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Targeting both HIF-1 and HIF-2 in human colon cancer cells improves tumor response to sunitinib treatment.
Burkitt, Kyunghee; Chun, Sang Y; Dang, Duyen T; Dang, Long H.
Afiliação
  • Burkitt K; Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.
Mol Cancer Ther ; 8(5): 1148-56, 2009 May.
Article em En | MEDLINE | ID: mdl-19435875
Sunitinib is an oral small-molecule multitargeted receptor tyrosine kinase inhibitor that has recently been shown to have clinical benefit as a single agent in renal cell cancer and gastrointestinal stromal tumors, leading to its Food and Drug Administration approval for treatment of these cancers. However, the benefit is short-lived; and for the majority of cancers, sunitinib single-agent clinical activity is low. Therefore, combination strategies with sunitinib are currently in clinical development. The hypoxia-inducible transcription factors, HIF-1 and HIF-2, induce gene programs important for cancer cell growth and angiogenesis. We hypothesized that inhibiting HIF-1 and HIF-2 would further improve tumor response to sunitinib therapy. To test this hypothesis, HIF-1α and HIF-2α genes were disrupted in colon cancer cells. We found that disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes led to improved tumor response to sunitinib. For xenografts in which both HIF-1α and HIF-2α genes were disrupted, there was prolonged complete remission with sunitinib treatment in 50% of mice. This enhanced response was mediated by two potential mechanisms. First, tumor angiogenesis and perfusion were almost completely inhibited by sunitinib when both HIF-1α and HIF-2α genes were disrupted. The enhanced inhibitory effect on tumor angiogenesis was mediated by the inhibition of multiple proangiogenic factors, including vascular endothelial growth factor and angiopoietin-like protein 4, and the induction of the antiangiogenic factor, thrombospondin 1. Second, disruption of HIF-1α, HIF-2α, or both HIF-1α and HIF-2α genes directly inhibited tumor cell proliferation. These preclinical findings have clinical implications and suggest novel clinical trials.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirróis / Neoplasias do Colo / Fatores de Transcrição Hélice-Alça-Hélice Básicos / Subunidade alfa do Fator 1 Induzível por Hipóxia / Indóis Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Assunto da revista: ANTINEOPLASICOS Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirróis / Neoplasias do Colo / Fatores de Transcrição Hélice-Alça-Hélice Básicos / Subunidade alfa do Fator 1 Induzível por Hipóxia / Indóis Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Mol Cancer Ther Assunto da revista: ANTINEOPLASICOS Ano de publicação: 2009 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos