Acute dasatinib exposure commits Bcr-Abl-dependent cells to apoptosis.
Blood
; 114(16): 3459-63, 2009 Oct 15.
Article
em En
| MEDLINE
| ID: mdl-19706883
ABSTRACT
Pioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells. Such acute treatments with clinically achievable dasatinib concentrations also irreversibly committed Bcr-Abl+ CML cell lines to apoptotic cell death. Potent transient Bcr-Abl inhibition using the alternative inhibitor, nilotinib, also resulted in cell death. These findings demonstrate that in vitro assays designed to model in vivo pharmacokinetics can predict clinical efficacy. Furthermore, they challenge the widely held notion that continuous target inhibition is required for optimal efficacy of kinase inhibitors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinas
/
Tiazóis
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Leucemia Mielogênica Crônica BCR-ABL Positiva
/
Proteínas de Fusão bcr-abl
/
Apoptose
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Inibidores de Proteínas Quinases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2009
Tipo de documento:
Article