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1.
Sci Rep ; 8(1): 5533, 2018 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-29615783

RESUMO

S100ß protein and SOX2-double positive (S100ß/SOX2-positive) cells have been suggested to be adult pituitary stem/progenitor cells exhibiting plasticity and multipotency. The aim of the present study was to isolate S100ß/SOX2-positive cells from the adult anterior lobes of rats using a specific antibody against a novel membrane marker and to study their characteristics in vitro. We found that cluster of differentiation (CD) 9 is expressed in the majority of adult rat S100ß/SOX2-positive cells, and we succeeded in isolating CD9-positive cells using an anti-CD9 antibody with a pluriBead-cascade cell isolation system. Cultivation of these cells showed their capacity to differentiate into endothelial cells via bone morphogenetic protein signalling. By using the anterior lobes of prolactinoma model rats, the localisation of CD9-positive cells was confirmed in the tumour-induced neovascularisation region. Thus, the present study provides novel insights into adult pituitary stem/progenitor cells involved in the vascularisation of the anterior lobe.


Assuntos
Células-Tronco Adultas/citologia , Diferenciação Celular , Endotélio Vascular/citologia , Adeno-Hipófise/irrigação sanguínea , Prolactinoma/patologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Tetraspanina 29/metabolismo , Células-Tronco Adultas/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Endotélio Vascular/metabolismo , Masculino , Adeno-Hipófise/citologia , Adeno-Hipófise/metabolismo , Prolactinoma/irrigação sanguínea , Prolactinoma/induzido quimicamente , Prolactinoma/metabolismo , Ratos , Ratos Wistar
2.
Endocrine ; 52(3): 641-51, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26662185

RESUMO

Dopamine agonists (DAs) are the first-line treatment of prolactinomas. They function through the dopamine 2 receptor (D2R) in the tumor cells. Endocan, also called endothelial cell-specific molecule-1 (ESM1), has been described as a marker of neoangiogenesis. However, whether ESM1 promotes the resistance of prolactinomas to DA therapy is largely unknown. In our study, 25 patients with prolactinomas were divided into resistant- and sensitive- groups according to the clinical response to bromocriptine. We found that ESM1-microvessel density of resistant prolactinomas was significantly higher than that of sensitive prolactinomas (47.9 ± 11.6, n = 8, vs 13.1 ± 2.8, n = 17, p = 0.0006), indicating that ESM1 was a DA resistance-related gene. Immunostaining showed that ESM1 was expressed in tumor vessels and sporadic tumor cells, and ESM1 was overlapped with the Smooth Muscle Actin (SMA) and von Willebrand Factor (VWF) in the tumor vessels. Silencing of ESM1 markedly suppressed the viability of GH3 and MMQ cells in vitro, and furthermore, significantly increased the sensitivity of GH3 and MMQ cells to DA treatment. Additionally, silencing of ESM1 down-regulated the angiogenesis-associated genes, such as VEGFR2, FGF2, CD34, CD31, VWF, and EGFR. Knockdown of ESM1 decreased endothelial tube formation of HUVECs, and significantly increased the sensitivity of HUVECs to Avastin treatment. Therefore, we first demonstrate that DA resistance-related ESM1 promotes the angiogenesis and tumor cells growth of prolactinomas, suggesting that ESM1 may be a novel therapeutic target for prolactinomas.


Assuntos
Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/genética , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Proteoglicanas/fisiologia , Adolescente , Adulto , Idoso , Animais , Bromocriptina/farmacologia , Bromocriptina/uso terapêutico , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Células Cultivadas , Agonistas de Dopamina/farmacologia , Feminino , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/genética , Prolactinoma/irrigação sanguínea , Prolactinoma/genética , Proteoglicanas/antagonistas & inibidores , Ratos , Adulto Jovem
3.
J Int Med Res ; 40(4): 1284-94, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22971480

RESUMO

OBJECTIVE: To investigate the roles of angiogenesis, thrombospondin-1 (TSP-1) and transforming growth factor-ß1 (TGF-ß1) in invasive and noninvasive prolactinoma. METHODS: TSP-1 and TGF-ß1 protein were examined using immunohistochemistry and Western blotting in 81 prolactinomas. Angiogenesis was assessed by measuring microvessel density via CD34 immunostaining. RESULTS: Microvessel density was significantly higher in invasive prolactinomas than in noninvasive prolactinomas. Immunohistochemistry demonstrated that significantly fewer invasive prolactinomas were positive for TSP-1 compared with noninvasive prolactinomas (17.9% versus 50.0%, respectively), and significantly higher numbers of invasive prolactinomas were positive for TGF-ß1 compared with noninvasive prolactinomas (82.1% versus 42.9%, respectively). Microvessel density was significantly lower in TSP-1-positive prolactinomas than in TSP-1-negative prolactinomas, and significantly higher in TGF-ß1-positive prolactinomas than in TGF-ß1-negative prolactinomas. CONCLUSIONS: These results suggest a close relationship between angiogenesis and tumour invasiveness in prolactinoma. TSP-1 and TGF-ß1 may play important roles in the progression of prolactinoma, by affecting angiogenesis.


