抗恶性肿瘤药

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1、高分飞抗恶性肿瘤药AntineoplasticAgents概述恶性肿瘤(malignanttumor,malignantneoplasm)，又称癌症(cancer)。全世界每年死于恶性肿瘤的患者达数百万之多，约占总死亡人数的1/4。目前人类第二大死因。WorldwideoverallannualcancerincidenceDeathratesforheartdiseaseandcanceramongpeopleyoungerandolderthanage85.癌症特点不受机体约束的增殖与细胞增殖有关的基因被开启或激活；与细

2、胞分化有关的基因被关闭或抑制；局部侵袭(localinvasiveness)转移(metastasis)低分化(lessdifferentiated)保留原组织一些特征TheAimofCancerTreatmentsPalliation——缓解症状，姑息治疗AlleviationofsymptomsIncreasedsurvivalandimprovedqualityoflifeRemission——临床治愈allmacroscopicandmicroscopicfeaturesofthecancerdisappear,th

3、oughdiseaseisknowntopersistCure——治愈allthecellsoftheclonemustbedestroyed目前主要治疗手段SixEstablishedTherapeuticModalitiesSurgery(外科手术)：实体瘤Rediotherapy(放射治疗)：鼻咽癌、早期声带癌Cytotoxicchemotherapy(化学治疗,化疗)Endocrinetherapy(内分泌治疗)Immunotherapy(免疫治疗)Biological/targetedtherapy(生物治疗)CT

4、Mtreatment(中医治疗)Multi-modalitytreatment肿瘤化疗的障碍毒性反应选择性差“杀敌一千，自损五百”耐药性不敏感从单一治疗向综合治疗从单一药物到联合用药从姑息治疗向根治治疗从细胞毒性药物向针对机制多环节新型药物抗恶性肿瘤药的三大趋势BiologicbasisofchemotherapyCellCycleandCancer细胞周期的调控1322001年生理学或医学奖LelandH.Hartwell(1939-,USA)控制点(checkpoint)RTimothyHunt(1943-,UK)周期蛋

5、白依赖性激酶(cyclindependentkinase,Cdk)PaulM.Nurse(1949-,UK)细胞周期蛋白(cyclin)CellCycleMITOSISENTRY(G2/M)ReplicationCompleteGrowth/ProteinSynthesisadequateNoDNADamageS-PHASEENTRY(G1/S)MitosisComplete?signal-cyclindegradationGrowth/ProteinSynthesis(G1CYCLINS)NoDNADamageOTHERS

6、MITOSISEXIT:?couplingtoS-phaseSPHASE:couplingtomitosisalsoinresponsetoDNAdamageG1sequenceofeventssignalingfromcellsurface生长比率(Growthfraction,GF)GF大：早期。急性白血病、何杰金病、绒癌，对药物敏感；GF小：晚期。慢性白血病、多数实体瘤，对药物敏感↓GF=肿瘤增殖期细胞数总肿瘤细胞数静止细胞群非增殖细胞群（G0期）对药物不太敏感，是复发根源。Thegrowthfractionofatu

7、mordeclinesexponentiallyovertime.Thegrowthrateofatumorpeaksbeforeitisclinicallydetectable.Tumorsizeincreasesslowly,goesthroughanexponentialphase,andslowsagainasthetumorreachesthesizeatwhichlimitationofnutrientsorauto-orhostregulatoryinfluencescanoccur.Themaximumgro

8、wthrateoccursat1/e,thepointatwhichthetumorisabout37%ofitsmaximumsize.Tumorbecomesdetectableataburdenofabout109(1cm3)cellsandkillsthepatientatatum