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Toxicol Sci ; 156(1): 275-288, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28115644

RESUMEN

Chemotherapy-induced peripheral neuropathy (CIPN) is a major, dose-limiting adverse effect experienced by cancer patients. Advancements in mechanism-based risk mitigation and effective treatments for CIPN can be aided by suitable in vitro assays. To this end, we developed a multiparametric morphology-centered rat dorsal root ganglion (DRG) assay. Morphologic alterations in subcellular structures of neurons and non-neurons were analyzed with an automated microscopy system. Stains for NeuN (a neuron-specific nuclear protein) and Tuj-1 (ß-III tubulin) were used to identify neuronal cell nuclei and neuronal cell bodies/neurites, respectively. Vimentin staining (a component of Schwann cell intermediate filaments) was used to label non-neuronal supporting cells. Nuclei that stained with DAPI, but lacked NeuN represented non-neuronal cells. Images were analyzed following 24 h of continuous exposure to CIPN-inducing agents and 72 h after drug removal to provide a dynamic measure of recovery from initial drug effects. Treatment with bortezomib, cisplatin, eribulin, paclitaxel or vincristine induced a dose-dependent loss of neurite/process areas, mimicking the 'dying back' degeneration of axons, a histopathological hallmark of clinical CIPN in vivo. The IC50 for neurite loss was within 3-fold of the maximal clinical exposure (Cmax) for all five CIPN-inducing drugs, but was >4- or ≥ 28-fold of the Cmax for 2 non-CIPN-inducing agents. Compound-specific effects, eg, neurite fragmentation by cisplatin or bortezomib and enlarged neuronal cell bodies by paclitaxel, were also observed. Collectively, these results support the use of a quantitative, morphologic evaluation and a DRG cell culture model to inform risk and examine mechanisms of CIPN.


Asunto(s)
Antineoplásicos/efectos adversos , Ganglios Espinales/efectos de los fármacos , Neuronas/efectos de los fármacos , Animales , Biomarcadores/metabolismo , Cuerpo Celular/efectos de los fármacos , Cuerpo Celular/metabolismo , Cuerpo Celular/patología , Forma del Núcleo Celular/efectos de los fármacos , Forma de la Célula/efectos de los fármacos , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Electroforesis Capilar , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Procesamiento de Imagen Asistido por Computador , Cinética , Peso Molecular , Proteínas del Tejido Nervioso/química , Proteínas del Tejido Nervioso/metabolismo , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuritas/patología , Neuronas/metabolismo , Neuronas/patología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Forma de los Orgánulos/efectos de los fármacos , Tamaño de los Orgánulos/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/patología , Ratas
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