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1.
Mol Cancer Ther ; 11(4): 1036-47, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22389468

RESUMEN

The c-Met pathway has been implicated in a variety of human cancers for its critical role in tumor growth, invasion, and metastasis. PF-04217903 is a novel ATP-competitive small-molecule inhibitor of c-Met kinase. PF-04217903 showed more than 1,000-fold selectivity for c-Met compared with more than 150 kinases, making it one of the most selective c-Met inhibitors described to date. PF-04217903 inhibited tumor cell proliferation, survival, migration/invasion in MET-amplified cell lines in vitro, and showed marked antitumor activity in tumor models harboring either MET gene amplification or a hepatocyte growth factor (HGF)/c-Met autocrine loop at well-tolerated dose levels in vivo. Antitumor efficacy of PF-04217903 was dose-dependent and showed a strong correlation with inhibition of c-Met phosphorylation, downstream signaling, and tumor cell proliferation/survival. In human xenograft models that express relatively high levels of c-Met, complete inhibition of c-Met activity by PF-04217903 only led to partial tumor growth inhibition (38%-46%) in vivo. The combination of PF-04217903 with Recepteur d'origine nantais (RON) short hairpin RNA (shRNA) knockdown in the HT29 model that also expresses activated RON kinase-induced tumor cell apoptosis and resulted in enhanced antitumor efficacy (77%) compared with either PF-04217903 (38%) or RON shRNA alone (56%). PF-04217903 also showed potent antiangiogenic properties in vitro and in vivo. Furthermore, PF-04217903 strongly induced phospho-PDGFRß (platelet-derived growth factor receptor) levels in U87MG xenograft tumors, indicating a possible oncogene switching mechanism in tumor cell signaling as a potential resistance mechanism that might compromise tumor responses to c-Met inhibitors. Collectively, these results show the use of highly selective inhibition of c-Met and provide insight toward targeting tumors exhibiting different mechanisms of c-Met dysregulation.


Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Pirazinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Triazoles/farmacología , Animales , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Ratones , Ratones Desnudos , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
2.
J Nucl Med ; 52(8): 1261-7, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21764800

RESUMEN

UNLABELLED: The ability of PET to image functional changes in tumors is increasingly being used to evaluate response and predict clinical benefit to conventional and novel cancer therapies. Although the use of (18)F-FDG PET is well established, 3'-deoxy-3'-(18)F-fluorothymidine ((18)F-FLT) PET has potential advantages as a more specific marker of cellular proliferation. c-MET signaling is frequently dysregulated in cancer and is therefore an attractive therapeutic target. Crizotinib (PF-2341066) is a novel adenosine triphosphate-competitive c-MET kinase inhibitor with antitumor activity in a range of tumor models. The aim of this study was to investigate the utility of PET of glucose metabolism and cell proliferation to monitor tumor response to crizotinib in 2 cell lines with aberrant c-MET signaling. METHODS: Mice bearing GTL-16 or U87MG xenografts were evaluated for changes in tumor volume and (18)F-FDG and (18)F-FLT uptake after daily oral treatment with up to 50 mg/kg crizotinib. GTL-16 and U87MG cells were treated with crizotinib in vitro and analyzed for (3)H-2-deoxyglucose uptake and expression of activated MET, AKT, and ERK by immunoblotting. RESULTS: Treatment of c-MET-amplified GTL-16 xenografts with 50 mg/kg crizotinib caused tumor regression that was associated with a slow reduction in (18)F-FDG uptake (P < 0.05, day 13) and reduced expression of the glucose transporter 1, GLUT-1. Although baseline (18)F-FDG uptake into U87MG tumors was substantially higher than in GTL-16 tumors, (18)F-FDG uptake into U87MG tumors remained unchanged on treatment at 50 mg/kg crizotinib, despite tumor growth inhibition of 93% on day 8 of treatment. These findings were confirmed in vitro, where treatment of U87MG cells with 1 µM crizotinib had no demonstrable effect on glucose uptake. Furthermore, these cells demonstrated constitutive, crizotinib-independent phosphoinositide 3-kinase pathway signaling as demonstrated by phosphorylated AKT and ribosomal protein S6. Both U87MG and GTL-16 tumors showed high baseline uptake of (18)F-FLT, which was reduced by 50% and 53% on days 4 and 8 of treatment, respectively. CONCLUSION: While the results provide a strong rationale to investigate the use of (18)F-FLT PET as a clinical biomarker for monitoring tumor response to c-MET inhibition, (18)F-FDG PET may be a less robust marker.


