多靶点抗肿瘤新药索拉非尼的临床应用及评价

:,,,Te:l(010)87788428E-mai:[e-mail]##多靶点抗肿瘤新药索拉非尼的临床应用及评价贺飞,樊英,汤致强(-,100021):R97911:A:1001-2494(2007)15-1197-0280%~85%,3%,2005,RCC2A20051230FDA,10ON-YX,,,4-{4-[3-(4--3--)-]-}--2-,11索拉非尼的甲苯磺酸盐结构式Fig1Structureofsorafenibtosylate1EGFRPDGFsc-KITFLT3RTKs[1-2]RTKs,RASGDPGTP,,VEGFsbFGFPDGFsRTKs,[3-4]:VEGFsPDGF,RAF/MEK/ERKRAFc-RAF-c-RAFb-RAF,c-RAFb-RAF/VEGFR-2VEG-FR-2VEGFR-3PDGFR-BFLT3c-KIT[5]RAF,RTKs,c-KITFLT3RTKsRAF2,c-RAFb-RAF,IC502,22,38nmol#L-1[6]FLT3,c-KIT,VEGFR2,VEGFR3PDGFR-BRTKRTK,VEGFR-2VEGFR-2VEGFR-3PDGFR-BFLT-3c-KIT,MAPKKRASNSCLCNCI-H460A549KRASBRAF,,MAPK314C/,68%:60%,80%01044L#kg-1#h-10113L#kg-1#h-10115L#kg-1#h-1,Vss,017L#kg-1:9h,6h,4h,14C,CYP,CYP2B6,2C8,2C9P450(CYP2C19)(CYP2D6)(CYP3A4),CYP2C19CYP2D6CYP3A414C,,77%,19%,5017%,[7]4(TARGETs),903Motzer,1B1,451(400mg2),452,222,#1197#200784215ChinPharmJ,2007August,Vol142No11510%2%,1(CR),10%(PR),74%,2%PR,53%,2412(P=01000001)FKSI,4522166,367,171,1961913,1519(P=01015)[8],IF-Na58,19%,CR2%[9],,137,PR7,MR5;SD75,PD31;PFS123d,OS280d,TTP129dFlaherty[10]35,100,200,400mg,2RECEIST,11PR,3114%Amaravadi[11]temozolomide58,24%,20%Welch[12]26,1PR,5CA125PR54NSCLC,(ITT)52,51,17,15,83d5,solafenib,,:5-FU/6,2,400mg;65;16,,7[8],,,;,,,5%8,:,,,,,,,REFERENCES[1]SCHLESSINGERJ1Cellsignalingbyreceptortyrosinekinases[J]1Cell,2000,103(2):211-2251[2]ZWICKE,BANGEJ,ULLRICHA1Receptortyrosinekinasesastargetsforanticancerdrugs[J]1TrendsMolMed,2002,8(1):17-231[3]BERGERSG,SONGS,MEYER-MORSEN,etal1BenefitsofTar-getingbothpericytesandendothelialcellsinthetumorvasculaturewithkinaseinhibitors[J]1JClinInvest,2003,111(9):1287-12951[4]ALAVIA,HOODJD,FRAUSTOR,etal1RoleofRafinvascularprotectionfromdistinctapoptoticstimuli[J]1Science,2003,301(5629):94-961[5]WILHELMSM,CARTERC,TANGL,etal1BAY43-9006exhib-itsbroadspectrumoralantitumoractivityandtargetstheRAF/MEK/ERKpathwayandreceptortyrosinekinasesinvolvedintumorprogressionandangiogenesis[J]1CancerRes,2003,64(19):7099-71091[6]KUMARR,ANGELINNIS,CZENEK,etal1BRAFmutationsinmetastaticmelanoma:apossibleassociationwithclinicaloutcome[J]1ClincalCancerRes,2003,9(9):3362-33681[7]STRUMBERGD,RICHLYH,HILGERRA,etal1PhaseIclinicalandpharmacokineticstudyofNovelRafkinaseandvascularendo-thelialgrowthfactorreceptorinhibitorBAY43-9006inpatientswithadvancedrefractorysolidtumors[J]1JClinOncol,2005,23(5):965-9721[8]ZHOUAP,SUNY1Recentadvancesinsorafenib:Amultipletar-getedant-itumoragent[J]1OncologyProgressNov,2006,4(6):529-5331[9]RYANCW,GOLDMANBH,LARAPN,etal1Sorafenibplusin-terferon-A2b(IFN)asfirst-linetherapyforadvancedrenalcellcar-cinoma(RCC):SWOG0412[C]1ProcASCO,2006,43:Abstr45251[10]FLAHERTYKT,BROSEM,SCHUCHTERL,etal1PhaseI/IItrialofBAY43-9006,carboplatin(C)andpaclitaxel(P)demon-stratespreliminaryantitumoractivityintheexpansionchortofpa-tientswithmetastaticmelanoma[C]1ProcClinOncol,2004,23:Abstr,75071[11]AMARAVADIRK,SCHUCHTERLM,KRAMERA,etal1Pre-liminaryresultsofarandomizedphasestudycomparingtwoschedulesoftemozolomideincombinationwithsorafenibinpatientswithadvancedmelanoma[C]1ProcASCO,2006,43:Abstr80091[12]WEICHS,HIRTEH,SCHILDERRJ,etal1PhaseIIstudyofsor-afenib(BAY43-9006)incombinationwithgemcitabineinrecur-rentepithelialovariancancer:APMHphaseconsortiumtrial[C]1ProcASCO,2006,43:Abstr50841(:2006-12-27)#1198#ChinPharmJ,2007August,Vol142No115200784215