肿瘤多药耐药性及其逆转策略

:2007202213;:2007205214:1.475004,,2.:(19752),,,,1,2:;;:R965:A:100028578(2007)10208042040(multidrugresistance,MDR)MDR,[1]1MDRMDR,,1.1MDR1.1.1P2MDRP2(P2glycoprotein,P2gp)MDR1170kD,ABC(ATP2bindingcassette)[2]P2gpATP,ATP,,MDR[3]1.1.2MDR(multidrugresistanceassociatedpro2tein,MRP)1531190kD[4]P2gp,ABCMRPMDR[5]1.1.3MDR(breastcancerresistanceprotein,BCRP)65572.6kD,ABC,BCRP[6]BCRP[7]1.1.4MDR(lungresistance2relatedprotein,LRP)110kDLRPP2gpMRPBCRP,MDR,LRP,[8]1.2MDR1.2.12S2MDR2S2(glutathione2s2transferase,GST),,GSTGST(glutathione,GSH),,GST,,1.2.2MDR(topoisomerase,Topo)DNA[9],DNA,DNA,TopoMDR,,Topo,,,,TopoMDR:;;;MDR1P2gp;Topo1.2.3CMDRC(proteinkinaseC,PKC),MDR,PKCMDR[10,11]P2gpPKC40820073410©1994-2008ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(PCD),,,bcl22p531.3.1bcl22bcl22,18(18q21)bcl22,bcl22bcl22,bcl22,[12,13]bcl22mR2NA,bcl22,[14]bcl22,1.3.2p53p53p53,DNAG1/S,DNA,p53(p53),,,MDR1/P2gpMDRc2mycrasfas/apo21bcr/ablc2erB22/neu1.4DNAMDRDNA,DNADNADNA:(1)DNA6O622DNA(062methyl2guanineDNAethyltransferaes,MGMT)DNAO6,DNA(2)(nucleotideexci2sionrepair,NER),27229DNA,NERDNADNA(3)(mismatchrepair,MMR)MMRDNA,MMR,2MDRMDR,MDR2.1MDR,MDR,MDR,:()()(A)()2.2(),MDRMDR,MRP,MDR[15]mdr12mRNA,P2gp,[16](TTD),[17](CEP)NF2B,MDR[18]RHU,MDR/P2gp[19],K256/A02[20]P2gp,VCRBEL27402[21],P2gpMRP[22]MCF27/ADR,P250820073410©1994-2008ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.[23]MCF27/ADMP2gpMCF27/ADMMDR[24]P2gp,,K562/A02,MCF27/ADM,KB/VCR[25]P2gp,MDR[26227]P2gpMCF27/ADM[28229]bcl22,[30],MDR2.3,MDRMDR1RNA,MDR2.3.1(antisenseoligodeoxynucleotides,ASODN)RNADNAMDR,MDRMDR1ASODNMDR1P2gp,[31]ASODN3’KB2A21,KB2A216.4,ASODN1.8[32]MRPASODNMCF27/VPMRPmRNA[33]P27P2gp,ASODNP27P2gp,[34],2.3.2RNARNA,,RNA,RNAmRNAmRNA,MDR[35]MRPSMMC27721/ADM,ADMDNRSMMC27721/ADMIC500.487g/ml0.328g/ml,RF97.4109.3,24h,MRPmRNA,48hMRPMRPRNAMRP,MDR[36]52FuMDR1RNA,52Fu,MDR1RNASMMC27721/ADMMDR1mRNAP2gp,SMMC27721/ADMIC5031.25%62.96%[37]RNA,MDR2.3.3RNA,mRNAGUC,RNA,,bcl22mRNAbcl22,,,[38]Kowalski[39]BCRP257RNOV,257RNOV2RzB1BCRPmRNA,IC50(the50%in2hibitoryconcentration)[40](MDR1),,MDR1HepG2MDR1mRNAP2gp,,200MDR1mRNA(RZ135RZ106)MDR1mRNAP2gp,P2gp[41]2.3.4RNARNA(RNAinter2ference,RNAi)2123RNA(smallinterferenceRNAs,siRNA)mRNA,,[42]MDR1siR2NA(pSN/mdr1apSN/mdr1b)OVCAR/AROVCAR/MDR,60820073410©1994-2008ChinaAcademicJournalElectronicPublishingHouse.Allrightsreserved.