抗肿瘤靶向药物研究现状

AdvancesinresearchonsignaltransductionmechanismsandtheirinhibitorsfortheproliferationofpulmonaryarterysmoothmusclecellsLIMing-xing1WANGYong1JIANGDe-qi12WANGYan1YUShan-shan11．DeptofPharmacyZhujiangHospitalSouthernMedicalUniversityGuangzhou510282China2．DeptofBiopharmaceuticsYulinNormalUniversityYulinGuangxi537000ChinaAbstractPulmonaryarteryhypertensionPAHisachronicprogressivediseasecharacterizedbyapersistentelevationofpul-monaryvascularpressureandthediseasewouldlimittherightventricularfunctionseverelyfailtheorganandevenleadtodeathintheend．ThehistopathologicalchangeofPAHisfea-turedbytherestructuringofpulmonaryvesselsandtheabnor-malreproductionofpulmonaryarterysmoothmusclecellsPASMCsinperipheralvesselsisthemajorpathologicalbasisofpulmonaryvascularrestructuring．Thispapermainlyreviewstheresearchadvancesonsignaltransductionmechanismsandtheirinhibitorsinpromotingtheproliferationofpulmonaryarterysmoothmusclecells．KeywordspulmonaryarteryhypertensionPASMCsprolifera-tionsignaltransductionmechanismssignaltransductioninhibi-torsprogress2015－4－151544http//．cnki．net/kcms/detail/34．1086．Ｒ．20150415．1545．002．html1221211．1000502．133000doi10．3969/j．issn．1001－1978．2015．05．005A1001－1978201505－0610－05Ｒ-05Ｒ730．5Ｒ979．1。。。。《2014》2010309196。、2015[e-mail][e-mail]、、。、。、NSCLC、。、。11．1ATP1。1．1．12001FDA1PDGF。chronicmyelogenousleukemiaCML、GISTSCLC2。3239CML463CHＲ100%12CCyＲ83%18MMＲ30%9CHＲ、CCyＲMMＲ88%、30%、22%12CHＲ、CCyＲMMＲ·016·ChinesePharmacologicalBulletin2015May315610～450%、25%、17%18CHＲ22%CCyＲ16．7%。GIST80%～90%4。、。1．1．22003FDAATPEGFＲ。ⅢBNSCLC5－6。NSCLC11%18%37%82.6%SD50%55%MST5.19.97。ⅢWJTOG34058NEJGSG0029EGFＲNSCLC。。1．1．3FDA2004NSCLC、2005EGFＲATPATP。Zhou10OPTIMAL165EGFＲNSCLCPFSNSCLC。、。1．1．42007FDAATP。PhCML。、、Ⅲ11846PhCML1CCyＲ。CML2487%、PFS64%12。、。1．21．2．12005FDA13。ＲCC、。1442。、。1．2．22006FDAGISTＲCC。Barone1534411181TTP2.8OS5．8。GISTPFSOS4。。1．2．32006FDACMLPhALL。387CMLPFSCML16。、。1．2．42007FDAEGFＲ-1-2HEＲ-2。ⅡHEＲ-217。3994PFS27.118.618。、。、。1．2．52009FDA。ＲCC、NSCLC。435ＲCC、ⅢOS30%3%PFS9.24.219。Altorki20NSCLC。、。1．2．62011FDAVEGF、EGFＲETrearrangedduringtransfection。、。21NSCLCNSCLCPFSOS。、。1．2．7VEGFＲPDGFＲ·116·ChinesePharmacologicalBulletin2015May315c-kit。22。、、。、。1．2．8FDA20121VEG-FＲ1、VEGFＲ2、VEGFＲ3ＲCC。3Ⅱ1ＲＲ44.2%TTP15.729.92ＲCCＲＲ22.6%PFS7.413.63ＲＲ55%PFS12.923。、。1．31．3．1mitogenextracellularkinaseMEK1/2EＲK1/2caspaseEＲK1/2。、、NSCLC。87NSCLC、DOCDOC9.45.2PFS5.32.1ＲＲ37%0%24。、。1．3．2MLN9708ixazomibcitrateMLN9708。ⅠMLN970825。1．3．3。20S26。27VAD++15CＲ3nCＲ5CＲ+nCＲ853．3%100．0%15/15OＲＲ86.7%。、。、、。1．