心腦血管藥理食管癌放療增敏研究translationvgrtchchina

心腦血管藥理食管癌放療增敏研究translationvgrtchchina高危宮頸癌患者盆腔放療結(jié)合同期化療與盆腔及腹主動(dòng)脈旁淋巴引流區(qū)放療的比較M.Morrisetal,NEJM,340:1137-1143,1999.高危宮頸癌患者盆腔放療結(jié)合同期化療與盆腔及腹主動(dòng)脈旁淋巴引流區(qū)放療的比較M.Morrisetal,NEJM,340:1137-1143,1999.

放療

放療+化療 (n=193)(n=195)5年總生存率 58% 73(p=0.004)局部復(fù)發(fā)率

35% 19%(p<0.001)遠(yuǎn)處復(fù)發(fā)轉(zhuǎn)移

33% 14%(p<0.001)放療:45Gy+腔內(nèi)治療

(totaldose≥85Gy)化療:cddp(75mg/m2,d1),5Fu(1g/m2/d,d1-4),x3放化療綜合治療空間協(xié)同作用

(e.g.乳腺癌)獨(dú)立的細(xì)胞殺傷作用

(e.g.霍奇金淋巴瘤)相互作用

(e.g.頭頸,宮頸,非小細(xì)胞肺癌)“稀釋”毒性

(e.g.霍奇金淋巴瘤)絕經(jīng)前高危乳腺癌患者術(shù)后放療和輔助化療

DanishBreastCancerCooperativeGroup82bTrialM.Overgaardetal.,N.Engl.J.Med.,337:949-955,1997放化療綜合治療空間協(xié)同作用(e.g.乳腺癌)獨(dú)立的細(xì)胞殺傷作用(e.g.霍奇金淋巴瘤)相互作用(e.g.頭頸,宮頸,非小細(xì)胞肺癌)“稀釋”毒性(e.g.霍奇金淋巴瘤)

放療

化療

化療+放療

(EF,40Gy)(MOPP/ABVD) (IF,

≤40Gy)10年總生存

80-90% 80-90% ≈90%并發(fā)癥

(RR)-白血病

11.0 70.0 ?-淋巴瘤

21.0 22.0 ?-實(shí)體腫瘤

2.8 1.1 ?-心臟

2.2-3.1 ≈1.0 ?I期和II期

霍奇金淋巴瘤(病理類型好和較好)放化療綜合治療空間協(xié)同作用(e.g.乳腺癌)獨(dú)立的細(xì)胞殺傷作用(e.g.霍奇金淋巴瘤)相互作用(e.g.頭頸,宮頸,非小細(xì)胞肺癌)“稀釋”毒性(e.g.霍奇金淋巴瘤)頭頸鱗癌：對(duì)照-無化療

Pignonetal.,Lancet355:949-955,2000頭頸鱗癌：對(duì)照-無化療Pignonetal.,Lancet355:949-955,2000放化療綜合治療DoseEffectRTRT+CHAdditivityDoseEffectRTDoseEffectRTRT+CHSupra-additivity在SA-NH腫瘤中單次放療合并氟脲嘧啶(800mg/kg)的劑量修飾因素RADIATIONDOSE(Gy)GROWTHDELAY±SE(days)6810121416182022241920212223242526272829AbsoluteGrowthDelayDMF=1.57NormalizedGrowthDelayDMF=1.2RTaloneDose(Gy)S.F.1.0E-031.0E-021.0E-011.0E+0005101520RTRT+CH放化療綜合治療1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CH1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CH1.0E-031.0E-021.0E-011.0E+0005101520Dose(Gy)S.F.RTRT+CHRedrawnfromSteel增強(qiáng)無相互作用抑制放化療綜合治療在人類鱗癌細(xì)胞株(SQD9)中dFdC對(duì)放射的增強(qiáng)作用10-410-310-210-110002468101214RxalonedFdC(5μM)for3hpriortoRxSurvivingFractionAbsorbeddose(Gy)DMF=1.3DMF=1.3DMF=1.3