Asunto(s)
Didesoxinucleósidos/farmacología , Fluorodesoxiglucosa F18/farmacología , Tomografía de Emisión de Positrones/métodos , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Animales , Biomarcadores/metabolismo , Línea Celular Tumoral , Proliferación Celular , Crizotinib , Modelos Animales de Enfermedad , Glucosa/metabolismo , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Trasplante de Neoplasias , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Piridinas/farmacología , Transducción de Señal
3.
Clin Cancer Res ; 16(21): 5177-88, 2010 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-20829331

RESUMEN

PURPOSE: P-cadherin is a membrane glycoprotein that functionally mediates tumor cell adhesion, proliferation, and invasiveness. We characterized the biological properties of PF-03732010, a human monoclonal antibody against P-cadherin, in cell-based assays and tumor models. EXPERIMENTAL DESIGN: The affinity, selectivity, and cellular inhibitory activity of PF-03732010 were tested in vitro. Multiple orthotopic and metastatic tumor models were used for assessing the antitumor and antimetastatic activities of PF-03732010. Treatment-associated pharmacodynamic changes were also investigated. RESULTS: PF-03732010 selectively inhibits P-cadherin-mediated cell adhesion and aggregation in vitro. In the P-cadherin-overexpressing tumor models, including MDA-MB-231-CDH3, 4T1-CDH3, MDA-MB-435HAL-CDH3, HCT116, H1650, PC3M-CDH3, and DU145, PF-03732010 inhibited the growth of primary tumors and metastatic progression, as determined by bioluminescence imaging. Computed tomography imaging, H&E stain, and quantitative PCR analysis confirmed the antimetastatic activity of PF-03732010. In contrast, PF-03732010 did not show antitumor and antimetastatic efficacy in the counterpart tumor models exhibiting low P-cadherin expression. Mechanistic studies via immunofluorescence, immunohistochemical analyses, and 3'-[(18)F]fluoro-3'-deoxythymidine-positron emission tomography imaging revealed that PF-03732010 suppressed P-cadherin levels, caused degradation of membrane ß-catenin, and concurrently suppressed cytoplasmic vimentin, resulting in diminished metastatic capacity. Changes in the levels of Ki67, caspase-3, and 3'-[(18)F]fluoro-3'-deoxythymidine tracer uptake also indicated antiproliferative activity and increased apoptosis in the tested xenografts. CONCLUSIONS: These findings suggest that interrupting the P-cadherin signaling pathway may be a novel therapeutic approach for cancer therapy. PF-03732010 is presently undergoing evaluation in Phase 1 clinical trials.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Cadherinas/inmunología , Metástasis de la Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Células HCT116 , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Metástasis de la Neoplasia/prevención & control , Trasplante de Neoplasias , Neoplasias/patología , Trasplante Heterotópico , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto/métodos
4.
Clin Cancer Res ; 15(14): 4630-40, 2009 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-19584159