Assuntos
Neoplasias Hipofisárias/metabolismo , Prolactinoma/metabolismo , Trombospondina 1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Neovascularização Patológica , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/patologia , Prolactinoma/irrigação sanguínea , Prolactinoma/patologia , Estatísticas não Paramétricas , Carga Tumoral , Adulto Jovem
4.
Zh Vopr Neirokhir Im N N Burdenko ; 75(2): 41-50; discussion 50, 2011.
Artigo em Russo | MEDLINE | ID: mdl-21793295

RESUMO

Treatment of prolactin-secreting pituitary adenomas by dopamine agonists is highly effective and currently is used as basic treatment in most cases, however, literature sources practically do not contain data about possible complications of this therapy. We described a total of 11 cases of deterioration due to primary treatment of macroprolactinomas by cabergoline in the series of 176 patients. The first group included patients with enlargement of the tumor producing deterioration of the symptoms (onset of visual disorders and/or cephalgia). This occurred in 3 (1.7%) cases due to intratumoral hemorrhage or cystic transformation, and in 1 (0.6%) case as a result of growth of cabergoline-resistant tumor. The second group was made up of 6 (3.4%) cases of nasal CSF leak which developed within 3 to 6 weeks after start of treatment. All patients with CSF leak had adenomas with high sensitivity to the drug which produced rapid and significant shrinking of the tumor. The third group was presented by the single case (0.6%) of visual deterioration due to development of empty sella syndrome with dislocation of chiasm and optic nerves into sellar cavity.


Assuntos
Agonistas de Dopamina/efeitos adversos , Ergolinas/efeitos adversos , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adolescente , Adulto , Cabergolina , Rinorreia de Líquido Cefalorraquidiano/diagnóstico por imagem , Rinorreia de Líquido Cefalorraquidiano/etiologia , Rinorreia de Líquido Cefalorraquidiano/cirurgia , Agonistas de Dopamina/administração & dosagem , Agonistas de Dopamina/uso terapêutico , Ergolinas/administração & dosagem , Ergolinas/uso terapêutico , Humanos , Hemorragias Intracranianas/diagnóstico por imagem , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/cirurgia , Masculino , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/diagnóstico por imagem , Neoplasias Hipofisárias/cirurgia , Prolactinoma/irrigação sanguínea , Prolactinoma/diagnóstico por imagem , Prolactinoma/cirurgia , Radiografia , Resultado do Tratamento , Transtornos da Visão/diagnóstico por imagem , Transtornos da Visão/etiologia , Transtornos da Visão/cirurgia , Adulto Jovem
5.
J Pharmacol Exp Ther ; 337(3): 766-74, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21406548

RESUMO

Prolactin-secreting adenomas are the most frequent type among pituitary tumors, and pharmacological therapy with dopamine agonists remains the mainstay of treatment. But some adenomas are resistant, and a decrease in the number or function of dopamine D2 receptors (D2Rs) has been described in these cases. D2R knockout [Drd2(-/-)] mice have chronic hyperprolactinemia and pituitary hyperplasia and provide an experimental model for dopamine agonist-resistant prolactinomas. We described previously that disruption of D2Rs increases vascular endothelial growth factor (VEGF) expression. We therefore designed two strategies of antiangiogenesis using prolactinomas generated in Drd2(-/-) female mice: direct intra-adenoma mVEGF R1 (Flt-1)/Fc chimera (VEGF-TRAP) injection for 3 weeks [into subcutaneously transplanted pituitaries from Drd2(-/-) mice] and systemic VEGF neutralization with the specific monoclonal antibody G6-31. Both strategies resulted in substantial decrease of prolactin content and lactotrope area, and a reduction in tumor size was observed in in situ prolactinomas. There were significant decreases in vascularity, evaluated by cluster of differentiation molecule 31 vessel staining, and proliferation (proliferating cell nuclear antigen staining) in response to both anti-VEGF treatments. These data demonstrate that the antiangiogenic approach was effective in inhibiting the growth of in situ dopamine-resistant prolactinomas as well as in the transplanted adenomas. No differences in VEGF protein expression were observed after either anti-VEGF treatment, and, although serum VEGF was increased in G6-31-treated mice, pituitary activation of the VEGF receptor 2 signaling pathway was reduced. Our results indicate that, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF might contribute to adequate vascular supply and represent a supplementary therapeutic target in dopamine agonist-resistant prolactinomas.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Proteínas Recombinantes de Fusão/uso terapêutico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Animais , Anticorpos Monoclonais/metabolismo , Proliferação de Células/efeitos dos fármacos , Dopamina/metabolismo , Feminino , Hiperplasia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Hipófise/irrigação sanguínea , Hipófise/metabolismo , Hipófise/patologia , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Prolactina/sangue , Prolactinoma/irrigação sanguínea , Prolactinoma/metabolismo , Prolactinoma/patologia , Receptores de Dopamina D2/genética , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular/imunologia , Fator A de Crescimento do Endotélio Vascular/metabolismo
7.
Int J Radiat Oncol Biol Phys ; 71(5): 1470-6, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18538948

