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1.
Blood ; 119(22): 5133-43, 2012 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-22368270

RESUMO

Internal tandem duplication (ITD) of the fms-related tyrosine kinase-3 (FLT3) gene occurs in 30% of acute myeloid leukemias (AMLs) and confers a poor prognosis. Thirteen relapsed or chemo-refractory FLT3-ITD(+) AML patients were treated with sorafenib (200-400 mg twice daily). Twelve patients showed clearance or near clearance of bone marrow myeloblasts after 27 (range 21-84) days with evidence of differentiation of leukemia cells. The sorafenib response was lost in most patients after 72 (range 54-287) days but the FLT3 and downstream effectors remained suppressed. Gene expression profiling showed that leukemia cells that have become sorafenib resistant expressed several genes including ALDH1A1, JAK3, and MMP15, whose functions were unknown in AML. Nonobese diabetic/severe combined immunodeficiency mice transplanted with leukemia cells from patients before and during sorafenib resistance recapitulated the clinical results. Both ITD and tyrosine kinase domain mutations at D835 were identified in leukemia initiating cells (LICs) from samples before sorafenib treatment. LICs bearing the D835 mutant have expanded during sorafenib treatment and dominated during the subsequent clinical resistance. These results suggest that sorafenib have selected more aggressive sorafenib-resistant subclones carrying both FLT3-ITD and D835 mutations, and might provide important leads to further improvement of treatment outcome with FLT3 inhibitors.


Assuntos
Antineoplásicos/administração & dosagem , Benzenossulfonatos/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Regulação Leucêmica da Expressão Gênica , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Piridinas/administração & dosagem , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Aldeído Desidrogenase/biossíntese , Aldeído Desidrogenase/genética , Família Aldeído Desidrogenase 1 , Animais , Antineoplásicos/efeitos adversos , Benzenossulfonatos/efeitos adversos , Medula Óssea/enzimologia , Medula Óssea/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Janus Quinase 3/biossíntese , Janus Quinase 3/genética , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/patologia , Masculino , Metaloproteinase 15 da Matriz/biossíntese , Metaloproteinase 15 da Matriz/genética , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Transplante de Neoplasias , Niacinamida/análogos & derivados , Compostos de Fenilureia , Estrutura Terciária de Proteína , Piridinas/efeitos adversos , Retinal Desidrogenase , Sorafenibe , Fatores de Tempo , Transplante Heterólogo , Tirosina Quinase 3 Semelhante a fms/metabolismo
2.
Cancer Chemother Pharmacol ; 76(6): 1199-207, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26553104

RESUMO

PURPOSE: Adjunct chemoradiation is offered to unresectable esophageal squamous cell carcinoma (ESCC) patients, while its use is limited in tumors with strong resistance. Oxygen carriers or anti-hypoxic drugs belong to an emerging class of regulators that can alleviate tumor hypoxia. METHODS: We investigate the potential use of a novel oxygen carrier YQ23 in sensitizing chemoresistant ESCC in a series of subcutaneous tumor xenograft models developed using ESCC cell lines with different strengths of chemosensitivities. RESULTS: Tumor xenografts were developed using SLMT-1 and HKESC-2 ESCC cell lines with different strengths of resistance to two chemotherapeutic drugs, 5-fluorouracil and cisplatin. More resistant SLMT-1 xenografts responded better to YQ23 treatment than HKESC-2, as reflected by the induced tumor oxygen level. YQ23 sensitized SLMT-1 xenografts toward 5-fluorouracil via its effect on reducing the level of a hypoxic marker HIF-1α. Furthermore, a derangement of tumor microvessel density and integrity was demonstrated with a concurrent decrease in the level of a tumor mesenchymal marker vimentin. Similar to the 5-fluorouracil sensitizing effect, YQ23 also enhanced the response of SLMT-1 xenografts toward cisplatin by reducing the tumor size and the number of animals with invasive tumors. Chemosensitive HKESC-2 xenografts were irresponsive to combined YQ23 and cisplatin treatment. CONCLUSIONS: In all, YQ23 functions selectively on chemoresistant ESCC xenografts, which implicates its potential use as a chemosensitizing agent for ESCC patients.


Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Esofágicas/tratamento farmacológico , Hemoglobinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Sinergismo Farmacológico , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Fluoruracila/farmacologia , Humanos , Masculino , Camundongos Nus , Oxigênio/metabolismo , Carga Tumoral/efeitos dos fármacos
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