A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines 英文参考文献.docVIP

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A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines 英文参考文献.doc

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A Comparison of Azacitidine and Decitabine Activities in Acute Myeloid Leukemia Cell Lines 英文参考文献

AComparisonofAzacitidineandDecitabineActivitiesin AcuteMyeloidLeukemiaCellLines PaulW.Hollenbach1,AaronN.Nguyen1,HelenBrady1,MichelleWilliams2,YuhongNing1 ,Normand Richard1,LeslieKrushel2,SharonL.Aukerman1,CarlaHeise1,KyleJ.MacBeth1* 1CelgeneCorporation,SanFrancisco,California,UnitedStatesofAmerica,2DepartmentofBiochemistryandMolecularGenetics,UniversityofColoradoDenverSchoolof Medicine,Aurora,Colorado,UnitedStatesofAmerica Abstract Background:Thecytidinenucleosideanalogsazacitidine(AZA)anddecitabine(DAC)areusedforthetreatmentofpatients withmyelodysplasticsyndromesandacutemyeloidleukemia(AML).Fewnon-clinicalstudieshavedirectlycomparedthe mechanismsofactionoftheseagentsinahead-to-headfashion,andtheagentsareoftenviewedasmechanisticallysimilar DNA hypomethylating agents. To better understand the similarities and differences in mechanisms of these drugs, we comparedtheirinvitroeffectsonseveralendpointsinhumanAMLcelllines. Methodology/PrincipalFindings:BothdrugseffectedDNAmethyltransferase1depletion,DNAhypomethylation,andDNA damageinduction,withDACshowingequivalentactivityatconcentrations2-to10-foldlowerthanAZA.Atconcentrations above1mM,AZAhadagreatereffectthanDAConreducingcellviability.Bothdrugsincreasedthesub-G1fractionand apoptosismarkers,withAZAdecreasingallcellcyclephasesandDACcausinganincreaseinG2-M.Totalproteinsynthesis wasreducedonlybyAZA,anddrug-modulatedgeneexpressionprofileswerelargelynon-overlapping. Conclusions/Significance: These data demonstrate shared mechanisms of action of AZA and DAC on DNA-mediated markers of activity, but distinctly different effects in their actions on cell viability, protein synthesis, cell cycle, and gene expression.ThedifferentialeffectsofAZAmaybemediatedbyRNAincorporation,asthedistributionofAZAinnucleicacid ofKG-1acellswas65:35,RNA:DNA. Citation:HollenbachPW,NguyenAN,BradyH,WilliamsM,NingY,etal.(2010)AComparisonofAzacitidineandDecitabineActivitiesinAcuteMyeloidLeukemia CellLines.PLoSONE5(2):e9001.doi:10.1371/journal.pone.00090