RESUMO

PURPOSE: Vascular disrupting agents are anticancer agents that typically produce a cytostatic tumor response. Vessel size index magnetic resonance imaging (MRI) allows for the estimation of the fractional blood volume (fBV) and blood vessel size (Rv). We assessed whether the vessel size index parameters provided imaging biomarkers for detecting early tumor response to a vascular disrupting agent. METHODS AND MATERIALS: GH3 prolactinomas were grown subcutaneously in 12 rats. Vessel size index MRI was performed with Sinerem, an ultrasmall superparamagnetic iron oxide intravascular contrast agent, to determine the tumor fBV and Rv. MRI was performed before and at 24 h after treatment with either the vascular disrupting agent, 5,6-dimethylxanthenone 4-acetic acid (DMXAA) (n = 6) or with the drug vehicle (n = 6). After treatment, the tumors were analyzed histologically and correlates with the MRI findings sought. RESULTS: Histogram analysis showed non-normal distributions of Rv and fBV. The 25th percentiles of the fBV and Rv were significantly reduced (p < 0.01) after treatment with DMXAA, with an increase in the regions of low-measured fBV. For the treated and control tumors, the fraction of tumor with an fBV of < or =1% correlated with the histologically determined percentage of necrosis (r = 0.77, p < 0.005). The fraction of tumor with an fBV of < or =1% in treated tumors was significantly increased compared with before treatment (p < 0.05) and with that in the controls (p < 0.05). CONCLUSION: The vessel size index results were consistent with the known action of DMXAA to cause vascular collapse, with histogram analysis of the fBV providing the most sensitive indicator of response. In particular, the parameter, the fraction of tumor with an fBV of < or =1% is a potential biomarker that correlates with the histopathologic measure of tumor necrosis.


Assuntos
Antineoplásicos/uso terapêutico , Determinação do Volume Sanguíneo/métodos , Prolactinoma/irrigação sanguínea , Prolactinoma/tratamento farmacológico , Xantonas/uso terapêutico , Animais , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Volume Sanguíneo , Meios de Contraste , Dextranos , Feminino , Óxido Ferroso-Férrico , Ferro , Imageamento por Ressonância Magnética , Nanopartículas de Magnetita , Tamanho do Órgão , Óxidos , Prolactinoma/patologia , Prolactinoma/fisiopatologia , Ratos , Ratos Endogâmicos WF , Fluxo Sanguíneo Regional
8.
Life Sci ; 79(18): 1741-8, 2006 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-16846617

RESUMO

The process of angiogenesis has been found to be essential for the development of estrogen-induced pituitary prolactinoma in Fischer 344 rats. Thalidomide [(alpha-(N-phthalimido)-glutarimide] is known to be a potent immunomodulatory drug with antiangiogenic properties, but its effect on lactotroph cell secretory function and pituitary prolactinoma formation has not been described yet. The purpose of this study was to examine the effects of thalidomide on secretion of prolactin (PRL) and vascular endothelial growth factor (VEGF), cell proliferation, apoptosis and angiogenesis within the anterior pituitary gland in long-term diethylstilboestrol (DES)-treated male F344 rats in vivo and in vitro. It was found that DES sharply increased serum PRL and VEGF levels. On the other hand, simultaneous treatment of F344 rats with thalidomide for the last 15 days of the experiment attenuated the stimulatory effect of DES on PRL and VEGF secretion. It also diminished prolactin cell proliferation evaluated as the number of proliferating cell nuclear antigen (PCNA)-positive stained cell nuclei and increased the number of apoptotic bodies determined by the terminal deoxynucleotidyl-mediated dUTP nick-end labeling (TUNEL) method in sections of the DES-induced pituitary prolactinoma. The density of pituitary microvessels evaluated by microscopic counting of CD-31-positive blood vessels was also diminished by the tested drug. In addition, thalidomide (10(-4) to 10(-6) M) inhibited cell proliferation, prolactin and VEGF secretion from rat pituitary prolactinoma cells cultured in vitro. In conclusion, our results provide strong evidence for the antiprolactin and antitumor activity of thalidomide in experimentally DES-induced pituitary adenoma.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactina/metabolismo , Prolactinoma/tratamento farmacológico , Talidomida/uso terapêutico , Inibidores da Angiogênese/metabolismo , Animais , Apoptose , Núcleo Celular/química , Proliferação de Células/efeitos dos fármacos , Dietilestilbestrol/toxicidade , Estrogênios/toxicidade , Neovascularização Patológica/metabolismo , Hipófise/química , Hipófise/patologia , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Prolactina/sangue , Prolactinoma/irrigação sanguínea , Prolactinoma/metabolismo , Antígeno Nuclear de Célula em Proliferação/análise , Ratos , Ratos Endogâmicos F344 , Fator A de Crescimento do Endotélio Vascular
9.
Front Horm Res ; 35: 50-63, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16809922

