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Métodos Terapéuticos y Terapias MTCI
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Br J Cancer ; 103(3): 347-53, 2010 Jul 27.
Artículo en Inglés | MEDLINE | ID: mdl-20628392


BACKGROUND: Non-small-cell lung cancer (NSCLC) is an aggressive disease in which vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are implicated in tumour growth, tumour resistance to radiation and chemotherapy, and disease relapse. We have investigated the anti-tumoural effects of BMS-690514, an inhibitor of both vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signalling pathways, as a single agent and in combination with ionising radiation (IR) on several NSCLC cell lines. METHODS: Radiosensitisation of several NSCLC cell lines by BMS-690514 was assessed in vitro using clonogenic assay and in vivo using nude mice. RESULTS: In vitro studies showed that BMS-690514 alone decreases clonogenic survival of NSCLC cells lines but no potential enhancement of IR response was observed in the combination. In tumour-bearing mice, BMS-690514 alone inhibits the growth of NSCLC xenografts, including the T790M mutation-harbouring H1975 tumour. The concomitant combination of BMS-690514 and radiation did not increase mice survival in comparison with treatment with IR alone. In contrast, BMS-690514 markedly enhances the anti-tumour effect of radiation in a sequential manner on H1299 and H1975 xenografts. Immunohistochemistry revealed a qualitative reduction in vessel area after administrations of BMS-690514, compared with vehicle-treated controls, suggesting that revascularisation may explain the schedule dependency of the tumour-growth delay observed. CONCLUSION: The results of association with radiation show that BMS-690514 may be a successful adjuvant to clinical radiotherapy. These findings are of translational importance because the clinical benefits of anti-EGFR and anti-VEGFR therapy might be schedule dependent.

Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Piperidinas/uso terapéutico , Pirroles/uso terapéutico , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Triazinas/uso terapéutico , Animales , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , División Celular/efectos de los fármacos , División Celular/efectos de la radiación , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Terapia Combinada , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/genética , Exones , Humanos , Ratones , Ratones Desnudos , Mutación , Trasplante de Neoplasias , Eliminación de Secuencia , Trasplante Heterólogo
Bull Cancer ; 96 Suppl: S69-74, 2009 Dec.
Artículo en Francés | MEDLINE | ID: mdl-20034872


KRAS mutations are currently the most frequently mutated oncogenes in non-small cell lung cancers (NSCLC). A growing body of evidence suggests that targeting RAS could be an efficient strategy in NSCLC. Several approaches have been developed to target either RAS protein or downstream effectors such as RAF or MEK. First clinical trials evaluating farnesyltransferases inhibitors have led to unsuccessful results. However, targeting RAF and MEK could be a more efficient approach in NSCLC.

Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Genes ras/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Animales , Antineoplásicos/uso terapéutico , Bencenosulfonatos/uso terapéutico , Farnesiltransferasa/antagonistas & inhibidores , Humanos , Ratones , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Mutación/genética , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/fisiología , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piperidinas/uso terapéutico , Piridinas/uso terapéutico , Quinolonas/uso terapéutico , Sorafenib , Quinasas raf/antagonistas & inhibidores , Proteínas ras/antagonistas & inhibidores , Proteínas ras/fisiología