S1作用机制与临床肿瘤治疗

S-1作用机制与临床肿瘤治疗之进展Content5-FU类药物的发展与现状口服5-FU药物的特点和S-1的临床优势S-1和DPD在实体瘤的临床研究进展小结及展望25FU：发展及现状35-FU是广泛使用的化疗药物,单药或合并其他药物均有效抗瘤谱广5-FU半衰期短(6-15分钟)临床特性时间依赖剂量依赖合并生物调节剂Leucovorin可增效5-FU的代谢和作用机制FUMP5-FUFdUMPdTMPdUMPF-β-alanine（神经毒性、心脏毒性、手足综合症）DNAFUTP抑制RNA功能抑制DNA合成分解活化DPD三元化合物LV5,10-CH2-THF5FUTS85%15%半衰期非常短:6-15mins4FdUTP大肠癌Meta分析:5-FU持续静滴Vs5-FU快速推注比较（N=1219）5FU持续静滴5FU快速推注P值疗效CR3%19%2%=0.002PR12%中数生存（mo）12.1(11-13.1)11.3(10.5-12)血液毒性（3-4#）4%31%P＜10-16手足症34%13%P＜10-7522%14%Metaanal.JCO，199816：301-3085-FU的衍生物及其发展多年来，围绕如何提高5-FU的疗效并降低毒性，其研发思路主要围绕2条主线发展；不断改善结构以期待达到同样的目的添加生物调节剂提高疗效，降低不良反应为主；5-FUTegafurUFTS-1HCFU5DFURXelodaCVI给药提高疗效,减轻毒性.6口服氟尿嘧啶类药物研发历程7替加氟优福啶氟铁龙卡培他滨替吉奥8DIF:OralDPD-InhibitoryFluoropyrimidineDrugsTS-1,UFT,DoxifluridineandCapecitabine单次口服给药之5-Fu血药浓度的比较9S-1优势Tmax3.5hrs:IncreasingslowlyT1/22~4hrs:DecreasingslowlyLongerPlasmaconsof5-FUMimicCVI5-FU(1hr;0.66hr)(2hrs;0.75hr)(1.5hrs;0.75hr)(3.5hrs;2~4hrs)TmaxT1/2TmaxT1/2TmaxT1/2TmaxT1/210UFUR:Tegafur/Uracil,1:4molarratioS-1:提升疗效降低胃肠道毒性及手足综合症11DPD=dihydropyrimidinedehydrogenase;F--Ala=-fluoro--alanine;FdUMP=activeformof5-FU;GI=gastrointestinal;OPRT=orotatephosphoribosyltransferase(OPRT)骨髓毒性神经毒性手足综合症心脏毒性胃肠道毒性(腹泻,口腔炎)抗肿瘤活性F--丙氨酸5-FU肿瘤胃肠道骨髓FdUMPOPRTFdUMPFdUMPS-1:-DPD-吉美嘧啶Gimeracil奥替拉西钾Oteracil替加氟Tegafur体内代谢减少FT进入体内的每日剂量FT1,200mg1967替加氟(FT)FT600mg1976优福定(UFT)FT:Ura(1:4)FT120mg1999愛斯万(S-1)FT:CDHP:Oxo(1:0.4:1)10yrs20yrs1:1/2:1/10JpnJClinOncol2009;39(1)2–151stDIF2ndDIF12Plasma5FUS-1CI5FUCmax(ng/ml)23093AUC0-10hr(ng.h/ml)1,364728PlasmaFBALS-1CI5FUCmax(ng/ml)1981,157AUC0-10hr(ng.h/ml)1,7259,46510名胃癌患者持续静滴5-FU(250mg/m2/day)5天,洗脱期9天口服S-1(40mg/m2/Bid)28天BritishJournalofCancer(2003)89,816–820ClinicalCancerResearchVol.8,2116–2122,2002S-1与5-FU持续静滴药代动力学比较13S-1血药5Fu浓度及ACU比CVI的高但5-Fu的代谢物F-BAL浓度却比CVI低DihydropyrimidineDehydrogenase(DPD)DihydropyrimidineDehydrogenaseTheDPDistheinitialandtherate-limitingenzymeinthecatabolismofpyrimidines.Theplasmaconcentrationof5-FUisregulatedbyDPD.Morethan80%ofanadministereddoseof5-FUisenzymaticallyinactivatedbyDPD.TheactivityofDPDisexclusivelypresentinthecytosolandtheenzymeseemstobeubiquitouslyexpressedwiththehighestactivitybeingfoundintheliverandperipheralbloodmonocytes.155-FU的代谢再探讨165-FUFdUMP氟尿嘧啶脱氧核苷FdUrd5-氟-2'-脱氧尿苷H2FUra脱水氟尿嘧啶F-ß-ala氟-ß-丙氨酸dUMP脱氧尿苷酸dTMP脱氧胸苷酸DNAThymidylatesynthase胸苷酸合成酶DPD二氢嘧啶脱氢酶dThdphosphorylase胸苷磷酸化酶大肠直肠癌DPD,TS,andTP基因表达与5-Fu/LV治疗之肿瘤缓解率关系17ClinicalCancerResearchVol.6;1322-1327,2000有反应没有反应TS,DPDLargePopulationStudyAssayedspecimenssummarizedbycancertypesINTERNATIONALJOURNALOFMOLECULARMEDICINE22:709-716,2008TheproteinexpressionofTS,DPDintumortissues(T)andmatchednon-canceroustissues(N)obtainedfrompatientswithheadandneck,gastric,colorectal,breast,lungandpancreaticcancer.17,613specimensWilcoxon'stest.