RESUMO

Dopamine receptor type 2 (D2R) knockout mice (KO) have chronic hyperprolactinemia, pituitary hyperplasia, and a moderate decrease in MSH content. They are also growth retarded evidencing an alteration in the GH-IGF-I axis. In D2R KO, lactotropes do not show dense secretory granules but degranulated cells and fewer somatotropes, gonadotropes and thyrotropes. Prolactin levels are always higher in female than in male knockouts, and in accordance, pituitary hyperplasia is observed at 8 months only in females. After 16 months of age, highly vascularized adenomas develop, especially in females. Prominent vascular channels in the hyperplastic and adenomatous pituitaries, as well as extravasated red blood cells not contained in capillaries is also a common finding. Prolactin is not the factor that enhances the hyperplastic phenotype in females while estrogen is a permissive factor. VEGF-A expression is increased in pituitaries from D2R KO. VEGF-A is expressed in follicle stellate cells. Because D2R receptors are found in lactotropes and not in follicle stellate cells, it may be inferred that a paracrine-derived factor from lactotropes is acting on follicle stellate cells to increase VEGF-A expression. VEGF-A does not induce pituitary cell proliferation, even though it enhances prolactin secretion. But it may act on adjacent endothelial cells and participate in the angiogenic process that increases the availability of different growth factors and mitogens. The D2R knockout mouse represents a unique animal model to study dopamine-resistant prolactinomas, and VEGF-A may be an alternative therapeutic target in this pathology.


Assuntos
Modelos Animais de Doenças , Camundongos Knockout/genética , Neoplasias Hipofisárias/genética , Prolactinoma/genética , Receptores de Dopamina D2/genética , Animais , Adesão Celular , Resistencia a Medicamentos Antineoplásicos , Feminino , Hiperplasia/etiologia , Masculino , Camundongos , Neovascularização Patológica , Peliose Hepática/etiologia , Hipófise/patologia , Prolactinoma/irrigação sanguínea , Prolactinoma/complicações , Receptores de Dopamina D2/deficiência , Caracteres Sexuais , Fator A de Crescimento do Endotélio Vascular/fisiologia
10.
Neoplasia ; 8(3): 199-206, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16611413

RESUMO

The dose-dependent effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on rat GH3 prolactinomas were investigated in vivo. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to assess tumor blood flow/permeability pretreatment and 24 hours posttreatment with 0, 100, 200, or 350 mg/kg DMXAA. DCE-MRI data were analyzed using K(trans) and the integrated area under the gadolinium time curve (IAUGC) as response biomarkers. High-performance liquid chromatography (HPLC) was used to determine the plasma concentration of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) following treatment to provide an index of increased vessel permeability and vascular damage. Finally, tumor necrosis was assessed by grading hematoxylin and eosin-stained sections cut from the same tumors investigated by MRI. Both tumor K(trans) and IAUGC were significantly reduced 24 hours posttreatment with 350 mg/kg DMXAA only, with no evidence of dose response. HPLC demonstrated a significant increase in plasma 5-HIAA 24 hours posttreatment with 200 and 350 mg/kg DMXAA. Histologic analysis revealed some evidence of tumor necrosis following treatment with 100 or 200 mg/kg DMXAA, reaching significance with 350 mg/kg DMXAA. The absence of any reduction in K(trans) or IAUGC following treatment with 200 mg/kg, despite a significant increase in 5-HIAA, raises concerns about the utility of established DCE-MRI biomarkers to assess tumor response to DMXAA.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Indóis/sangue , Imageamento por Ressonância Magnética , Neovascularização Patológica/tratamento farmacológico , Neoplasias Hipofisárias/patologia , Prolactinoma/irrigação sanguínea , Xantonas/uso terapêutico , Inibidores da Angiogênese/farmacocinética , Inibidores da Angiogênese/farmacologia , Animais , Área Sob a Curva , Biomarcadores , Permeabilidade Capilar , Linhagem Celular Tumoral/transplante , Meios de Contraste , Relação Dose-Resposta a Droga , Feminino , Gadolínio DTPA , Necrose , Transplante de Neoplasias , Prolactinoma/tratamento farmacológico , Prolactinoma/patologia , Ratos , Ratos Endogâmicos WF , Tela Subcutânea , Xantonas/farmacocinética , Xantonas/farmacologia
11.
Endocr J ; 52(1): 117-23, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15758567

