PURPOSE: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. EXPERIMENTAL DESIGN: 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.
PURPOSE: The aim of this study was to evaluate the antileukemia activity of a novel FLT3 kinase inhibitor, FI-700. EXPERIMENTAL DESIGN: The antileukemia activity of FI-700 was evaluated in humanleukemia 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 mouseleukemia 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.
Authors: Patrick P Zarrinkar; Ruwanthi N Gunawardane; Merryl D Cramer; Michael F Gardner; Daniel Brigham; Barbara Belli; Mazen W Karaman; Keith W Pratz; Gabriel Pallares; Qi Chao; Kelly G Sprankle; Hitesh K Patel; Mark Levis; Robert C Armstrong; Joyce James; Shripad S Bhagwat Journal: Blood Date: 2009-08-04 Impact factor: 22.113
Authors: Ellen Weisberg; Rosemary Barrett; Qingsong Liu; Richard Stone; Nathanael Gray; James D Griffin Journal: Drug Resist Updat Date: 2009-05-20 Impact factor: 18.500
Authors: A S Moore; A Faisal; D Gonzalez de Castro; V Bavetsias; C Sun; B Atrash; M Valenti; A de Haven Brandon; S Avery; D Mair; F Mirabella; J Swansbury; A D J Pearson; P Workman; J Blagg; F I Raynaud; S A Eccles; S Linardopoulos Journal: Leukemia Date: 2012-02-22 Impact factor: 11.528