抗肿瘤药.ppt

1,ANTINEOPLASTICAGENTS（抗肿瘤药）,2,SECTION1Introduction（概述）SECTION2AgentsdirectlyactingonDNA（作用于DNA的药物）SECTION3AgentsinterferingwithDNAsynthesis（干扰DNA合成的药物）SECTION4Antimitoticagents（抗有丝分裂的药物）SECTION5Newtargetsforantineoplasticagents（抗肿瘤药物的新靶点）,3,SECTON1Introduction,neoplasm（肿瘤）Themedicaltermforcancerortumorisneoplasm（肿瘤）,whichmeans“arelativelyautonomousgrowthoftissue.”Tumorisageneraltermindicatinganyabnormalmassorgrowthoftissue,notnecessarilylife-threatening.A“canceroustumor”isamalignantneoplasmwithpotentialdanger.,4,sarcomaIntheearlyembryoofamulticellularorganismbeforeorgansbegintoform,cellsarrangethemselvesinthreelayersectodermal,mesodermal,andendodermal.Mesodermalcellsformbone,muscle,cartilage,andrelatedtissues.Acancerthatarisesfrommesodermaltissueiscalledsarcoma.,5,carcinomaEctodermalcellsformskin,itsappendages,andnervetissue.EndodermalcellsformtheintestinalsystemanditsassociatedorgansAcancerarisesfromecto-orendodermalcellsiscalledacarcinoma.,6,BlastomaThesuffix-blastomaisusedtoindicatecertaintypesoftumorsthathaveprimitiveappearanceresemblingembryonicstructures.CancersofbloodAcancerofthebloodinvolvingabnormalincreaseofleukocytesiscalledleukemia.,7,Cellgrowthcycles,Inacellsnucleus,DNAreplicationoccursduringonlyonespecificpartofthecellcycle,calledSforsynthesis.BetweendivisionandSisaperiodcalledG1inwhichcellsgrow,butdonotmakeDNA.InG1,manymoleculessuchasenzymesaresynthesized.AnotherperiodcalledG2occursbetweenSandtheperiodcalledM,duringwhichthetwoDNAcopiesseparate.,8,Althougheachofthesefourmainperiodsofthecellcycle(G1,S,G2,M)isunique,allinproperorderarenecessaryfornewcellproduction.Normalandcancercellsbehavedifferently.Normalcell:G1G0G1Cancercell:G1,S,G2,MG0die,9,10,SECTON2AgentsdirectlyactingonDNA（作用于DNA的药物）,IAlkylatingagents（烷化剂）IIPlatinumComplex(金属铂配合物)IIIBleomycin(博来霉素类)IV作用于DNA拓扑异构酶(topoismerase)的药物,11,IAlkylatingagents,AlkylatingagentsarereactivecompoundsthatactonDNA,RNA,andcertainenzymes.1.Nitrogenmustards2.Aziridines3.Methanesulfonateestersandmultiplealcohols4.Nitrosoureas5.Triazemylimidazole6.Hydrazinederivatives）,12,IAlkylatingagents（烷化剂）,1.Nitrogenmustards（氮芥类）载体部分烷基化部分,13,Mechanismofnitrogenmustards,14,15,Manyderivativesofthenitrogenmustardshavebeensynthesizedwithvariousimprovements.Theseagentsarethoughttoreactwith7positionofguanineineachofthedoublestrandsofDNA,causingcross-linking,whichinterfereswithseparationofthestrandsandpreventsmitosis.,16,TheprincipleuseofmechlorethamineisincombinationchemotherapyofHodgkinsdiseaseandthenon-Hodgkinslymphomas.Ithaswideactivity,butmorerecentagentsaresaferandeasiertouse.Amajordisadvantageultimatelycarcinogenic,effectonbonemarrowstemcells,culminatinginaformofacutemyelogenousleukemia.,MechlorethamineHydrochloride(盐酸氮芥),MechlorethaminoxideHydrochloride(盐酸氧氮芥),*,17,ChlorambucilChlorambucilisusedchieflyinchroniclymphocyticleukemia,usuallyorallybecauseofitsfavorableaqueoussolubilityasthesodiumsaltandrapidconversiontothefreedrug.Sideeffectsareanorexia厌食,nausea,andvomiting.,18,*MelphalanItiseffectiveinmultiplemyeloma(骨髓瘤)andhashadaroleinthetreatmentofbreastandovariancancers.