RESUMO

Functioning pituitary adenomas may exhibit spontaneous remission after pituitary apoplexy usually in association with hypopituitarism. We report two patients who presented with sudden headache and double vision, showed a ring-enhanced sellar tumor on MRI, underwent transsphenoidal surgery that revealed a coagulation necrotic adenoma without massive hemorrhage, and showed normal pituitary function after the surgery. Definitive diagnoses were made based on immunohistochemistry of the necrotic cells. The findings were consistent with the presence of selective infarct of a GH adenoma and a prolactinoma that had led to remission of acromegaly and menstrual disturbance, respectively, without pituitary insufficiency. In contrast to hemorrhagic apoplexy, infarctive apoplexy tends to affect only the tumor and thus presents with mild symptoms and lack pituitary deficiencies.


Assuntos
Adenoma/irrigação sanguínea , Infarto/fisiopatologia , Apoplexia Hipofisária/fisiopatologia , Neoplasias Hipofisárias/irrigação sanguínea , Acromegalia/etiologia , Adenoma/complicações , Adenoma/diagnóstico , Adenoma/cirurgia , Adulto , Feminino , Hormônio do Crescimento Humano/metabolismo , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Neoplasias Hipofisárias/complicações , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/cirurgia , Período Pós-Operatório , Prolactinoma/irrigação sanguínea , Prolactinoma/fisiopatologia , Remissão Espontânea
12.
Adv Exp Med Biol ; 566: 75-81, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16594137

RESUMO

Modulation of tumour oxygenation may be used to increase or decrease tumour hypoxia in order to improve the effect of radiotherapy or bioreductive drugs, respectively. Magnetic resonance imaging (MRI) and near infrared spectroscopy (NIRS) are techniques sensitive to blood deoxyhemoglobin concentration (Hb) that can be used to investigate tumour hypoxia indirectly via blood oxygenation levels. In this study we have used NIRS to determine absolute Hb and changes in deoxyhemoglobin and oxyhemoglobin (HbO) in subcutaneous rodent tumours for challenges that alter blood flow and oxygenation, with the aim to better interpret our MRI data. Both carbogen [95% O2 + 5% CO2] and 100% O2 breathing produced a similar and significant reduction in Hb and increase in HbO, but a negligible change in HbT (= Hb + HbO). In contrast, N2 breathing to terminal anoxia and intravenous hydralazine produced a negligible increase in Hb, but large reductions in HbO and HbT. HbT is proportional to blood volume, so our data suggests large blood volume decreases occur with challenges likely to cause reduced arterial blood pressure. Hence MRI techniques that measure the R2* relaxation rate, which varies linearly with total Hb, will underestimate the effects of hypotensive agents at increasing tumour hypoxia.


Assuntos
Oxigênio/sangue , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/irrigação sanguínea , Prolactinoma/sangue , Prolactinoma/irrigação sanguínea , Animais , Dióxido de Carbono/farmacologia , Feminino , Hemoglobinas/metabolismo , Hidralazina/farmacologia , Hiperóxia/fisiopatologia , Hipóxia/fisiopatologia , Imageamento por Ressonância Magnética , Oxigênio/farmacologia , Oxiemoglobinas/metabolismo , Neoplasias Hipofisárias/tratamento farmacológico , Neoplasias Hipofisárias/radioterapia , Prolactinoma/tratamento farmacológico , Prolactinoma/radioterapia , Tolerância a Radiação , Ratos , Ratos Endogâmicos WF , Fluxo Sanguíneo Regional , Espectroscopia de Luz Próxima ao Infravermelho
13.
Pituitary ; 8(1): 17-23, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16411064

RESUMO

Tumours are dependent on angiogenesis for growth and inhibition of angiogenesis has become a target for antineoplastic therapy. In the pituitary, unlike other tissues, vascularization is lower in adenomas compared to the normal gland. Despite this finding, a relationship between increased vascularity and several aspects of prolactinoma behaviour such as size, invasiveness, surgical outcome and malignancy, has been demonstrated. The process of angiogenesis is the result of a balance of stimulating and inhibiting factors. It is likely that an interaction between gene expression (such as pituitary tumour transforming gene (PTTG) and a novel gene located within the Edpm5 quantitative trait locus), hormonal stimuli including oestrogens, dopamine, 16 kDa fragments of prolactin and proangiogenic and antiangiogenic growth factors (for example, vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2), determine the final angiogenic phenotype of prolactinomas, and thus subsequent tumour behaviour. The elucidation of all the factors involved in the regulation of angiogenesis and their interactions might open new possibilities in the treatment of prolactinomas, especially in those cases with resistance or intolerance to dopamine agonists.


