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Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868
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Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868
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Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868
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Journal Article
Sensitivity and gene expression profile of fresh human acute myeloid leukemia cells exposed ex vivo to AS602868
2011
Overview
PURPOSE: The need for new treatment options for acute myeloid leukemia (AML) is increasing. AS602868 is a novel investigational drug with reported activity on AML cells. METHODS: We studied gene expression profiles in AML blasts exposed to AS602868 in order to better understand its mechanism of action. We analyzed the in vitro cytotoxicity of AS602868 alone or in combination with daunorubicin, etoposide or cytarabine. To document AS602868-induced IKK2 inhibition in fresh AML cells, a flow cytometry analysis of IκB was performed. Finally, the effect of AS602868 on gene expression in fresh AML cells was analyzed. RESULTS: The results show that AML cells are globally as sensitive to AS602868 as they are to cytarabine, with large interindividual variations. Combinations with conventional antileukemic agents showed enhanced cytotoxic activity in subsets of patients. IKK2 appeared to be effectively inhibited by 100 μM AS602868 in fresh leukemic cells. Gene expression profiling and gene ontology analyses identified several groups of genes induced/inhibited by exposure to AS602868 and/or exhibiting a correlation with sensitivity to this agent in vitro. Of note, the expression of several genes related to immune function was found to be significantly altered after exposure to AS602868. CONCLUSION: These data suggest that AS602868 is cytotoxic against fresh human AML blasts and provide insights regarding the mechanisms of cytotoxicity.
Publisher
Springer Verlag
