盐酸伊立替康致迟发性腹泻作用机制及防治的研究进展_张晓光

9920129September,2012,Vol.9,No.9100700R994.11;R979.1B1672-8629201208-0535-04。。PUBMED2001-2011。、、。。UGT1A1StudyontheDevelopmentoftheMechanismofAction,PreventionandTreatmentforIrinotecan-inducedDiarrheaZHANGXiao-guangZHANGXia(DepartmentofOncology,theMilitaryGeneralHospitalofBeijingPLA,Beijing100700,China)Abstract:ObjectiveToreviewthemechanismofirinotecan-inducedtypediarrheaandthepreventionandtherapyforit.MethodsAnalyzetheirinotecan-induceddiarrheabasedontherelevanceliteraturesearchedonthePUBMEDandCNKIfrom2001to2011.ResultsMetabolicprocessesofirinotecanisaffectedbyavarietyofmetabolicen－zymes,genesandproteins.Manydrugshavedifferenttherapeuticeffectsforthedelayeddiarrhea.ConlusionMakeanin-depthunderstandingofthemechanismofirinotecan-induceddelayeddiarrhea,whichcanfurtherimproveitssafetyandefficacy.Keywords:irinotecan;diarrhea;UGT1A1;preventionandtreatmentCPT-117--10-[4-1--1-]DNAIS。DNAII、DNA、DNA[1]。CPT-115-FU、、。-。PUBMED2001～2011。13511[2]24h、、、、。①②、③④⑤、。NCICTCν4.02[3]0～5。22.1CESSN-387--10-CPT-11100～1000[4]。CPT-11P450CYP3A4APC7--10-[4-N-5--1-]-NPC7--10-4--1--。APCSN-38[5]。NPCSN-38。CESCPT-11SN-38SN-38UGT1A1SN-38G。SN-38Gβ-SN-38CPT-11SN-38SN-38。SN-385359920129September,2012,Vol.9,No.9、。SN-38SN-38,。、[67]。BI、REC、GR、MR[8]BICPTAUCSN-38SN-38GAUC。SN-38UTG1A1CPT-11[910]。RECSN-38AUCCPT-11AUCCPT-11SN-38CECPT-11。GRSN-38GAUCSN-38AUC[8]。Iyer[11]SN-38GRTA7/TA7TA6/TA7TA6/TA650％25％。17SN-38。2.2CPT-11SN-38。SN-38UGT1A1SN-38GUGT1A1SN-38[12]。UGT1A1TATA5-8TA。6TA。TAUGT1A1。UGT1A1-UGT1A1*28TATA7TAUGT1A1SN-38G[8]。CPT-11UGT1A1*28SN-38[13]。Glimelius[14]NordicVI140CPT-115-FUUGT1A1、ABCB1、TYMSMTHFRUGT1A1*28*28。[15]UGT1A1*28CPT-11。UGT1A9UGT1A7[16]。mucinMUC。CPT-11MUC[17]。[1819]ABCATPABCB1ABCC1ABCC2andABCG2ABC。ABCB1CPT-11SN-38[2021]ABCB13435T/TC/C、C/T.CPT-11[22]。[23]ABCB1。、。Han[24]107ABCC23972CCABCG234GAorAA。OATP1B1OATP-COATP2LST1SLCO1B1。。HAN[25]CPT-11SLCO1B1-11187AAGA33SLCO1B1-388GGSLCO1B1-388GG。33.1BensonCID3、、[26]。3.1.1CPT-11TNF-α。4mg2h2mg12h48h。2010。3.1.25369920129September,2012,Vol.9,No.9,。Rosenoff14730mg/440mg/4[27]。3.1.3。10mg·L-110～153～4。0.4mg·mL-1。5mL3～4。[26]。3.23.2.1β-[28]β-,SN-38GSN-38。β-。Kehrer[29]CPT-113350mg4mg2h2mg12h21000mg3d2～5。。。3[30]。3.2.2CPT-11-αIL-6IL-1β-γ。CPT-1160mg·kg-1100mg/kg、、SN-38[3132]。。218CPT-113350mg·m-2400mg1331～2。[33]。