Document Detail


Evaluation of checkpoint kinase targeting therapy in acute myeloid leukemia with complex karyotype.
MedLine Citation:
PMID:  22258035     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
There has been considerable interest in targeting cell cycle checkpoints particularly in emerging and alternative anticancer strategies. Here, we show that checkpoint abrogation by AZD7762, a potent and selective CHK1/2 kinase inhibitor enhances genotoxic treatment efficacy in immature KG1a leukemic cell line and in AML patient samples, particularly those with a complex karyotype, which display major genomic instability and chemoresistance. Furthermore, these data suggest that constitutive DNA-damage level might be useful markers to select AML patients susceptible to receive checkpoint inhibitor in combination with conventional chemotherapy. Moreover, this study demonstrates for the first time that AZD7762 inhibitor targets the CD34(+)CD38(-)CD123(+) primitive leukemic progenitors, which are responsible for the majority of AML patients relapse. Finally, CHK1 inhibition does not seem to affect clonogenic potential of normal hematopoietic progenitors.
Authors:
Christine Didier; Cécile Demur; Fanny Grimal; Denis Jullien; Stéphane Manenti; Bernard Ducommun
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-01
Journal Detail:
Title:  Cancer biology & therapy     Volume:  13     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-04-06     Completed Date:  2012-10-15     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  307-13     Citation Subset:  IM    
Affiliation:
INSERM, U1037, Cancer Research Center of Toulouse, CNRS ERL 5294, Toulouse, France. christine.didier@inserm.fr
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MeSH Terms
Descriptor/Qualifier:
Aged
Apoptosis / drug effects,  genetics
Cell Cycle Checkpoints / drug effects
Cell Line, Tumor
Humans
Karyotype
Leukemia, Myeloid, Acute / drug therapy*,  enzymology*,  genetics,  pathology
Middle Aged
Molecular Targeted Therapy
Protein Kinase Inhibitors / pharmacology*
Protein Kinases / genetics,  metabolism*
Thiophenes / pharmacology*
Urea / analogs & derivatives*,  pharmacology
Chemical
Reg. No./Substance:
0/3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; 0/Protein Kinase Inhibitors; 0/Thiophenes; 57-13-6/Urea; EC 2.7.-/Protein Kinases; EC 2.7.11.1/Checkpoint kinase 1
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