論文 - 詳細
| RRC ID | 43069 |
|---|---|
| 著者 | Kiyoi H, Shiotsu Y, Ozeki K, Yamaji S, Kosugi H, Umehara H, Shimizu M, Arai H, Ishii K, Akinaga S, Naoe T. |
| タイトル | A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations. |
| ジャーナル | Clin Cancer Res |
| 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. |
| 巻・号 | 13(15 Pt 1) |
| ページ | 4575-82 |
| 公開日 | 2007-8-1 |
| DOI | 10.1158/1078-0432.CCR-07-0225 |
| PII | 13/15/4575 |
| PMID | 17671144 |
| MeSH | 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 Leukemia / 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* fms-Like Tyrosine Kinase 3 / genetics |
| IF | 10.107 |
| 引用数 | 29 |
| WOS 分野 | ONCOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | |