肿瘤化疗所致恶心呕吐的发生机制和药物治疗的研究进展-张晓静

#(Correspondingauthor),e-mail:[e-mail]张晓静　张　频#　　,100021○　化疗所致恶心、呕吐(CINV)是肿瘤患者最常见的不良反应。如果没有镇吐治疗,70%～80%接受化疗的患者会出现恶心、呕吐症状。其程度受化疗药物致吐强弱等多因素的影响。在20世纪90年代5-HT3受体阻滞剂和地塞米松的联合应用使得70%的急性CINV得到了有效的控制。近年来开发了新一代半衰期更长、亲和力更高的5-HT3受体阻滞剂palonosetron(帕洛诺司琼)。此外,随着对P物质和NK-1受体研究的深入以及NK-1受体阻滞剂aprepitant的问世,急性和迟发性CINV的完全缓解率有了进一步提高。根据近年的新进展和NCCN止吐治疗指南新版本的修订,本文综述了CINV的机制和药物治疗的研究进展。关键词　CINV　　5-HT3　NK1中图分类号　R730.53　　　文献标识码　AAdvancesinmechanismandtreatmentofchemotherapy-inducednauseaandvomitingZhangXiaojing　　ZhangPinCancerHospital,CAMS&PUMC,Beijing100021,ChinaAbstract　Chemotherapyplaysasignificantroleinthecombinedtherapyoftumour.Chemotherapeuticregimenshaveimprovedandaremorefinelytargetedthaninthepast,butchemotherapy-inducednauseaandvomiting(CINV)remainsamajorobstacleandaffectspatientssatisfactionwithtreatment.About70%～80%patientswillfaceCINVwithoutpretreatment.Effortstoimproveantiemeticcontrolfurtherareongoing.First-generationserotoninreceptorantagonistscombinedwithdexamethasonegreatlyimprovedthecontrolofCINVduringthe1990s.Thenewadvancementinvolvestheuseofanew5-HT3receptorantagonist(palono-setron)thatdiffersfromavailableserotoninantagonistsinitsmarkedlylongerhalf-life(40h)andgreaterbindingaffinityforthetype-threeserotoninreceptor.AnotherverypromisingareafocusesonsubstancePasatherapeutictarget.SubstancePexertsitseffectsbybindingtotheneurokininNK-1receptor.Studieswith348　　　　2006744　ONCOLOGYPROGRESS,July2006,Vol.4,No.4综述selectiveNK-1antagonistshavedemonstratedpromisingantiemeticactivity.Oneagentinthisnewtherapeuticclass(aprepitant)recentlyreceivedregulatoryapprovalintheUnitedStatesforuseincombinationwitha5-HT3antagonistanddexamethasone,defininganewstandardofcareforhighly-emetogenicchemotherapy.ThisreviewfocusesontheadvancesinmechanismandtreatmentofCINV.Keywords　CINV　　antiemetictherapy　　5-HT3antagonist　　NK-1antagonistOncolProg,2006,4(4)　　、(CINV),。,,70%～80%、[1,2]。、,,。,、、,。、,。CINV。1　1.1　、,,,。,、、、、。,,。,。1.2　、:,、;、、;;,,。:,、,。:,;,,,,。1.3　、CINV3[3]:1.3.1　、　24。5～6,。5-HT。1.3.2　、　24。40%～50%24～48,5～7,,,。,,P,,[4]。1.3.3　、　,。,。1.4　CINV,。、、,NCCN2006、、4(1)[5,6]。、、、、,[7～9]。2　CINV2.1　、,。(emeticcenter)。(parvi-cellularreticularformation),、、,ONCOLOGYPROGRESS,July2006,Vol.4,No.42006744　　349　　综述1　[5,6](%)90();;250mgm2;≥50mgm2;1.5gm2;;30～90≤250mgm2;;50mgm2;≤1.5gm2;;≥1gm2;();;;;;;250mgm2;50mgm2;;();();75mgm2;()10～30;100～200mgm2;;;;C;;;;;;;();50～250mgm2;;;10α;;;;;;50mgm2;;;;;;;;　　＊(chemoreceptortriggerzone,CTZ),。4。,,5-HT,5-HT3[10,11]。CTZ,。CTZ(areapos-trema),,,。CTZ,,、、、5-HT3;。、,。