卵巢癌化疗耐药机制的研究进展

(内蒙古自治区人民医院，内蒙古呼和浩特010017)卵巢癌是妇科常见的恶性肿瘤，死亡率居妇科之首。化疗是目前治疗卵巢癌的重要手段之一。化疗耐药是影响卵巢癌病人生存率的主要原因。卵巢癌化疗耐药是多基因多因素共同参与的结果。近年来卵巢癌化疗耐药相关基因成为监测预后的指标。本文从细胞内药物积聚减少、药物外排增加、药物失活增强;药物作用的靶点异常;细胞凋亡调控的异常;对DNA损伤的耐受性增加或损伤后的修复功能增强;细胞微环境的改变这几方面对化疗耐药的研究进展作一综述。卵巢癌;化疗;耐药机制R730．5A1004－2113201205－0853－07STUDYOFTHEMECHANISMSOFRESISTANCETOCHEMOTHERAPYINOVARIANCANCERJIYa－nanSuyileInnerMongoliaAutonomousRegionPeople'sHospitalHohhot010017ChinaAbstractOvariancancerisacommongynecologicmalignancyandthemortalityrateranksfirstinthegynecological．Chemotherapyisoneoftheimportantmeansforthetreatmentofovariancancer．Re-sistancetochemotherapyisthemainimpactofthesurvivalrateofpatientswithovariancancer．Poly-genicandmultifactorialareresultedoftheovariancancerresistancetochemotherapy．Inrecentyearsassociatedgeneswhichovariancancerresistancetochemotherapybecomeaindicatorstomonitortheprognosisofovariancancer．Thisarticlediscussedtheresearchprogressofchemotherapyresistancefromthefollowingaspectsincludingthereducedintracellulardrugaccumulation、increaseddrugefflux、enhanceddruginactivationtheexceptionofdrugtargetsabnormalregulationofapoptosisen-hancethetoleranceaftertheDNAdamagedorstrengthentherepairfunctionitimpairedchangedincellularmicroenvironment．KeywordsOvarianCancerChemotherapyResistancemechanisms70%FIGOⅢ、Ⅳ。115%～25%80%·358·内蒙古医学院学报2012103452012－07－092012－09－181973－。。5a20%～30%。、、DNA。1、、。。1．1多药耐药(MDR)基因MDR2。MDRmdrMDR1、MDR3。MDR7q21．1MDR1P－P－gpMDRMDR3。P－gPATP。P－gpATPATP。P－gP3。MDR1。MDR1。Seiden、MDR1。。Luan、SK-OV3A2780MDR1。MDR1mRNA。Duan4SKOV3TRAG－3。TRAG－3799bpRNATRAG－3mRNA。TRAG－3TRAG－3MDR1。TRAG－3。Horvath5LRPMRP16。。。MRP－1LRP－1。。Katsaros6MRPLRP。1．2谷胱甘肽转移酶(GST)Glutathioneγ－γ－glutamyl－cysteinesynthetaseGCSglutathionesynthetase－S－Glutathione－S－transferaseGSTs－SGlutathioneS－conjugateexportpump－。IshikawaDNA。7·458·JournalOfInnerMongoliaMedicalCollegeOct．2012Vol．34No．5。GCSbuthioninesulfoximine。buthi-oninesulfoximine。。GSTs。GSTs8α、μ、πθGSTsGSTGSTs。genetransfectionGSTs。VanDerZee9GSTGSTπ。GSTπ。VanDerZee9GSTπGSTπGreenGSTπ。VanDerZeeGST。1．3离子转运蛋白家族coppertransportersATPeoppertransportingphosphorylatedATPase。coppertransportedCTRlATP7AATP7B。ATP7AATP7BATP7AATP7B10。ATP7B11。Gob12ATP7BATP7BP＜0．01。Safaei13ATP7BcDNAATP7BATP7B60%。Ara14SKOV3。OMC6PAlATP7BSKOV3ATP7B。ATPTASamimi15ATPTA。CTRlHolzer16。CTRl35%～36%CTRl。。2。。、αββ。β17β。Mozzetti1841βⅢβmRNA。Ⅲβ。3·558·内蒙古医学院学报201210345、、。。。3、19。CaspaseCaspase。Caspase－3CaspaseCaspase－3。Caspase20。caspase－3p53。bax、bakbadCbcl－2C。caspase－3。bcl－2Ccaspase－3。caspase21。p53。p53baxbcl－2。bcl－2。bcl－2bcl－222。