| | |  | | | | Record from Web of Science® | | | | | | |
| A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo |
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| Author(s): Levis M, Allebach J, Tse KF, Zheng R, Baldwin BR, Smith BD, Jones-Bolin S, Ruggeri B, Dionne C, Small D |
| Source: BLOOD Volume: 99 Issue: 11 Pages: 3885-3891 Published: JUN 1 2002 |
| Times Cited: 214 References: 42 |
| Abstract: Constitutively activating internal tandem duplication (ITD) and point mutations of the receptor tyrosine kinase FLT3 are present in up to 41% of patients with acute myeloid leukemia (AML). These FLT3/ITD mutations are likely to be important because their presence is associated with a poor prognosis. Both types of mutations appear to activate the tyrosine kinase activity of FLT3. We describe here the identification and characterization of the Indolocarbazole derivative CEP-701 as a FLT3 inhibitor. This drug potently and selectively inhibits autophosphorylation of wild-type and constitutively activated mutant FLT3 in vitro in FLT3/ITD-transfected cells and in human FLT3-expressing myeloid leukemia-derived cell lines. We demonstrate that CEP-701 induces a cytotoxic effect on cells in a dose-responsive fashion that parallels the inhibition of FLT3. STAT5 and ERK1/2, downstream targets of FLT3 in the signaling pathway, are inhibited in response to FLT3 inhibition. In primary leukemia blasts from AML patients harboring FLT3/ITD mutations, FLT3 is also inhibited, with an associated cytotoxic response. Finally, using a mouse model of FLT3/ITD leukemia, we demonstrate that the drug inhibits FLT3 phosphorylation in vivo and prolongs survival. These findings form the basis for a planned clinical trial of CEP-701 in patients with AML harboring FLT3-activating mutations. (C) 2002 by The American Society of Hematology. |
| Document Type: Article |
| Language: English |
| Reprint Address: Small, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Oncol, Bunting Blaustein Canc Res Bldg,Rm 251,1650 Orela, Baltimore, MD 21231 USA |
Addresses:
1. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21231 USA
2. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21231 USA
3. Cephalon, W Chester, PA USA |
| Publisher: AMER SOC HEMATOLOGY, 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA |
| Subject Category: Hematology |
| IDS Number: 555QL |
| ISSN: 0006-4971 |
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| | | | | | | | | Record from Web of Science® | | | | | | | | | |