ThedrugGleevec(alsoknownasimatinibmesylateorSTI-571)wasapprovedbytheFDAin2001forthetreatmentofCML,chronicmyeloidleukemia.WhiletrADItionalcytotoxiccancertreatmentssuchaschemotherapyorradiationtherapykillalldividingcells,Gleevecactsonamoleculartargetbyamechanismthatismorespecifictocancercells.Traditionalcytotoxiccanceragentshaveserioussideeffectssuchasnausea,weightloss,hairlossandseverefatiguethatresultfromtheirlackofspecificityinkillingcells.GleevecwasdesignedasaninhibitorofaspecificreceptorassociatedwithCML,andsoproduceslessseveresideeffectsthanothercanceragents.CMLisassociatedinmostcaseswithaspecificchromosomaldefect,atranslocationbetweenchromosomes9and22thatcreatesthePhiladelphiachromosome.Thistranslocationoccursatthesiteinthegenomeofaproteintyrosinekinasecalledabl,creatingtheabnormalbcr-ablprotein,afusionoftheablgenewithanothergenecalledbcr.Thekinaseactivityofablinthebcr-ablfusionisactivatedandunregulated,drivingtheuncontrolledcellgrowthobservedinCML.Whitebloodcellscontainingthebcr-ablmutationbecomeabletoproliferateintheabsenceofgrowthfactorstheynormallyrequire.Gleevecinhibitsablkinaseactivity,helpingtoreverseuncontrolledcellgrowth.GleevecalsoinhibitsthePDGFtyrosinekinaseandthec-kittyrosinekinase.Thereareavarietyofcellularsubstratesofthebcr-ablkinasethatmaybeinvolvedincellulartransformation.Bcr-ablisassociatedwiththecytoplasmaspartofalargesignalingcomplex.Someofthedownstreamfactorsinbcr-ablsignalingincludePI3kinase/AKTandSTATtranscriptionfactors.Theactivationofbcr-ablalsorepressesapoptosisthroughinductionofanti-apoptosisfactorssuchasBad,allowingtransformedcellstodivide.JAK2kinaseactivityappearstobeonetargetofbcr-abl.Grb-2phosphorylationbybcr-ablmayplayaroleindown-regulationoftyrosinekinasesignaling.STAT5maybeinvolvedinthefailureofapoptosisinbcr-ablcells.Inadditiontosupportingtheideathatcancertherapiestargetingspecificmoleculartargetsshouldbeefficaciouswithfewersideeffects,Gleevechasalsodemonstratedthatdrugsinhibitingproteinkinasescanbedevelopedsuccessfully.Tyrosinekinasesareimportantinarangeofcellularprocesses,includingothercancers,andwillprovideadditionaldrugtargets.Gleevecitselfhasalreadydemonstratedpotentialinothercancerssuchasgastrointestinalstromaltumorthatdonotrespondtoexistingtreatments.AlthoughGleevechasproducedverystrongclinicalresponsesinpatientswithearlystageCML,patientswithlatestagediseasehavehadaninitialresponsefollowedbyarelapseofdrugresistantCMLcells.CancercellsinpatientswithGleevecresistantcancereitherhadamplificationofthebcr-ablgene,ormutationofakeyaminoacidinvolvedinbindingdrugfromthreoninetoisoleucine.

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