(zincribbondomain2containing1protein,ZNRD1)[43],[44]ZNRD1siRNAHL260/VCR,,P2gpbcl22,siRNAABCG2siRNARNAABCG2mRNA,ABCG2RNA[45]RNA,RNAi3,,MDR,:[1]KrishnaR,MayerLD.Multidrugresistance(MDR)incancer.Mechanisms,reversalusingmodulatorsofMDRandtheroleofMDRmodulatorsininfluencingthePharmacokineticsofanti2cancerdrug[J].EurJPharmSci,2000,11(4):2652283.[2]HigginsCF.ABCtransporters:frommicroorganismstoman.AnnuRevCellBiol,1992,8:672113.[3].P2gp[J].,2004,17(4):2572260.[4]KrishnamacharyN,CenterMS.TheMRPgeneassociatedwithanon2P2glycoproteinmultidrugresistanceencodesa1902kDamembraneboundglycoprotein[J].CancerRes,1993,53(16):365823661.[5]ZamanGJ,LankelmaJ,VanTellingenO,etal.Roleofgluta2thioneintheexportofCompoundsfromcellsbythemultidrug2resistance2associatedprotein[J].ProcNatlAcadSciUSA,1995,92(17):769027694.[6]KageK,TsukaharaS,SugiyamaT,etal.Dominant2negativein2hibitionofbreastcancerResistanceproteinasdrugeffluxpumpthroughtheinhibitionofSSdependenthomodimeriza2tion[J].IntJCancer,2002,97(5):6262630.[7]LitmanT,BrangiM,HudsonE,etal.Themultidrug2resistantphenotypeassociatedwithoverexpressionofthenewABChalf2transporter,MXR(ABCG2)[J].JCellSci,2000,113(Pt11):201122021.[8]SchefferGL,SchroeijersAB,IzquierdoMA,etal.Lungresist2ance2relatedprotein/majorvaultproteinandvaultsinmulti2drugresistantcancer[J].CurrOpinOncol,2000,12(6):5502556.[9]ZimiN,MartelliAM,SubatelliP,etal.The180kDisoformoftopoiso-meraseislocalizedinthemucleolusandbelongstothestructuralelementsofthenucleolarremnant[J].ExpCellRes,1992,200(2):4602466.[10]BeckJF,BruggerD,BrischweinK,etal.Anticancerdrug2me2diatedinductionofmultidrugresistance2associatedgenesandproteinkinaseCisozymesintheT2lymphoblastoidcelllineC2CRF2CEMandinblastsfrompatientswithacutelymphoblasticleukemias[J].JpnJCancerRes,2001,92(8):8962903.[11]BruggerD,BrischweinK,LiuC,etal.Inductionofdrugresist2anceandproteinkinaseCgenesinA2780ovariancancercellsafterincubationwithantineoplasticagentsatsublethalconcen2trations[J].AnticancerRes,2002,22(6C):422924232.[12]KuhiJS,KrajewskiS,DuranGE,etal.Spontaneousoverex2pressionofthelongformofthebal2xproteininhighlyresist2antP388leukemia[J].BrJCancer,1997,75(2):2682274.[13]BlockburnRV,GaloforoSS,BernsCM,etal.Differentialin2ductionofcelldeathinhumangliomacelllinesbysodiumni2troprusside[J].Cancer,1998,82(6):113721145.[14]BleomA,LockhorstH.Bcl22antisensetherapyinmultiplemy2eloma[J].PathoiBiol,1999,47(2):2162220.[15],,,.[J].,2004,4(17):186221863.[16].K562/A02[D].:(),2001,5.[17],,,.K562/ADM[J].,2003,18(4):3472349.[18].EAC/ADRB[D].(),2002,4.[19].RHU[D].:(),2