*p0.05;**p0.001TumorTumorNormalNormalDPDTSDPDlowTSlowDPDhighTSlowDPDlowTShighDPDhighTShighDPDTSDPDaverageTSaverageExpressionIntensityExpressionTypeTS,DPDLargePopulationStudyTS.DPDdiscussionmeeting2005TS,DPDLargePopulationStudyDPDTSmRNADPDTSProteinColonCancerGastricCancerDPDTSmRNADPDTSProteinExpressionIntensityINTERNATIONALJOURNALOFMOLECULARMEDICINE22:709-716,2008Singleagent5FU/LV10~25%UFT/LV34%S-139.5%S-1/LV57.1%Singleagent5FU/LV20%UFT28%S-146%21TS,DPDLargePopulationStudyPancreaticCancerDPDTSmRNADPDTSProteinINTERNATIONALJOURNALOFMOLECULARMEDICINE22:709-716,2008ExpressionIntensityDPDTSmRNADPDTSProteinLungCancerSingleagent5FUNAUFT8.7%S-122%Singleagent5FU0~7%UFT/LV0~17%S-121.1~37.5%)S-1+Gems44%0.67DPDTS1.99mRNAN=630%47.6%4.8%47.6%132.1(ng/mg)DPDTS23.6(ng/mg)ProteinN=1020.0%60.0%10.0%10.0%HepatocellularCarcinoma?ExtremelyHigherinDPDdistributionDPDmayplayakeyroleTS,DPDLargePopulationStudyTS.DPDdiscussionmeeting20051stlineHCCRR21.7%PFS3.7moOS16.6moHighDPDexperienceinHCC!?23S-1晚期一线肝癌(不能局部治疗)24非小细胞肺癌病人体内DPD与TS表达试验84位肺癌病人体内正常细胞与肺癌细胞之TSandDPD活性表达pmol/mgMedianMeanCancerSpecimens肿瘤组织0.0510.061NonCancerSpecimens正常组织0.0310.03925TSactivitiespmol/(mg/min)MedianMeanCancerSpecimens肿瘤组织341.4398.4NonCancerSpecimens正常组织97.9107.3DPDactivitiesBothenzymeactivitiesweresignificantlyhigherinlungcancerspecimensthaninthecorrespondingnormaltissuefromthesamespecimens.(p0.0001)Lungcancer(2005)49;47~54胰腺癌病人组织DPD活性检测12pancreaticcancerpatientsPancreatictumorsandnormalpancreatictissuessurroundingthetumorsDPDactivityMean(nmol/mgprotien/hr)Pancreatictumortissue胰腺癌组织6.59±5.36Normaltissue正常胰腺组织2.69±1.8826CancerInvestigation2000;18(6):516-20DIF第一代UFUR(UFT)临床研究进展27NSABPC-0628N.Wolmark,etal.JClinOncol24:2059-20642006PatientswithstageIIorIIIcoloncancer(N=1,608)Leucovorin500mg/m2iv(2hr)qwkx65-Fluorouracil500mg/m2ivbolusqwkx6Followby2-weekrestperiod(n=803)Tegafur-Uracil300mg/m2/dayp.o.X28daysLeucovorin90mg/dayp.o.x28daysFollowby1-weekrestperiod(n=805)3cycles5cycles24weeks-stageII:stageIII=47%:53%-StudydesignissuperiorityMedianfollow-up,5.2yrsOralTegafur-UracilisasEffectiveas5-FU29NSABPC-06PatientsNo.1,608EfficacyUFT5-FUPvalue3-yrDFS74.5%74.5%NS5-yrDFS67%68.2%NS3-yrOS85%84%NS5-yrOS78.7%78.7%NSNS=NotsignificantJClinOncol24:2059-20642006NSABPC-06Effi