RESUMEN

PURPOSE: Checkpoint kinase 1 (Chk1) plays a critical role in the activation of mitotic spindle checkpoint and DNA damage checkpoint. We examined the preclinical use of the Chk1 inhibitor PF-00477736 as a docetaxel-sensitizing agent. Specifically, we investigated the correlation between PF-00477736-mediated modulation of biomarkers and the sensitization of docetaxel efficacy. EXPERIMENTAL DESIGN: In vitro and in vivo studies using COLO205 and other cell lines were done to assess PF-00477736-induced enhancement of docetaxel efficacy and effects on associated biomarkers. RESULTS: PF-00477736 significantly enhanced the docetaxel-induced efficacy in tumor cells and xenografts. Docetaxel induced dose- and time-dependent increase in the levels of phosphorylated Chk1 (Ser(345)), phosphorylated histone H3 (Ser(10)), and gammaH2AX foci and promoted the cytoplasmic localization of phosphorylated Cdc25C (Ser(216)). PF-00477736 cotreatment suppressed docetaxel-induced changes in phosphorylated histone H3 and cytoplasmic phosphorylated Cdc25C (Ser(216)) levels and concurrently sensitized the docetaxel-induced apoptosis. Docetaxel alone or in combination with PF-00477736 induced significant antiproliferative activity in xenografts, shown via [18F]FLT-PET imaging. However, changes in [18F]FLT uptake did not reflect the potentiation of docetaxel efficacy. In contrast, bioluminescence imaging showed that PF-00477736 sensitized docetaxel-induced suppression of tumor survival. CONCLUSIONS: Docetaxel triggers mitotic spindle checkpoint activation at low concentrations and activates both the DNA damage checkpoint and the spindle checkpoint at high concentrations. In combination with docetaxel, PF-00477736 abrogates the mitotic checkpoint, as well as the DNA damage checkpoint, and results in sensitization to docetaxel. Chk1 inhibitor PF-00477736 offers a therapeutic potential for the enhancement of taxane therapy.


Asunto(s)
Benzodiazepinonas/farmacología , Neoplasias/tratamiento farmacológico , Proteínas Quinasas/metabolismo , Pirazoles/farmacología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Benzodiazepinonas/administración & dosificación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1) , Didesoxinucleósidos , Docetaxel , Sinergismo Farmacológico , Radioisótopos de Flúor , Histonas/metabolismo , Humanos , Ratones , Ratones Desnudos , Neoplasias/metabolismo , Neoplasias/patología , Fosforilación/efectos de los fármacos , Pirazoles/administración & dosificación , Taxoides/administración & dosificación , Taxoides/farmacología , Tomografía Computarizada de Emisión , Carga Tumoral/efectos de los fármacos , Fosfatasas cdc25/metabolismo
5.
Clin Cancer Res ; 15(1): 238-46, 2009 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-19118051

RESUMEN

PURPOSE: Tumors grafted s.c. or under the mammary fat pad (MFP) rarely develop efficient metastasis. By applying bioluminescence imaging (BLI) technology, the MDA-MB-435-HAL-Luc subrenal capsule (SRC) model was compared with the MFP model for disease progression, metastatic potential, and response to therapy. EXPERIMENTAL DESIGN: The luciferase-expressing MDA-MB-435-HAL-Luc cell line was used in both MFP and SRC models. BLI technology allowed longitudinal assessment of disease progression and the therapeutic response to PD-0332991, Avastin, and docetaxel. Immunohistochemical analysis of Ki67 and CD31 staining in the primary tumors was compared in these models. Caliper measurement was used in the MFP model to validate the BLI quantification of primary tumors. RESULTS: The primary tumors in MDA-MB-435-HAL-Luc MFP and SRC models displayed comparable growth rates and vascularity. However, tumor-bearing mice in the SRC model developed lung metastases much earlier (4 weeks) than in the MFP model (>7 weeks), and the metastatic progression contributed significantly to the survival time. In the MFP model, BLI and caliper measurements were comparable for quantifying palpable tumors, but BLI offered an advantage for detecting the primary tumors that fell below a palpable threshold and for visualizing metastases. In the SRC model, BLI allowed longitudinal assessment of the antitumor and antimetastatic effects of PD-0332991, Avastin, and docetaxel, and the results correlated with the survival benefits of these agents. CONCLUSIONS: The MDA-MB-435-HAL-Luc SRC model and the MFP model displayed differences in disease progression. BLI is an innovative approach for developing animal models and creates opportunities for improving preclinical evaluations of anticancer agents.