inhibitorofapoptosisproteinsIAPCaspaseCaspase。SurvivinIAPG2/M。SurvivinG2/M、Caspase3、23。Sur-vivin、。survivin。mRNAcaspase－324。。。survivin。25survivin。survivin。survivinsurvivin。4DNADNA。DNA。DNA526homologousrecombinationalrepairHRR、non－homologousendjoiningNHEJ、nu．cleotideexcisionrepairNER、baseexcisionrepairBERmismatchrepair．MMR。DNA27。DNA28。1breast－cancerassociatedgene1BRCA1DNA。HusainRNA·658·JournalOfInnerMongoliaMedicalCollegeOct．2012Vol．34No．5．BRCA1。BRCA1DNA。Zhou29BRCA1。30BRCA1mRNADDP。BRCA1mRNADNA。NERDNADNA31。NER。BERDNA。BERDNA、。Xrayrepaicrosscomplementing1XRCC119q13．2－13．3BER32。DNAB、DNAⅢpolyadenosinediphosphate－ribosepoly－merasePARPBER。PARP－13AB。XRCC1。MMRDNA33。DNA2MMR．MMRDNAMMR。。DNA。DNA。534。extracellularmatrixECM。ECM、。ⅥⅥ。Ⅵ。ⅥⅥ。Sherman35。。。。。。。、。1SoodAKBullerRE．DrugresistanceinovariancancerfromthelaboratorytotheclinicJ．ObstetGynecol199892312－3192DuanZBrakoraKASeidenMV．InhibitionofABCB1MDR1andABCB4MDR3expressionbysmallinterferingRNAandreversalofpaclitaxelresistanceinhu-manovariancancercellsJ．MolCancerTher200437833－8383SciutoRPasqualoniRBergomicSetal．Tc－Prognostic·758·内蒙古医学院学报201210345valueofsestamibiwashoutinpredictingresponseoflocallyadvancedbreastcancertoneoadjuvantchemotherapyJ．JNuclMed2002436745－7514DuanIFellerAJJobHceta1．TRAG－3anovelgenei-solatedfromtaxolresistanceovariancarcinomacelllineJ．Gene1999229755HorvathVBlanarovaOSvihalkova－SindlerovaLetal．PlatinumIVcomplexwithadamantylamineovercomesin-trinsicresistancetocisplatininovariancancercellsJ．GynecolOncol2006102132－406KrasznaiZTFriedlanderENagyAetal．QuantitativeandfunctionalassayofMDR1/P170－mediatedMDRinascitescellsofpatientswithovariancancerJ．AnticancerRes2005252A1187－11927SurowiakPMaternaVKaplenkoIetal．Augmentedex-pressionofmetallothioneinandglutathioneS－transferasepiasunfavourableprognosticfactorsincisplatin－treatedo-variancancerpatientsJ．VirchowsArch20054473626－6338BeeghlyAKatsarosDChenHetal．GlutathioneS－trans-ferasepolymorphismsandovariancancertreatmentandsurvivalJ．GynecolOncol20061002330－3379VanDerZeeAGHollemaHDeJongSetal．P－glycopro-teinexpressionandDNAtopoisomeraseandactivityinbeingtumorsoftheovaryandinmalignanttumorsoftheo-varybeforeandafterplatinum/cydophamidechemotherapyJ．CancerRes19915121591510KuoMTChenHHSollgISeta1．Therolesofcopper-transportersincisplatinresistanceJ．CancerMetastasisRev200726171－8311NakayamaKKanzakiATeradaKeta1．PrognosticvalueoftheCutransportingATP7Ainovariancarcinomapatientsreceivingcisplatin－basedchemotherapyJ．ClinCancerRes20041082804－281112SamimiGVarkiNMWilczynskiS．eta1．Increaseinex-opressionofth