CINV,PNK-1CINV,NK1。。2.2　CINV。、、、,5-HTP。5-HT5-HT3;PNK-1[12]。2.2.1　5-HT5-HT3CINV　90%5-HT。5-HT3(M)、350　　　　2006744　ONCOLOGYPROGRESS,July2006,Vol.4,No.4;(areapostrema)。5-HT5-HT3。5-HT5-HT3(),、CTZ,[13～15]。5-HT3CINV,。Cubeddu5-HT,5-HT3。5-HT,[16]。2.2.2　PNK-1CINV　P11,;NKA(neurokininA、A、A)NKB(neurokininB、B)。P,G,1(NK-1)、2(NK-2)3(NK-3)。PNK-1,NK-1P。P5-HT,。、、、,P[17]。P,P。P,P,NK1,P[18]。P。NK1(NK-1、NK-2、NK-3),P,P[19]。NK-17G,,IP3,,,。NK-1,P(dorsalmotornucleusofthevagusnerve),NK-1。3　3.1　5-HT35-HT3CINV,CINV、。5-HT3:(ondansetron)、(granisetron)、(tropisetron)、(azasetron)、(dolasetron)[20],502,。(Palonosetron)5-HT3,5-HT3,40,30。48。ⅠⅡ,[21]。3Ⅲ[2,22,23],(24),2～5(1～5)。[22](0.25mg0.75mg)(100mg)。569,DDP(50mgm2)、CBP、CTX,。,。0.25mg、0.75mg100mg3CINV63%、54%52.9%,CINV54%,56.6%38.7%。CINV(0.25mg,P=0.004;0.75mg,P0.001)。ONCOLOGYPROGRESS,July2006,Vol.4,No.42006744　　351　　(5.4%)。[23]。563,0.25mg0.75mg,32mg3,CINV81%、73.5%68.6%,CINV74.1%、64.6%55.1%。0.25mg32mgCINV(P0.001)。0.25mg0.75mg32mg3[2]。667。,67%。,。CINV:59.2%(0.25mg)、65.5%(0.75mg)57%(32mg),CINV45.3%、48%38.9%,。,,。(10%)(5%)。5-HT3。CINV,,。3.2　NK-1D2,5-HT3-1。2003aprepitant、,———NK-1。5-HT3,NK-1;[24]。AprepitantNK-1,,052(520)054(523)[25,26]。DDP≥70mgm2。,aprepitant132mg,aprep-itant125mg12mg;2～3aprepitant80mg,2～48mg;32mg,20mg;2～416mg,1～3aprepitant。5CINV。,aprepitant。052,73%52%(P0.001)[25];05463%43%(P0.001)[26]。CINV(1)CINV(2～5),aprepitant(P0.001)。Aprep-itant。、、()、aprepitant(aprepitant)CINV[27]。866,99%。120mg,8mg(2)aprepitant,2～38mg(2)aprepitant;aprepitant112mg,8mg(2)aprepitant125mg,2～3aprepitant80mg。5CINV。aprepitant,50.8%42.5%(P=0.015)。CINV(1),aprepitant(75.7%vs69%,P=0.034),(2～5)aprepitant(55.4%vs49.1%)。,。,aprepitantCINV,。2006NCCN,、CINV,aprepi-tant、5-HT33,CINVaprepitant。NK-1,vofopitant(GR-205,171),CJ-11,974,CP-122,721[28],352　　　　2006744　ONCOLOGYPROGRESS,July2006,Vol.4,No.4。4　MASCC(theMultinationalAssociationofSup-portiveCareinCancer)[5]2006NCCN,(1),(2)。5　2090,5-HT3CINV,70%CINV;5-HT3palonosetron(40),,,,palonosetron()。,30%50%。P,、、、,NK-1。NK-1;。ApreptiantNK-1,CINV20%,CINV30%。NCCN。,CINVCINV,。CINV,;CINV,,CINV,CINV。2　MASCCNCCN　CINV(1)　CINV(2～5)5-HT3+DEX+NK-1DEX+NK-15-HT3+DEX+NK-1()5-HT3+DEXDEX5-HT3DEX+NK-1()DEX　5-HT3:5-HT3;DEX:;NK-1:NK-1　　　1.WiserW,BergerA.Practicalmanagementofchemotherapy-inducednauseaandvomiting.Oncology(WillistonPark),2005,19∶6372.AaproM,etal.Palonosetroniseffectiveinpreventingacuteanddelayedchemotherapy-inducednauseaandvomitinginpa-tientsrecievinghighlyemetogenicchemotherapy(HEC)[Ab-stract].SupportCareCancer,2003,11∶A173.JordanK,KasperC,SchmollHJ.Chemotherapy-in