3．42007FDAmTOＲmTOＲ1、2αVEGFＲCC。Ⅲ626ＲCCα-PFSOSα-28。、。1．3．52009FDAmTOＲFK506-12mTOＲmTOＲ。hypoxiainduciblefac-torHIFHIF-1VEGF29。1．3．62011FDAVEGF-APIGFVEGFＲ。2013FDAFOLFIＲI+5-+。、。2。2．1BNHL。32NHL2062.50%928.13%39.38%30。ⅢCHOP+++NHLCＲ76%EFS3.8CHOPCＲ63%EFS1531。32CHOPNHLOＲＲ79.2%OＲＲ54.2%。、、。2．2HEＲ-2HEＲ-233。HEＲ-2OＲＲ77%SD18%14．393%34。、。2．3EGFＲEGFＲEGFＲ。CＲYSTALFOLFIＲI++PFS9.9ＲＲ57.3%15%35。。·216·ChinesePharmacologicalBulletin2015May3152．42004FDA。36MetaOSPFSOSPFS。、、。2．5EGFＲ37。79OＲＲ40%28.21%38。、。3。。。1．J．201334281－3．1WangLH．TheresearchprogressofmoleculartargetedcancerdrugsJ．JMudanjiangMedUniv201334281－3．2．J．20133077526－8．2WangYJWangN．TypesoftumormoleculartargetedtherapiesandmechanismsofactionJ．ChinJPractSurg20133077526－8．3．J．2012383563－6．3MengYLiuCSLiWetal．Efficacyanalysisofimatinibintreat-mentofpatientswithchronicmyeloidleukemiaJ．JJilinUnivMedEdi2012383563－6．4．J．2012393172－5．4ZhengJFanSQ．Advanceofthetargetedanti－tumordrugswithsmallmoleculecompoundsJ．JIntOncol2012393172－5．5MaemondoMMinegishiYInoueAetal．First-linegefitinibinpatientsaged75orolderwithadvancednon-smallcelllungcancerharboringepidermalgrowthfactorreceptormutationsNEJ003studyJ．JThoracicOncol2012791417－22．6OizumiSKobayashiKInoueAetal．Qualityoflifewithge-fitinibinpatientswithEGFＲ-mutatednon-smallcelllungcancerqualityoflifeanalysisofNorthEastJapanstudygroup002trialJ．Oncologist2012176863－70．7LeeMSiuＲKTingKetal．EffectofNell-1deliveryonchon-drocyteproliferationandcartilaginousextracellularmatrixdepositionJ．TissueEngPartA20101651791－800．8MitsudomiTMoritaSYatabeYetal．Gefitinibversuscisplatinplusdocetaxelinpatientswithnon-small-celllungcancerharbou-ringmutationsoftheepidermalgrowthfactorreceptorWJTOG3405anopenlabelrandomisedphase3trialJ．LancetOncol2010112121－8．9MokTSD'arcangeloMCalifanoＲetal．Clinicaloutcomeswitherlotinibinpatientswithepidermalgrowthfactorreceptormu-tationJ．Drugs20127213－10．10ZhouCWuYLChenGetal．Erlotinibversuschemotherapyasfirst-linetreatmentforpatientswithadvancedEGFＲmutation-positivenon-small-celllungcancerOPTIMALCTONG-0802amulticentreopen-labelrandomisedphase3studyJ．LancetOncol2011128735－42．11．NilotinibJ．201228725－6．11LuZYChenY．NilotinibJ．ChinPharmInform201228725－6．12KantarjianHMGilesFJBhallaKNetal．Nilotinibiseffec-tiveinpatientswithchronicmyeloidleukemiainchronicphaseaf-terimatinibresistanceorintolerance24-monthfollow-upresultsJ．Blood201111741141－5．13．J．201239121507－13．13YuPLiuBLiJ．Ｒesearchprogressofmoleculartargetedtherapyfornon-smallcelllungcancerJ．CancerＲesPrevTreatment