HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations.

AbstractPURPOSE:
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.
AuthorsHitoshi Kiyoi, Yukimasa Shiotsu, Kazutaka Ozeki, Satomi Yamaji, Hiroshi Kosugi, Hiroshi Umehara, Makiko Shimizu, Hitoshi Arai, Kenichi Ishii, Shiro Akinaga, Tomoki Naoe
JournalClinical 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
PMID17671144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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
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)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: