A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations.
Clin Cancer Res
; 13(15 Pt 1): 4575-82, 2007 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-17671144
ABSTRACT
PURPOSE:
The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. EXPERIMENTALDESIGN:
The antileukemia activity of FI-700 was evaluated in human leukemia cell lines, mutant or wild-type (Wt)-FLT3-expressing mouse myeloid precursor cell line, 32D and primary acute myeloid leukemia cells, and in xenograft or syngeneic mouse leukemia models.RESULTS:
FI-700 showed a potent IC(50) value against FLT3 kinase at 20 nmol/L in an in vitro kinase assay. FI-700 showed selective growth inhibition against mutant FLT3-expressing leukemia cell lines and primary acute myeloid leukemia cells, whereas it did not affect the FLT3 ligand (FL)-driven growth of Wt-FLT3-expressing cells. These antileukemia activities were induced by the significant dephosphorylations of mutant FLT3 and STAT5, which resulted in G(1) arrest of the cell cycle. Oral administration of FI-700 induced the regression of tumors in a s.c. tumor xenograft model and increased the survival of mice in an i.v. transplanted model. Furthermore, FI-700 treatment eradicated FLT3/ITD-expressing leukemia cells, both in the peripheral blood and in the bone marrow. In this experiment, the depletion of FLT3/ITD-expressing cells by FI-700 was more significant than that of Ara-C, whereas bone marrow suppression by FI-700 was lower than that by Ara-C.CONCLUSIONS:
FI-700 is a novel and potent FLT3 inhibitor with promising antileukemia activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridinas
/
Pirimidinas
/
Leucemia
/
Inibidores Enzimáticos
/
Tirosina Quinase 3 Semelhante a fms
/
Mutação
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2007
Tipo de documento:
Article
País de afiliação:
Japão