(Gy-1) (Gy-2)Rx 0.30 0.02Rx+dFdC 0.38 0.04放化療合理的綜合應(yīng)用調(diào)整DNA/染色體的修復(fù)調(diào)節(jié)腫瘤細(xì)胞增殖增加腫瘤細(xì)胞丟失加強(qiáng)放療導(dǎo)致的核苷類似物誘導(dǎo)的凋亡作用增加腫瘤細(xì)胞再充氧放化療綜合治療：細(xì)胞水平/分子水平相互作用DNA損傷染色體細(xì)胞凋亡誘導(dǎo)修復(fù)異常周期5-FuMTXHUdFdCF-ara-A-??---/+?-/+---?++++?+++???--?抗代謝藥DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleVinca-alcaloidesEtoposideCamptothecineTaxanes????-+??-?--+++-/++?+-/++植物衍生藥放化療綜合治療：細(xì)胞水平/分子水平相互作用DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleAdriamycinMitomycin-CBleomycinActinomycin-D-???-/+?-+?-/+--/+?+?+????-抗生素類藥放化療綜合治療：細(xì)胞水平/分子水平相互作用DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleCis-platinumBCNUCyclophosphamide+???++??---?????烷化劑放化療綜合治療：細(xì)胞水平/分子水平相互作用放化療綜合治療細(xì)胞水平

/分子水平相互作用或組織水平相互作用?在SA-NH腫瘤中通過分割放療和氟脲嘧啶注射對(duì)再增殖延緩進(jìn)行調(diào)節(jié)5791113150510152025Timeafterfirstfraction(day)controlFludarabine(400mg/kg)q.d.x44.5Gyq.d.x4Fludarabine3hpriortoRTMeantumordiameter±se(mm)TumorradiosensitizationNormaltissueradio-toxicityEFFICACYDMF=2.0DMF=1.2TherapeuticRatio=DMFTDMFNT治療增益比的概念 Acuteeffect LateeffectAntimetabolites 5-Fu ++(GI,skin) MTX ++(GI) HU ++(GI) dFdC ++(GI) ±(lung) F-ara-A ++(GI) ±(SNC)Alkylatingagents cis-platinum ++(GI) +(kidney) BCNU ++(GI) +(lung) cyclophosphamide ++(GI,skin) +(lung, bladder,SNC)Antimetabolites adriamycine ++(GI,skin) +(heart,lung) mitomycin-C ++(GI,BM) +(lung) bleomycin ++(skin,GI) +(skin,lung) actinomycine-D ++(GI,BM,skin) +(lung)Plantderivatives Vinca-alcaloides -(GI,BM) ? Etoposide ? ? Taxanes +(GI) ?放化療綜合治療：正常組織毒副作用高危宮頸癌患者盆腔放療結(jié)合同期化療與盆腔及腹主動(dòng)脈旁淋巴引流區(qū)放療的比較M.Morrisetal,NEJM,340:1137-1143,1999.

放療

放療+化療 (n=193)(n=195)Earlytoxicity(G3-5) 10(5%) 88(45%)Earlytoxicity*(G3-5) 4(2%) 20(10%)Latetoxicity(G3-5) 22(11%) 24(12%)*

nonhematologiconlyRT:45Gy+brachytherapy(totaldose≥85Gy)Chemo:cddp(75mg/m2,d1),5Fu(1g/m2/d,d1-4),x3

高危宮頸癌患者盆腔放療結(jié)合同期化療與盆腔及腹主動(dòng)脈旁淋巴引流區(qū)放療的比較M.Morrisetal,NEJM,340:1137-1143,1999.EnhancementfactorEffectontumorcontrolEffectonnormaltissuetoxicity543212345EarlyLateLocalrelapse局部晚期頭頸鱗癌采用放化療交替治療M.Merlanoetal,NEJM,327:1115-1121,1992.EnhancementfactorEffectontumorcontrolEffectonnormaltissuetoxicityEarlyLat