Asunto(s)
Proteínas Luminiscentes , Trasplante de Neoplasias/métodos , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Animales , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Bevacizumab , Línea Celular Tumoral , Docetaxel , Femenino , Humanos , Riñón , Neoplasias Pulmonares/secundario , Glándulas Mamarias Humanas , Ratones , Ratones Desnudos , Ratones SCID , Neoplasias Experimentales/tratamiento farmacológico , Piperazinas/uso terapéutico , Piridinas/uso terapéutico , Taxoides/uso terapéutico
6.
Mol Cancer Ther ; 7(4): 818-28, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18413795

RESUMEN

AG-012986 is a multitargeted cyclin-dependent kinase (CDK) inhibitor active against CDK1, CDK2, CDK4/6, CDK5, and CDK9, with selectivity over a diverse panel of non-CDK kinases. Here, we report the potent antitumor efficacies of AG-012986 against multiple tumor lines in vitro and in vivo. AG-012986 showed antiproliferative activities in vitro with IC(50)s of <100 nmol/L in 14 of 18 tumor cell lines. In vivo, significant antitumor efficacy induced by AG-012986 was seen (tumor growth inhibition, >83.1%) in 10 of 11 human xenograft tumor models when administered at or near the maximum tolerated dose for 8 or 12 days. AG-012986 caused dose-dependent hypophosphorylation at Ser(795) of the retinoblastoma protein, cell cycle arrest, and apoptosis in vitro. Colony-forming assays indicated that the potency of AG-012986 substantially decreased with treatment time of <24 h. In vivo, AG-012986 also showed dose-dependent retinoblastoma Ser(795) hypophosphorylation, cell cycle arrest, decreased Ki-67 tumor staining, and apoptosis in conjunction with antitumor activity. Studies comparing i.p. bolus with s.c. implanted minipump dosing regimens revealed that in vivo efficacy correlated with the duration of minimally effective plasma levels rather than maximal drug plasma levels. Dosing optimization of AG-012986 provided guidance for selecting a treatment schedule to achieve the best antitumor efficacy while minimizing the risk of adverse side effects.


Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Benzamidas/farmacocinética , Western Blotting , Ciclo Celular/efectos de los fármacos , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Ensayo de Unidades Formadoras de Colonias , Humanos , Técnicas para Inmunoenzimas , Etiquetado Corte-Fin in Situ , Ratones , Ratones Desnudos , Ratones SCID , Fosforilación/efectos de los fármacos , Proteína de Retinoblastoma/metabolismo , Tiazoles/farmacocinética , Distribución Tisular , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto
7.
Mol Cancer Ther ; 6(12 Pt 1): 3314-22, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18089725

RESUMEN

A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC(50) value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G(1)-S-phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells (IC(50) values, approximately 30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase-mediated nick-end labeling and Annexin V staining (IC(50) values, 25-50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-gamma, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL.


Asunto(s)
Antineoplásicos/farmacología , Linfoma Anaplásico de Células Grandes/patología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Piridinas/farmacología , Quinasa de Linfoma Anaplásico , Animales , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Crizotinib , Ensayos de Selección de Medicamentos Antitumorales , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Ratones , Ratones SCID , Fosforilación , Proteínas Tirosina Quinasas/metabolismo , Pirazoles , Proteínas Tirosina Quinasas Receptoras
8.
Cancer Res ; 67(9): 4408-17, 2007 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-17483355

RESUMEN

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.


Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Piperidinas/farmacología , Piridinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Animales , Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Procesos de Crecimiento Celular/efectos de los fármacos , Crizotinib , Perros , Relación Dosis-Respuesta a Droga , Células Endoteliales/efectos de los fármacos , Femenino , Humanos , Masculino , Ratones , Ratones Desnudos , Neovascularización Patológica/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles , Proteínas Tirosina Quinasas Receptoras/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias Gástricas/irrigación sanguínea , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patología , Ensayos Antitumor por Modelo de Xenoinjerto
9.
Artículo en Español | LILACS, CUMED | ID: lil-411991

