抗肿瘤多肽药物的作用机制及研究进展

[e-mail]150076、、。、、、、。、。、、。Ｒ979．1A2095－5375201612－0717－004doi10．13506/j．cnki．jpr．2016．12．010Ｒesearchprogressandmechanismofanti－tumorpeptidesdrugsWANGShujingLIUHuanZHAOJiankaiＲENShuangSUNWeiweiZHANGWenjunZHANGJianingZHANGHanSchoolofPharmacyHarbinUniversityofCommerceHarbin150076ChinaAbstractCancerisakindofmalignantdiseasewhichisadifficultproblemintheworld．Atpresentmanyclinicaltherapyanddrugsareunabletoavoidthedrawbackssuchaspoortargetingstrongsideeffectsanddrugresistance．Itisim-portanttolookforanti－tumordrugswhicharehigheffectivelowtoxicandeasilyavailable．Peptidesstandoutbecauseoftheirfeaturesinmanykindsofanti－tumordrugsthatdependsontheirsmallmolecularweightstrongtargetinghighactivi-tylowtoxicityeasytowearmembraneandsoon．Peptideshavegetextensiveattentionintheanti－tumorexperimentalstudyandclinicalapplication．Thispaperclassifiedanti－tumorpeptidesaccordingtothemechanismandsourcesrespectivelyin-troducedapoptosis－promotingpeptidesimmunotherapiedpeptidesfusionalpeptidesandotherpeptidesinthehopeofpro-vidingreferenceforscreeningclassifyingandstudyinganti－tumorpeptide．KeywordsAnti－tumorCellapoptosisFusionpeptidesImmunotherapy。、、、、。20151、。、、、、、、。1。2。、、3。1．13004。Tri-didemnumsolchrmBdidemninB·717··JournalofPharmaceuticalＲesearch2016Vol．35No．12B16P388≥100nmol·L－1HL－60didemninB5。AplidinedidemninB6。1．2、7。IAPCaspase3、Caspase7、Caspase9。/IAPSmac/DIABLOIAPs8。Samc/DIABLOGuo9AVPIAla－Val－Pro－Ilesmacsmac。Bcl－2BH1、BH2、BH3、BH4BH3BH3BH310。2。11。12。13。2．1。checkpointblockade14。T4CTLA－41PD－1T15。CTLA－4/PD－1PD－1/PD－L1PD－1、CTLA－4T16。2．2。17。ⅠMHCⅠ。T18。Mahesh19。MC－38TＲAMP－C1ＲNAMC－38284391290MHCⅠMS7MHCⅠ。7IC50T2Ｒeps1Adpgk。CD8。T。2．3、、。20。。Hp91HMGB1Bbox。。Diahnn21HEＲ－222。33．1Bastiaan23KahalalideFⅡ。。Sewell24ATPKF。3．210dolas-tatin1025。90%26。3．3、27。Mere15MTTA549IC5034．90μg·mL－128。·817··JournalofPharmaceuticalＲesearch2016Vol．35No．124。29。、、。4．1。CPPs。100。。TAT30。31－－6TAT－OSBP－MKK6E3TATOSBPHO8910MKK6。32。33TAT－DV1－BH3。DV1CXCＲ4CXCＲ4。DV1CXCL12CXCＲ4。BH3P53。34。4．235。VEGFVEFGＲ36。VEGFVEGFＲ37。38188Ｒe－MAG3－QKＲKＲKKSＲYKS188ＲeMAG3VEGFVEGFＲ。VEGFＲ39。4．3、。。avβ3。－－ＲGDavβ3ＲGD。HPMA－ＲGD。540。。、。。1．2012J．20162511－8．2DUQSXIENZHUANGＲB．Ｒecentdevelopmentofpep-tidedrugsandadvanceontheoryandmethodologyofpeptideinhibitordesignJ．MedChem2015113235－247．3FOSGEＲAUKHOFFMANNT．PeptidetherapeuticscurrentstatusandfuturedirectionsJ．DrugDiscovToday2015201122－128．4．KahalalideFJ．201311152－53．5．J．20104171031－1047．6MITTELMANACHUNHGPUCCIOCetal．PhaseIIclin-icaltrialofdidemninBinpatientswithrecurrentorrefractoryanaplasticastrocytomaorglioblastomamultiformeNSC325319J．