Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino/farmacología , Antígenos CD20/inmunología , Antineoplásicos Alquilantes/administración & dosificación , Clorhidrato de Bendamustina , Línea Celular Tumoral/efectos de los fármacos , Línea Celular Tumoral/trasplante , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Ratones , Ratones SCID , Compuestos de Mostaza Nitrogenada/administración & dosificación , Compuestos de Mostaza Nitrogenada/farmacología , Rituximab , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
N,N'-Diarylureas were prepared, and the structure-activity relationship relative to the CXCR2 receptor was examined. This led to the identification of a potent and highly selective CXCR2 antagonist, which in addition was shown to be functionally active both in vitro against human neutrophils and in vivo in rabbit models of ear edema and neutropenia.
Asunto(s)
Antiinflamatorios/síntesis química , Compuestos de Fenilurea/síntesis química , Receptores de Interleucina-8B/antagonistas & inhibidores , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Unión Competitiva , Células CHO , Calcio/metabolismo , Quimiocina CXCL1 , Quimiocinas , Factores Quimiotácticos , Quimiotaxis , Cricetinae , Humanos , Hipersensibilidad Tardía/inducido químicamente , Hipersensibilidad Tardía/tratamiento farmacológico , Técnicas In Vitro , Péptidos y Proteínas de Señalización Intercelular , Interleucina-8 , Neutropenia/inducido químicamente , Neutropenia/tratamiento farmacológico , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Neutrófilos/fisiología , Compuestos de Fenilurea/química , Compuestos de Fenilurea/farmacología , Conejos , Ensayo de Unión Radioligante , Receptores de Interleucina-8A/antagonistas & inhibidores , Receptores de Interleucina-8A/metabolismo , Receptores de Interleucina-8B/metabolismo , Relación Estructura-ActividadRESUMEN
Much evidence implicates IL-8 as a major mediator of inflammation and joint destruction in rheumatoid arthritis. The effects of IL-8 and its related ligands are mediated via two receptors, CXCR1 and CXCR2. In the present study, we demonstrate that a potent and selective nonpeptide antagonist of human CXCR2 potently inhibits (125)I-labeled human IL-8 binding to, and human IL-8-induced calcium mobilization mediated by, rabbit CXCR2 (IC(50) = 40.5 and 7.7 nM, respectively), but not rabbit CXCR1 (IC(50) = >1000 and 2200 nM, respectively). These data suggest that the rabbit is an appropriate species in which to examine the anti-inflammatory effects of a human CXCR2-selective antagonist. In two acute models of arthritis in the rabbit induced by knee joint injection of human IL-8 or LPS, and a chronic Ag (OVA)-induced arthritis model, administration of the antagonist at 25 mg/kg by mouth twice a day significantly reduced synovial fluid neutrophils, monocytes, and lymphocytes. In addition, in the more robust LPS- and OVA-induced arthritis models, which were characterized by increased levels of proinflammatory mediators in the synovial fluid, TNF-alpha, IL-8, PGE(2), leukotriene B(4), and leukotriene C(4) levels were significantly reduced, as was erythrocyte sedimentation rate, possibly as a result of the observed decreases in serum TNF-alpha and IL-8 levels. In vitro, the antagonist potently inhibited human IL-8-induced chemotaxis of rabbit neutrophils (IC(50) = 0.75 nM), suggesting that inhibition of leukocyte migration into the knee joint is a likely mechanism by which the CXCR2 antagonist modulates disease.