3.2.3CPT-11SN-38SN-38。YoonKJ[34]。Hicks[4]SN-38。。3.2.4TNF-α[35]。IFN-γIL-1βTNF-αiNOS。DNA。RDP582.5、510mg·kg-1IFN-γIL-1βTNF-α[36]。3.2.5E2PGE2Na+-K+-ATP。Trifan[37]CPT-112COX-2PGE2。CPT-11230.1、0.3、1、3、10、30、50、150mg·kg-130mg·kg-1。PGE2PGE2CPT-11。3.2.6CPT-11SN-38α--Ph。。pHSN-38SN-38[38]。3.2.7SN-38CPT-11。34283/47.1%vs.25%[39]。5379920129September,2012,Vol.9,No.93.2.8CPT-11SN-3830%CPT-11。CPT-11、SN-38、SN-38G。300mg/kgd0-52/CPT-1110mg20mg20mg[40]。3.2.91。。[41]、、COX-2、。Shivaani[42]I、“PHY906”。3.2.101[43]33、、80mg+5%250mL。3。2chrysinSN-38SN-38G。Tobin[44]20CPT-113350mg·m-21210%3。3CPT-11460mg/kg400mg/kg/day8CPT-1TNF-α[45]。4、、、。UGT1A1、。、、。[1]ZhouY,GwadryFG,ReinholdWC,etal.Transcriptionalregula-tionofmitoticgenesbycamptothecin-inducedDNAdamage:microarrayanalysisofdoseandtime-dependenteffects[J].CancerRes,2002,62(6):1688-95.[2].[J].,2005,26(5):286-291.[3]SteinA,VoigtW,JordanK.Chemotherapy-induceddiarrhea:pathophysiology,frequencyandguideline-basedmanagement[J].TherAdvMedOncol.2010,2(1):51-63.[4]HicksLD,HyattJL,StoddardS,etal.Improved,se-lective,humanintestinalcarboxylesteraseinhibitorsdesignedtonodulate7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin(irinotecan;CPT-11)toxicity[J].MedChem,2009,52(12):3742-3752.[5]JessicaM.vanderBol,RonH.JMathijssen,Geert-JanM.Creemers,etal.ACYP3A4Phenotype-BasedDosingAlgorithmforIndivid-ualizedTreatmentofIrinotecan[J].ClinCancerRes,2010,2(16)736.[6]AndreaM.Stringer,RachelJ.Gibson,RichardM,etal.Irinote-can-inducedmucositisisassociatedwithchangesinintestinalmucins[J].CancerChemotherPharmacol,2009,64:123-132.[7]StringerAM,GibsonRJ,LogannRM,etal.Chemotherapy-induceddiarrheaisassociatedwithchangesintheluminalenvironmentintheDArat[J].ExpBiolMedJanuary,2007,;232(1):96-106.[8]AntonelloDiPaolo,GuidoBocci,MarialuisaPolillo,etal.Pharma-cokineticandPharmacogeneticPredictiveMarkersofIrinotecanActivityandToxicity[J].CurrentDrugMetabolism,2011,12:932-943.[9]CecchinE,InnocentiF,D'AndreaM,etal.PredictiveroleoftheUGT1A1,UGT1A7,andUGT1A9geneticvariantsandtheirhaplotypesontheoutcomeofmetastaticcolorectalcancerpatientstreatedwithfluorouracil,leucovorin,andirinotecan[J].Clin.Oncol,2009,27(15):2457-2465.[10]Ando,Y,Saka,H,Asai,G,etal.UGT1A1genotypesandglu-curonidationofSN-38,theactivemetaboliteofirinotecan[J].Ann.Oncol.,1998,9(8):845-847.2012-02-08538