RESUMEN

Se realizó un estudio de corte transversal para estimar la prevalencia de asma ocupacional en la población laboral expuesta del municipio Guantánamo durante el período de julio del 2000 a febrero del 2001. El universo de estudio estuvo integrado por 838 trabajadores pertenecientes a la industria sideromecánica y a la construcción; se trabajó con una muestra de 189 trabajadores, quienes fueron seleccionados a través de un muestreo estratificado polietápico. Se encontró que el mayor numero de trabajadores corresponden al sexo masculino, siendo la exposición ocupacional a polvos, y el tiempo de exposición elementos significativos de predicción de asma. Los síntomas y signos encontrados en la serie de estudio, en orden de frecuencia corresponden a la hiperreactividad bronquial con 58.3 (por ciento), tos 25.0 (por ciento), disnea 14.2 (por ciento) y sibilancia 2.3 (por ciento), asociándose la disfunción ventilatoria obstructiva reversible en 52.3 (por ciento) y los resultados positivos del prick- test en 66.7 (por ciento) de los individuos estudiados. Esta última constituye un elemento significativo de predicción de asma. Se detectan, según criterios de Brook, 17 trabajadores con diagnóstico de asma ocupacional, lo que representa una tasa general de 2 (por ciento)(AU)


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Asma/epidemiología , Enfermedades Profesionales/epidemiología , Medicina del Trabajo/métodos , Estudios Transversales
10.
Artículo en Español | CUMED | ID: cum-25081

RESUMEN

Se realizó un estudio de corte transversal para estimar la prevalencia de asma ocupacional en la población laboral expuesta del municipio Guantánamo durante el período de julio del 2000 a febrero del 2001. El universo de estudio estuvo integrado por 838 trabajadores pertenecientes a la industria sideromecánica y a la construcción; se trabajó con una muestra de 189 trabajadores, quienes fueron seleccionados a través de un muestreo estratificado polietápico. Se encontró que el mayor numero de trabajadores corresponden al sexo masculino, siendo la exposición ocupacional a polvos, y el tiempo de exposición elementos significativos de predicción de asma. Los síntomas y signos encontrados en la serie de estudio, en orden de frecuencia corresponden a la hiperreactividad bronquial con 58.3 (por ciento), tos 25.0 (por ciento), disnea 14.2 (por ciento) y sibilancia 2.3 (por ciento), asociándose la disfunción ventilatoria obstructiva reversible en 52.3 (por ciento) y los resultados positivos del prick- test en 66.7 (por ciento) de los individuos estudiados. Esta última constituye un elemento significativo de predicción de asma. Se detectan, según criterios de Brook, 17 trabajadores con diagnóstico de asma ocupacional, lo que representa una tasa general de 2 (por ciento)(AU)


Asunto(s)
Humanos , Masculino , Femenino , Adulto , Asma/epidemiología , Enfermedades Profesionales , Medicina del Trabajo , Industrias
11.
Curr Eye Res ; 24(5): 397-402, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-12434309

RESUMEN

PURPOSE: To show the presence and localization of type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) in rat corneal and conjunctival epithelia and investigate the association of ErbB2 with its intramembrane ligand Muc4. METHODS: Methacarn-fixed, paraffin-embedded sections of corneas and eyelids from female adult rats were immunocytochemically stained using antibodies against the ErbB receptors and Muc4. Sequential immunoprecipitation and immunoblot analyses were performed on epithelial lysates to investigate the presence of a complex of Muc4 and ErbB2 in corneal and conjunctival epithelia. RESULTS: Immunocytochemical staining demonstrated the presence of ErbB2, ErbB3 and ErbB4 growth factor receptors throughout the rat corneal and conjunctival epithelia. Co-immunoprecipitation of the epithelial lysates demonstrated that Muc4 and ErbB2 are present as a complex. CONCLUSIONS: The three type 1 growth factor receptors (ErbB2, ErbB3 and ErbB4) are present in the rat corneal and conjunctival epithelia, and ErbB2 is at least partly associated with Muc4. This demonstration of the presence and localization of these three type 1 growth factor receptors may help in understanding how these receptors contribute to ocular epithelial behavior and functions.


