Abstract | 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.
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Authors | Hitoshi Kiyoi, Yukimasa Shiotsu, Kazutaka Ozeki, Satomi Yamaji, Hiroshi Kosugi, Hiroshi Umehara, Makiko Shimizu, Hitoshi Arai, Kenichi Ishii, Shiro Akinaga, Tomoki Naoe |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 13
Issue 15 Pt 1
Pg. 4575-82
(Aug 01 2007)
ISSN: 1078-0432 [Print] United States |
PMID | 17671144
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antimetabolites, Antineoplastic
- Antineoplastic Agents
- Enzyme Inhibitors
- FI-700
- Pyridines
- Pyrimidines
- STAT5 Transcription Factor
- Cytarabine
- FLT3 protein, human
- Flt3 protein, mouse
- fms-Like Tyrosine Kinase 3
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Topics |
- Administration, Oral
- Animals
- Antimetabolites, Antineoplastic
(pharmacology)
- Antineoplastic Agents
(pharmacology)
- Blotting, Western
- Cell Proliferation
(drug effects)
- Cytarabine
(pharmacology)
- Drug Therapy, Combination
- Enzyme Inhibitors
(pharmacology)
- Humans
- Leukemia
(genetics, pathology)
- Mice
- Mice, Inbred C3H
- Mice, SCID
- Mutation
(genetics)
- Pyridines
(pharmacology)
- Pyrimidines
(pharmacology)
- STAT5 Transcription Factor
(genetics)
- Signal Transduction
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
- fms-Like Tyrosine Kinase 3
(antagonists & inhibitors, genetics)
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