would in turn stimulate NO production, increasing thyroid blood flow and tissue damage via organic peroxides.
Assuntos
Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos da radiação , Radioisótopos do Iodo/administração & dosagem , Niacinamida/administração & dosagem , Óxido Nítrico Sintase/biossíntese , Glândula Tireoide/enzimologia , Complexo Vitamínico B/administração & dosagem , Animais , Hipertireoidismo/complicações , Hipertireoidismo/radioterapia , Radioisótopos do Iodo/efeitos adversos , Masculino , Oxirredução/efeitos dos fármacos , Oxirredução/efeitos da radiação , Peróxidos/metabolismo , Ratos , Ratos Wistar , Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/complicações , Neoplasias da Glândula Tireoide/radioterapiaRESUMO
We have shown the selective uptake of borophenylalanine (BPA) by undifferentiated human thyroid cancer (UTC) ARO cells both in vitro and in vivo. Moreover, a 50% histologic cure of mice bearing the tumor was observed when the complete boron neutron capture therapy was applied. More recently we have analyzed the biodistribution of BOPP (tetrakis-carborane carboxylate ester of 2,4-bis-(alpha,beta-dihydroxyethyl)-deutero-porphyrin IX) and showed that when BOPP was injected 5 days before BPA, and the animals were sacrificed 60 min after the i.p. injection of BPA, a significant increase in boron uptake by the tumor was found (38-45 ppm with both compounds vs. 20 ppm with BPA alone). Five days post the i.p BOPP injection and 1h after BPA the ratios were: tumor/blood 3.75; tumor/distal skin 2. Other important ratios were tumor/thyroid 6.65 and tumor/lung 3.8. The present studies were performed in mice transplanted with ARO cells and injected with BOPP and BPA. Only in mice treated with the neutron beam and injected with the boronated compounds we observed a 100% control of tumor growth. Two groups of mice received different total absorbed doses: 3.00 and 6.01 Gy, but no further improvement in the outcome was found compared to the previous results using BPA alone (4.3 Gy).
Assuntos
Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/métodos , Deuteroporfirinas/uso terapêutico , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Neoplasias da Glândula Tireoide/radioterapia , Animais , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Deuteroporfirinas/administração & dosagem , Deuteroporfirinas/farmacocinética , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fenilalanina/administração & dosagem , Fenilalanina/farmacocinética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Transplante HeterólogoRESUMO
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.
Assuntos
Compostos de Boro/farmacocinética , Compostos de Boro/uso terapêutico , Terapia por Captura de Nêutron de Boro/veterinária , Doenças do Cão/metabolismo , Doenças do Cão/radioterapia , Fenilalanina/análogos & derivados , Fenilalanina/farmacocinética , Fenilalanina/uso terapêutico , Neoplasias da Glândula Tireoide/veterinária , Animais , Doenças do Cão/patologia , Cães , Feminino , Humanos , Masculino , Camundongos , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Distribuição TecidualRESUMO
An animal model of undifferentiated thyroid carcinoma (UTC), which may be useful for studying tumorigenesis and response to new therapies, is described. The UTC human cell line ARO was implanted into the back of the nude mice. The histology, induction of metastasis, and biokinetics of in vivo and in vitro growth, as well as cytogenetic and molecular aspects were studied. The tumor showed extensive viability with high mitotic activity. At 117 days, the tumors reached a size of 1,700 mm(3) and showed a central necrotic portion with a thin layer of viable cells. When the number of passages in the mouse increased the growth rate decreased. The cytogenetic and molecular studies did not show differences between the original line and the sublines that could explain this phenotypic change. Moreover, the original ARO cell line and its sublines showed a complex clonal karyotype including structural alterations with deletions and translocations involving chromosomes 5, 7, 8, 9p, 11p, 17q 19p, and 20q that were consistent with earlier reported data in UTC. This work provides an animal model of UTC pheno- and genotypically similar to the original human tumor, which may be useful for exploring new therapeutic modalities.
Assuntos
Carcinoma/patologia , Modelos Animais de Doenças , Neoplasias da Glândula Tireoide/patologia , Animais , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma/terapia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Análise Citogenética/métodos , Eletroforese , Genótipo , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/terapia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Undifferentiated thyroid carcinoma (UTC) lacks an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of 10B-boronated compounds by some tumors, followed by irradiation with an appropriate neutron beam. The radioactive boron originated (11B) decays releasing 7Li, gamma rays and alpha particles, and these latter will destroy the tumor. In order to explore the possibility of applying BNCT to UTC we have studied the biodistribution of BPA. In in vitro studies, the uptake of p-10borophenylalanine (BPA) by the UTC cell line ARO, primary cultures of normal bovine thyroid cells (BT), and human follicular adenoma (FA) thyroid was studied. No difference in BPA uptake was observed between proliferating and quiescent ARO cells. The uptake by quiescent ARO, BT, and FA showed that the ARO/BT and ARO/FA ratios were 4 and 5, respectively (p < 0.001). In in vivo studies, ARO cells were transplanted into the scapular region of NIH nude mice, and after 2 weeks BPA (350 or 600 mg/kg body weight) was injected intraperitoneally. The animals were sacrificed between 30 and 150 minutes after the injection. With 350 mg, tumor uptake was highest after 60 minutes and the tumor/normal thyroid and tumor/blood ratios were 3 and 5, respectively. When 600 mg/kg body weight BPA were administered, after 90 minutes the tumor/blood, tumor/normal thyroid, and tumor/distal skin ratios for 10B concentrations per gram of tissue were approximately 3, showing a selective uptake by the tumor. The present experimental results open the possibility of applying BNCT for the treatment of UTC.