Asunto(s)
Conjuntiva/metabolismo , Epitelio Corneal/metabolismo , Mucinas/metabolismo , Receptor ErbB-2/metabolismo , Animales , Epitelio/metabolismo , Receptores ErbB/metabolismo , Femenino , Inmunohistoquímica , Mucina 4 , Ratas , Ratas Endogámicas F344 , Receptor ErbB-3/metabolismo , Receptor ErbB-4
12.
Oncogene ; 21(49): 7524-32, 2002 Oct 24.
Artículo en Inglés | MEDLINE | ID: mdl-12386815

RESUMEN

Muc4/sialomucin complex (SMC) is a multifunctional glycoprotein complex which can repress apoptosis in transfected tumor cells. Its transmembrane subunit acts as an intramembrane ligand for the receptor tyrosine kinase ErbB2 to induce the phosphorylation of ErbB2 and, by acting synergistically with the ErbB3 ligand neuregulin, can potentiate the phosphorylation of ErbB2 and ErbB3. In the present study we show that Muc4/SMC alone robustly induces the phosphorylation of ErbB2 to enhance the tyrosine phosphate epitope (Tyr1248) recognized by anti-phospho-ErbB2. Although this tyrosine phosphorylation has been implicated in cell transformation, it does not activate any of the three mitogen-activated protein kinases (MAPKs) or protein kinase B/Akt of the phosphatidyl inositol 3-kinase pathway. Instead, Muc4/SMC expression induces up-regulation of the cell cycle inhibitor p27(kip), consistent with the expression of Muc4/SMC in differentiated, rather than proliferative, epithelial cells. Interestingly, a combination of Muc4/SMC and neuregulin down-regulate p27(kip) and activate protein kinase B/Akt. These observations suggest that Muc4/SMC acts as a regulator of differentiation by inducing a limited phosphorylation of ErbB2 and a modulator of proliferation when acting synergistically with neuregulin to induce a more extensive phosphorylation on both ErbB2 and ErbB3.


Asunto(s)
Proteínas de Ciclo Celular/genética , Regulación de la Expresión Génica/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Mucinas/fisiología , Receptor ErbB-2/metabolismo , Proteínas Supresoras de Tumor/genética , Animales , Adhesión Celular , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Activación Enzimática , Humanos , Ligandos , Mucina 4 , Mucinas/metabolismo , Fosforilación , Sialoglicoproteínas/metabolismo , Spodoptera , Células Tumorales Cultivadas , Tirosina/metabolismo , Regulación hacia Arriba
13.
Biochem J ; 368(Pt 1): 41-8, 2002 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-12186632

RESUMEN

Muc4/sialomucin complex (SMC) is a heterodimeric glycoprotein complex implicated in epithelial protection and overexpressed in some tumours. It is encoded by a single gene, and the two subunits are produced by proteolytic cleavage at a time before substantial O-glycosylation, near the time of transit from the endoplasmic reticulum to the Golgi. Although Muc4/SMC is translated as a membrane protein, it is produced as a soluble form in many epithelia. Transfection experiments using Cos-7, HBL-100 human epithelial, MCF-7 human breast tumour and HC11 mouse mammary cell lines showed that soluble rat Muc4/SMC is produced by a proteolytic cleavage mechanism and released by secretion from multiple cell lines, including both human and mouse normal epithelial cells and tumour cells. Similar transfection experiments demonstrated the same mechanism for the human analogue MUC4. Gel electrophoresis analyses of deglycosylated membrane and soluble transmembrane subunits and of the membrane-associated cleavage fragment indicated a released cleavage product of 25 kDa, resulting from cleavage between two epidermal growth factor-like domains. Further evidence for this site was obtained from deletion mutants removing this region of the protein, which blocked secretion. Finally, pulse-chase analyses of Muc4/SMC biosynthesis indicated no kinetic difference between the timing of the cleavage to release the soluble form and that to produce the two subunits, indicating that the soluble form is created early in transit to the cell surface. These studies provide the first clear evidence that membrane mucins can be released from cells by an intracellular proteolytic mechanism that leads to secretion of the soluble form of the mucin.


Asunto(s)
Proteínas de la Membrana/metabolismo , Mucinas/biosíntesis , Péptido Hidrolasas/metabolismo , Animales , Mama/citología , Células COS , Factor de Crecimiento Epidérmico/química , Humanos , Mucina 4 , Mucinas/metabolismo , Estructura Terciaria de Proteína
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