InvestNewDrugs1999172179－188．7．J．201537316－22．8．smac/DIABLOJ．20074729108－110．9GUOFNIMMANAPALLIＲPAＲANAWITHANASetal．Ectopicoverex－pressionofsecondmitochondria－derivedactivatorofcaspasesSmac/DIABLOorcotreatmentwith·917··JournalofPharmaceuticalＲesearch2016Vol．35No．12N－terminusofSmac/DIA－BLOpeptidepotentiatesepothi-loneBderivative－BMS247550andApo－2L/TＲAIL－in-ducedapoptosisJ．Blood20029993419－3426．10．BH3、SMACJ．2008312273－275．11COUZIN－FＲANKELJ．CancerimmunotherapyJ．Science201334261651432－1433．12．J．201224104－8．13．J．201560333155－3157．14BＲIANJAIANFPHIDEHOO．Immune－CheckpointBlockadeandActiveImmunotherapyforGliomaJ．Cancer20131151379－1412．15POWLESTEDEＲJPFINEGDetal．MPDL3280Aanti－PD－L1treatmentleadstoclinicalctivityinmetastaticblad-dercancerJ．Nature20145157528558－562．16GUBINMMZHANGXSCHUSTEＲHetal．Checkpointblockadecancerimmunotherapytargetstumour－specificmutantantigensJ．Nature20145157528577－581．17．J．2015316857－870．18．J．2016131482－83．19MAHESHYSUCHITJQUITPetal．Predictingimmuno-genictumourmutationsbycombiningmassspectrometryandexomesequencingJ．Nature201451514001572－576．20．J．20161114125－127．21DIAHNNFCＲEBECCASILASBetal．Enhancedanti－tumorimmuneresponsesanddelayoftumordevelopmentinhumanepidermalgrowthfactorreceptor2miceimmu-nizedwithanimmunostimulatorypeptideinpolyDL－lactic－coglycolicacidnanoparticlesJ．BreastCancerＲesearch201517481－7．22LIYWENGWANGDetal．AcomplementarystrategyforenhancementofnanoparticleintracellularuptakeJ．PharmＲes20143122054－2064．23BASTIAANNMAＲJANBCONSUELOMetal．Compati-bilityandstabilityoftheinvestigationalpolypeptidemarineanticanceragentkahalalideFininfusiondevicesJ．InvestigationalNewDrugs20011119273－281．24SEWELLJMMAYEＲILANGDONSPetal．ThemechanismofactionofKahalalideFVariablecellperme-abilityinhumanhepatomacelllinesJ．EurJCancer20054111223－228．25BAIＲPETTITGＲHAMELE．Dolastatin10apowerfulcytostaticpeptidederivedfromamarineanimal．InhibitionoftubulinpolymerizationmediatedthroughthevincaalkaloidbindingdomainJ．BiochemicalPharmacology1992432637－264526．LＲJ．201124111208－1211．27．J．2012333225－228．28．TNF－αIL－2IFN－γJ．201437571－74．29．J．2015399671－675．30．TATT7J．2015501104－110．31．J．201421221800－1806．32．TAT－OSBP－MKK6EJ．2015352161－167．33．CXCＲ4D．2014．34．TAT－N15p55PIKJ．2012214292－297．35．J．20132911－335．36YINGMCHENGYLUWY．Ｒecentadvancesandstrate-giesintumorvasculaturetargetednano－drugdeliverysys-temsJ．CurrPharmDesign201521113066－3075．37LINJINYLIZXetal．188Ｒe－labeledhyperbranchedpolysulfonamineasarobusttoolfortargetedcancerdiag-n