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Inhibition of Cellular Proliferation by Gleevec

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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REFERENCES:FletcherL.(2001)Approvalheraldsnewgenerationofkinaseinhibitors?Nat.Biotechnol.,19(7):599-600Gorre,M.E.etal.(2001)ClinicalresistancetoSTI-571cancertherapycausedbyBCR-ABLgenemutationoramplification.Science293:876-880;Mauro,M.J.,Druker,B.J.(2001)STI571:targetingBCR-ABLastherapyforCML.Oncologist6(3),233-8Pestell,K.(2001)Anti-cancerdrugsuccessemergesfrommolecularBIOLOGyorigins.TrendsPharmacol.Sci.,22(7),342Sattler,M.,Griffin,J.D.(2001)MechanismsoftransformationbytheBCR/ABLoncogene.IntJHematol73(3),278-91Xie,S.etal.(2001)InvolvementofJak2tyrosinephosphorylationinBcr-Abltransformation.Oncogene,20(43),6188-95

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