RESUMO
Imatinib inhibits Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The second-line inhibitors nilotinib and dasatinib are effective in patients with imatinib resistance resulting from Bcr-Abl kinase domain mutations. Bcr-Abl(T315I), however, is resistant to all Abl kinase inhibitors in clinical use and is emerging as the most frequent cause of salvage therapy failure. SGX393 is a potent inhibitor of native and T315I-mutant Bcr-Abl kinase that blocks the growth of leukemia cell lines and primary hematopoietic cells expressing Bcr-Abl(T315I), with minimal toxicity against Bcr-Abl-negative cell lines or normal bone marrow. A screen for Bcr-Abl mutants emerging in the presence of SGX393 revealed concentration-dependent reduction in the number and range of mutations. Combining SGX393 with nilotinib or dasatinib preempted emergence of resistant subclones, including Bcr-Abl(T315I). These findings suggest that combination of a T315I inhibitor with the current clinically used inhibitors may be useful for reduction of Bcr-Abl mutants in Philadelphia chromosome-positive leukemia.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Mutação de Sentido Incorreto , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Dasatinibe , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Pirimidinas/farmacologia , Tiazóis/farmacologiaRESUMO
We report here that shape-from-shading stimuli evoked a long-latency contextual pop-out response in V1 and V2 neurons of macaque monkeys, particularly after the monkeys had used the stimuli in a behavioral task. The magnitudes of the pop-out responses were correlated to the monkeys' behavioral performance, suggesting that these signals are neural correlates of perceptual pop-out saliency. The signals changed with the animal's behavioral adaptation to stimulus contingencies, indicating that perceptual saliency is also a function of experience and behavioral relevance. The evidence that higher-order stimulus attributes and task experience can influence early visual processing supports the notion that perceptual computation is an interactive and plastic process involving multiple cortical areas.