Assuntos
Neovascularização Patológica , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/fisiopatologia , Prolactinoma/irrigação sanguínea , Prolactinoma/fisiopatologia , Dopamina/genética , Dopamina/fisiologia , Agonistas de Dopamina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Estrogênios/genética , Estrogênios/fisiologia , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/fisiologia , Regulação Neoplásica da Expressão Gênica , Genes Neoplásicos , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/fisiologia , Neovascularização Patológica/genética , Neoplasias Hipofisárias/genética , Prolactina/genética , Prolactina/fisiologia , Prolactinoma/genética , Securina , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/fisiologia
14.
Neoplasia ; 6(2): 150-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15140404

RESUMO

Tumor vasculature is an attractive therapeutic target as it differs structurally from normal vasculature, and the destruction of a single vessel can lead to the death of many tumor cells. The effects of antivascular drugs are frequently short term, with regrowth beginning less than 24 hours posttreatment. This study investigated the duration of the response to the vascular targeting agent, ZD6126, of the GH3 prolactinoma, in which efficacy and dose-response have previously been demonstrated. GH3 prolactinomas were grown in the flanks of eight Wistar Furth rats. All animals were treated with 50 mg/kg ZD6126. The tumors were examined with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) 24 hours pretreatment and posttreatment, and at a single time between 48 and 96 hours posttreatment. No evidence of recovery of perfusion was observed even at the longest (96-hour) time point. Involvement of a statistician at the project planning stage and the use of DCE-MRI, which permits noninvasive quantitation of parameters related to blood flow in intact animals, allowed this highly significant result to be obtained using only eight rats.


Assuntos
Neovascularização Patológica/tratamento farmacológico , Compostos Organofosforados/administração & dosagem , Neoplasias Hipofisárias/irrigação sanguínea , Prolactinoma/irrigação sanguínea , Animais , Modelos Animais de Doenças , Imageamento por Ressonância Magnética , Necrose , Neovascularização Patológica/patologia , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Ratos , Ratos Endogâmicos WF , Fluxo Sanguíneo Regional/efeitos dos fármacos
15.
Br J Cancer ; 88(10): 1592-7, 2003 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-12771928

RESUMO

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time-concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T(2)*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R(2)* (=1/T(2)*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.


Assuntos
Fibrossarcoma/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Compostos Organofosforados/farmacocinética , Neoplasias Hipofisárias/irrigação sanguínea , Prolactinoma/irrigação sanguínea , Animais , Área Sob a Curva , Biomarcadores Tumorais/análise , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fibrossarcoma/patologia , Fibrossarcoma/veterinária , Camundongos , Necrose , Compostos Organofosforados/farmacologia , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/veterinária , Prolactinoma/patologia , Prolactinoma/veterinária , Ratos , Fluxo Sanguíneo Regional
16.
Oncol Rep ; 9(6): 1385-9, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12375053

RESUMO

The development of estrogen-induced pituitary prolactinoma in Fischer 344 (F344) rats is associated with enhanced neovascularization. This type of tumor is a rich source of basic fibroblast growth factor (bFGF), which possesses strong mitogenic and angiogenic properties. Pentosan polysulfate sodium (PPS) has been shown to exert antitumor activity by antagonizing the binding of bFGF to cell surface receptors. We have examined the effects of pentosan on tumor growth, hyperprolactinemia and angiogenesis in diethylstilbestrol-induced anterior pituitary adenoma in F344 rats. Chronic treatment with PPS did not cause any changes in the pituitary weight and serum prolactin concentration in comparison with untreated animals. The density of microvessels identified by CD-31 was also not affected by the tested drug. On the other hand, pentosan has been found to decrease cell proliferation evaluated by a number of PCNA-positive stained cell nuclei. Moreover, the TUNEL method has revealed an increased number of apoptotic bodies within the anterior pituitary after treatment with PPS. Despite the antiproliferative and proapoptotic activity of pentosan, the drug failed to inhibit tumor growth. This fact might be due to the lack of antiangiogenic activity of PPS in this experimental design.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Neovascularização Patológica/tratamento farmacológico , Poliéster Sulfúrico de Pentosana/uso terapêutico , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Dietilestilbestrol , Técnicas Imunoenzimáticas , Marcação In Situ das Extremidades Cortadas , Masculino , Neovascularização Patológica/patologia , Tamanho do Órgão/efeitos dos fármacos , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/induzido quimicamente , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prolactina/metabolismo , Prolactinoma/irrigação sanguínea , Prolactinoma/induzido quimicamente , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Endogâmicos F344 , Células Tumorais Cultivadas
17.
Magn Reson Imaging ; 19(2): 161-6, 2001 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11358653