Assuntos
Compostos de Boro/farmacocinética , Terapia por Captura de Nêutron de Boro , Fenilalanina/farmacocinética , Radiossensibilizantes/farmacocinética , Neoplasias da Glândula Tireoide/metabolismo , Adenoma/metabolismo , Animais , Boro , Compostos de Boro/uso terapêutico , Bovinos , Divisão Celular , Células Cultivadas , Humanos , Isótopos , Cinética , Camundongos , Camundongos Nus , Transplante de Neoplasias , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Radiossensibilizantes/uso terapêutico , Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/radioterapia , Células Tumorais CultivadasRESUMO
Radioiodine is used to treat thyroid cancer and hyperthyroidism. In order to reduce radiation hazard to the patient and to people in contact with the patient it would be desirable to obtain the same therapeutic effect with lower activities of the radioisotope. This could be achieved by the simultaneous administration of a compound that increases tissue radiosensitivity. In this study we analyzed the use of nicotinamide (NA) as a radiosensitizer to radioiodine, to increase 131I efficacy. NA administered during 30 days to Wistar rats failed to alter thyroid weight. The influence of NA on radiothyroidectomy induced by increasing doses of 131I was examined in otherwise nontreated rats. NA produced a significant increase in the ablation caused by radioiodine. Goiter was then induced by the administration of methylmercaptoimidazol (MMI) to rats, followed by the treatment with radioiodine with and without simultaneous administration of NA. Thyroid weight per 100 g of body weight ratio was not changed by NA alone; 131I administration caused a 25% decrease in goiter size, while 131I plus NA produced a reduction of the ratio of 46% (p < 0.01 vs. NA). No changes were observed in adenosine diphosphate (ADP)-ribosilation of thyroid nuclear protein in NA-treated rats. Thyroid blood flow (determined by 86Rb uptake) was increased by 84% by NA. In conclusion, nicotinamide has a significant radiosensitizing effect to 131I both in normal and goitrous rats. This action is because of an increase in thyroid blood flow, which probably enhances tissue oxgenation.
Assuntos
Bócio/radioterapia , Niacinamida/farmacologia , Tolerância a Radiação/efeitos dos fármacos , Adenosina Difosfato Ribose/metabolismo , Animais , Antitireóideos/farmacologia , Núcleo Celular/efeitos dos fármacos , Feminino , Radioisótopos do Iodo/farmacocinética , Metimazol/farmacologia , Ratos , Ratos Wistar , Fluxo Sanguíneo Regional/efeitos dos fármacos , Radioisótopos de Rubídio/farmacocinética , Glândula Tireoide/irrigação sanguínea , Glândula Tireoide/efeitos dos fármacosRESUMO
We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56%) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.
Assuntos
Carcinoma Mucoepidermoide/patologia , Dieta , Alimentos Fortificados , Lipoproteínas LDL/sangue , Neoplasias Pulmonares/patologia , Ácido gama-Linolênico/administração & dosagem , Análise de Variância , Animais , Ácidos Graxos/química , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Compostos de OrganotecnécioRESUMO
We have studied the effect of a gamma-linolenic acid (18:3 n-6, GLA)-supplemented diet on the growth of a human lung mucoepidermoid carcinoma (HLMC) implanted in athymic mice and on its uptake of human low density lipoproteins labeled with 99mTc (99mTc-LDL). Mice bearing the HLMC were divided into two experimental groups. One of them was administered a control diet (C diet) and the other one was given a diet supplemented with 25 mg GLA/g pellet (GLA diet) for three weeks (Table 1). A tumor growth inhibition with the GLA diet was evident at the second week of treatment, and a marked inhibition (56
) was reached at the end of the third week (Fig. 1). The GLA diet produced some changes in the total fatty acid composition of tumor, plasma and liver of host mice: GLA and arachidonic acid (20:4 n-6, AA) induced significant increases, whereas oleic (18:1 n-9, OA) and linoleic acids (18:2 n-6, LA) were decreased (Table 2). Tumors of those animals fed both diets were labeled by 99mTc-LDL, and no difference was observed in the ratio of tumor/liver and tumor/kidney uptake of host animal (Table 3). Results obtained using this experimental model suggest that the inhibitory effect of GLA on tumor growth is not related to the LDL tumor uptake.