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)局部復發(fā)率

35% 19%(p<0.001)遠處復發(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)獨立的細胞殺傷作用

(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)獨立的細胞殺傷作用(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)獨立的細胞殺傷作用(e.g.霍奇金淋巴瘤)相互作用(e.g.頭頸,宮頸,非小細胞肺癌)“稀釋”毒性(e.g.霍奇金淋巴瘤)頭頸鱗癌：對照-無化療

Pignonetal.,Lancet355:949-955,2000頭頸鱗癌：對照-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增強無相互作用抑制放化療綜合治療在人類鱗癌細胞株(SQD9)中dFdC對放射的增強作用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用調(diào)整DNA/染色體的修復調(diào)節(jié)腫瘤細胞增殖增加腫瘤細胞丟失加強放療導致的核苷類似物誘導的凋亡作用增加腫瘤細胞再充氧放化療綜合治療：細胞水平/分子水平相互作用DNA損傷染色體細胞凋亡誘導修復異常周期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：細胞水平/分子水平相互作用DNAdamageChromosomeCellApoptosisinductionrepairaberrationCycleCis-platinumBCNUCyclophosphamide+???++??---?????烷化劑放化療綜合治療：細胞水平/分子水平相互作用放化療綜合治療細胞水平

/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再增殖延緩進行調(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