RESUMO

The hypercapnia induced by carbogen (95% O(2)/5% CO(2)) breathing, which is being re-evaluated as a clinical radiosensitiser, causes patient discomfort and hence poor compliance. Recent preclinical and clinical studies have indicated that the CO(2) content might be lowered without compromising increased tumour oxygenation and radiosensitisation. This preclinical study was designed to see if lower levels of hypercapnia could evoke similar decreases in the transverse relaxation rate R(2)* of rodent tumours to those seen with carbogen breathing. The response of rat GH3 prolactinomas to 1%, 212% and 5% CO(2) in oxygen, and 100% O(2) breathing, was monitored by non-invasive multi-gradient echo MRI to quantify R(2)*. As the oxygenation of haemoglobin is proportional to the blood p(a)O(2) and therefore in equilibrium with tissue pO(2), R(2)* is a sensitive indicator of tissue oxygenation. Hyperoxia alone decreased R(2)* by 13%, whilst all three hypercapnic hyperoxic gases decreased R(2)* by 29%. Breathing 1% CO(2) in oxygen evoked the same decrease in R(2)* as carbogen. The DeltaR(2)* response is primarily consistent with an increase in blood oxygenation, though localised increases in tumour blood flow were also identified in response to hypercapnia. The data support the concept that levels of hypercapnia can be reduced without loss of enhanced oxygenation and hence potential radiotherapeutic benefit.


Assuntos
Dióxido de Carbono/sangue , Dióxido de Carbono/farmacologia , Imagem Ecoplanar , Oxigenoterapia , Oxigênio/sangue , Oxigênio/farmacologia , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Radiossensibilizantes/farmacologia , Animais , Linhagem Celular , Feminino , Transplante de Neoplasias , Consumo de Oxigênio/efeitos dos fármacos , Neoplasias Hipofisárias/irrigação sanguínea , Prolactinoma/irrigação sanguínea , Ratos , Ratos Endogâmicos WF , Fluxo Sanguíneo Regional/efeitos dos fármacos
18.
Appl Immunohistochem Mol Morphol ; 9(4): 364-70, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11759065

RESUMO

This study focused on the three-dimensional imaging of hormone-secreting cells and their microvascular environment in estrogen-induced prolactinoma of the rat pituitary gland. Adult female Wistar-Imamichi rats were injected with estradiol dipropionate and killed 7 weeks later. Some rats given estrogen for 7 weeks also were injected with bromocriptine before killing. To obtain a detailed three-dimensional image of microvessels, dialyzed fluorescein isothiocyanate (FITC)-conjugated gelatin was injected into the left ventricle of the rat heart. After the perfusion, the pituitary glands were resected and subjected to immunohistochemistry (IHC). To evaluate the effects of estrogen and bromocriptine, IHC was performed with antibodies against prolactin (PRL), adrenocorticotropic hormone (ACTH), and growth hormone (GH). With the combination, microvessels and cells containing PRL, ACTH, and GH could be clearly identified by confocal laser scanning microscopy (CLSM). The PRL cells increased in number and became hypertrophic after prolonged exposure to estrogen. With bromocriptine administration after estrogen treatment, however, PRL cells decreased in number and became atrophic. The current study revealed that estrogen and bromocriptine had significant effects on PRL secretion and the microvascular environment. Therefore, this technique (FITC injection and IHC) with CLSM is suitable for the three-dimensional imaging of hormone-secreting mechanisms under various conditions.


Assuntos
Estradiol/análogos & derivados , Estrogênios/farmacologia , Imageamento Tridimensional , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Hormônio Adrenocorticotrópico/análise , Animais , Bromocriptina/administração & dosagem , Bromocriptina/farmacologia , Estradiol/administração & dosagem , Estradiol/farmacologia , Estrogênios/administração & dosagem , Feminino , Hormônio do Crescimento/análise , Antagonistas de Hormônios/administração & dosagem , Antagonistas de Hormônios/farmacologia , Imuno-Histoquímica , Microcirculação/citologia , Microcirculação/efeitos dos fármacos , Microscopia Confocal , Hipófise/citologia , Hipófise/efeitos dos fármacos , Neoplasias Hipofisárias/irrigação sanguínea , Neoplasias Hipofisárias/induzido quimicamente , Neoplasias Hipofisárias/metabolismo , Prolactina/análise , Prolactinoma/irrigação sanguínea , Prolactinoma/induzido quimicamente , Prolactinoma/metabolismo , Ratos , Ratos Wistar
19.
J Clin Endocrinol Metab ; 85(8): 2931-5, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10946906

