Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.

Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Research Abstract Details 

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Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Abstract Text:

Mark Levis,Patrick Brown,B Douglas Smith,Adam Stine,Rosalyn Pham,Richard Stone,Daniel Deangelo,Ilene Galinsky,Frank Giles,Elihu Estey,Hagop Kantarjian,Pamela Cohen,Yanfeng Wang,Johannes Roesel,Judith E Karp,Donald Small,

We have developed a useful surrogate assay for monitoring the efficacy of FLT3 inhibition in patients treated with oral FLT3 inhibitors. The plasma inhibitory activity (PIA) for FLT3 correlates with clinical activity in patients treated with CEP-701 and PKC412. Using the PIA assay, along with in vitro phosphorylation and cytotoxicity assays in leukemia cells, we compared PKC412 and its metabolite, CGP52421, with CEP-701. While both drugs could effectively inhibit FLT3 in vitro, CEP-701 was more cytotoxic to primary samples at comparable levels of FLT3 inhibition. PKC412 appears to be more selective than CEP-701 and therefore less effective at inducing cytotoxicity in primary acute myeloid leukemia (AML) samples in vitro. However, the PKC412 metabolite CGP52421 is less selective than its parent compound, PKC412, and is more cytotoxic against primary blast samples at comparable levels of FLT3 inhibition. The plasma inhibitory activity assay represents a useful correlative tool in the development of small-molecule inhibitors. Our application of this assay has revealed that the metabolite CGP52421 may contribute a significant portion of the antileukemia activity observed in patients receiving oral PKC412. Additionally, our results suggest that nonselectivity may constitute an important component of the cytotoxic effect of FLT3 inhibitors in FLT3-mutant AML.

Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Publishing Authors By Initials

M Levis,P Brown,BD Smith,A Stine,R Pham,R Stone,D Deangelo,I Galinsky,F Giles,E Estey,H Kantarjian,P Cohen,Y Wang,J Roesel,JE Karp,D Small,

For similar enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: fms-like tyrosine kinase 3 research abstracts see: enzymes and coenzymes: enzymes: transferases: phosphotransferases: phosphotransferases (alcohol group acceptor): protein kinases: protein-tyrosine kinases: receptor protein-tyrosine kinases: fms-like tyrosine kinase 3 research

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Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Blood

VOLUME: 108

Page Numbers: 3477-83

Journal Abbreviation: Blood

ISSN: 0006-4971

DAY: 20

MONTH: 07

YEAR: 2006

Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 7603509

Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Keywords Mesh Terms:

KEYWORDS: fms-Like Tyrosine Kinase 3

MESH TERMS: antagonists & inhibitors

Chemical & Substance for Abstract: Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors. Information

Substance Name: FLT3 protein, human

Registry Number: EC 2.7.10.1

Grant and Affiliation Information for Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.

AFFILIATION: Kimmel Cancer Center at Johns Hopkins University, Baltimore, MD 21231, USA. levisma@jhmi.edu

Country: United States

AGENCY: United States NCI

GRANT: P30 CA 006973-44

ACRONYM: CA

MEDLINETA: Blood

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