RESUMO

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that are able to degrade the extracellular matrix and allow angiogenesis and tumor invasion. The vast majority of pituitary tumors are benign and do not metastasize to distant sites, although they may invade locally. The aim of this study was to determine whether expression of the collagenase MMP-9 may play a role in allowing angiogenesis and invasion by different pituitary tumor types. Tumor expression of MMP-9 was investigated using a monoclonal antibody on a series of well-characterized paraffin-embedded sections of pituitary tumors. Invasive macroprolactinomas (n = 11) were significantly more likely to express MMP-9 than noninvasive macroprolactinomas (n = 8) (P = 0.003). Invasive macroprolactinomas showed higher-density MMP-9 staining than noninvasive tumors (P < 0.05). MMP-9 expression did not differ between noninvasive tumors and normal pituitary gland, or between different sized prolactinomas. MMP-9 expression was related to aggressive tumor behavior. It was higher in invasive macroprolactinomas (P = 0.003) when compared with noninvasive macroprolactinomas or the normal anterior pituitary gland. In addition, although there was no difference in whether MMP-9 was present or not when nonfunctioning adenomas that recurred were compared with those that did not, samples of recurrent tumor at the second presentation were more likely to express MMP-9 (P = 0.01). Pituitary carcinomas were significantly more likely to be MMP-9 positive compared with normal anterior pituitary gland (P = 0.05), but there was no difference from invasive adenomas. Angiogenesis assessed by vascular density was related to MMP-9 expression (P < 0.05). In summary, we have shown the presence of MMP-9 expression in some invasive and recurrent pituitary adenomas, and in the majority of pituitary carcinoma. The mechanisms whereby MMP-9 expression influences tumor recurrence and invasiveness, and its association with angiogenesis, remains to be elucidated. However, these observations suggest that a future potential therapeutic strategy for some pituitary tumors may be administration of a synthetic MMP-9 inhibitor.


Assuntos
Adenoma/patologia , Carcinoma/patologia , Metaloproteinase 9 da Matriz/análise , Neoplasias Hipofisárias/enzimologia , Neoplasias Hipofisárias/patologia , Prolactinoma/patologia , Adenoma/irrigação sanguínea , Adenoma/enzimologia , Carcinoma/irrigação sanguínea , Carcinoma/enzimologia , Humanos , Imuno-Histoquímica , Invasividade Neoplásica , Recidiva Local de Neoplasia , Neovascularização Patológica , Adeno-Hipófise/enzimologia , Neoplasias Hipofisárias/irrigação sanguínea , Prolactina/análise , Prolactinoma/irrigação sanguínea , Prolactinoma/enzimologia
20.
Br J Cancer ; 82(12): 2007-14, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10864210

RESUMO

Both host carbogen (95% oxygen/5% carbon dioxide) breathing and nicotinamide administration enhance tumour radiotherapeutic response and are being re-evaluated in the clinic. Non-invasive magnetic resonance imaging (MRI) and 31P magnetic resonance spectroscopy (MRS) methods have been used to give information on the effects of nicotinamide alone and in combination with host carbogen breathing on transplanted rat GH3 prolactinomas. Gradient recalled echo (GRE) MRI, sensitive to blood oxygenation changes, and spin echo (SE) MRI, sensitive to perfusion/flow, showed large signal intensity increases with carbogen breathing. Nicotinamide, thought to act by suppressing the transient closure of small blood vessels that cause intermittent tumour hypoxia, induced a small increase in blood oxygenation but no detectable change in perfusion/flow. Carbogen combined with nicotinamide was no more effective than carbogen alone. Both carbogen and nicotinamide caused significant increases in the nucleoside triphosphate/inorganic phosphate (betaNTP/Pi) ratio, implying that the tumour cells normally receive sub-optimal substrate supply, and is consistent with either increased glycolysis and/or a switch to more oxidative metabolism. The most striking observation was the marked increase in blood glucose (twofold) induced by both nicotinamide and carbogen. Whether this may play a role in tumour radiosensitivity has yet to be determined.


Assuntos
Glicemia/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Metabolismo Energético/efeitos dos fármacos , Niacinamida/farmacologia , Oxigênio/metabolismo , Oxigênio/farmacologia , Prolactinoma/metabolismo , Animais , Feminino , Hidralazina/farmacologia , Imageamento por Ressonância Magnética , Prolactinoma/irrigação sanguínea , Ratos , Ratos Endogâmicos WF , Fatores de Tempo
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