*Formylmerphalan()-N-Formyl-4-bis-(b-chloroethyl)amino-phenylalanine（国产）降低毒性,19,Syntheticrouteofnitrogenmustards,20,*Cyclophosphamide(环磷酰胺)N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxidemonohydrate,21,Ifosfamide(异环磷酰胺)Trofosfamide(曲磷胺),22,2.Aziridines（乙撑亚胺类）,TretamineHexamethylmelamine(Triethylenemelamine,(HMM,六甲蜜胺)TEM,三曲他胺,三乙蜜胺),p472,23,Tepa*Thiotepa(替哌)(塞替哌),24,*MitomycinC(丝裂霉素C)MitomycinCcontainsthreegroupsthatcandamagecells:thequinonethatcanparticipateinfreeradicalreactionsgeneratingsuperoxides,andaziridinylandurethane（乌拉坦,氨基甲酸乙酯）.,25,ReactionschemeforbioreductiveactivationofmitomycinCandthesubsequentinterstrandcross-linkingofDNA.,26,3.Methanesulfonateestersandmultiplealcohols（甲磺酸酯及多元醇类）,*Busulfan(白消安，马利兰)双功能的烷化剂，临床对于慢性粒细胞白血病的疗效显著,27,DibromomannitolDibromodulcilol(二溴甘露醇)(DBD,二溴卫矛醇),Dianhydrogalactitol(DAG,脱水卫矛醇):R=HDiacetyldianhydrogalactitol(DADAG,脱水卫矛醇双乙酰化物):R=-COCH3,28,*Carmustine,BCNU（卡莫司汀,卡氮芥）,N,N-Bis(2-chloroethyl)-N-nitrosourea,4.Nitrosoureas（亚硝基脲类）,29,*SyntheticrouteofCarmustine(BCNU,卡莫司汀,卡氮芥),30,Lomustine(CCNU,洛莫司汀):R=Semustine(Me-CCNU,司莫司汀):R=Nimustine(ACNU,盐酸尼莫司汀):R=Ranimustine(雷莫司汀):R=,31,Decompositionofchloroethylnitrosoureas.,氨甲酰化,32,Streptozotocin(链左托星):R=CH3Chlorozotocin(DCNU,氯脲霉素):R=CH2CH2Cl,33,5.Triazemylimidazole（三氮烯咪唑类）,*Dacarbazine(DTIC,达卡巴嗪)5-(3,3-dimethyl-1-triazemyl)-imidazole-4-carboxamide临床用于黑色素病，何杰金氏病的治疗,34,Bioactivationofdacarbazine.,35,6.Hydrazinederivatives（肼类）,*ProcarbazineHydrochloride(丙卡巴肼，甲基苄肼)N-isopropyl-(2-methyl-hydrazino-p-toluamidehydrochloride),36,BioactivationofProcarbazinehydrochlorideinvivo.,p479,37,IIPlatinumComplex(金属铂配合物),*Cisplatin(顺铂)Cisplatinisthemostactivesingleagentagainstnonseminomatous(非精原细胞瘤的)testicularcancer,andcombinatedwithvinblastineandbleomycin,itisusuallycurative.Itisalsothemostactivesingleagentagainstovariancancer.Otherapplicationincludetreatmentofsquamousandtransitionalcellcarcinomas,andtreatmentofsmall-celllungcancer.,38,IIIBleomycin(博来霉素类),Bleomycinisagroupofglycopeptides,withantitumoractivity,isolatedfromStreptomycesverticillus（放线菌）.TheclinicalpreprationisamixtureofbleomycinA2,A2I,B1-4,etc,withA2thepredominantcomponent.BleomycincausesstrandscissionandfragmentofDNA.Itactsintheformofacupriccomplex,inhibitingDNAligase.Bleomycinhsbeenusedinbasalcellcarcinomaandpericardialsclerotherapy,aswellasincombinationtherapies,especiallybecauseitlacksbonemarrowtoxicityandimmunesuppression.Ithasmodestactivityinavarietyofsquamouscellcancer.,39,BleomycinA2:X=BleomycinB2:X=BleomycinA5:X=,p482,40,AntitumormechanismofBleomycin.p484,41,2.AgentsactingonTopoII(作用于TopoII的抗肿瘤药物)嵌入型抗肿瘤药物,L-苏氨酸D-缬氨酸L-脯氨酸N-甲基甘氨酸L-N-甲基缬氨酸放线菌素Dp485(ActinomycinD,Dactinomycin),吩噁嗪环,42,ActinomycinisthemostactiveofaseriesofcyclicpentapeptidesisolatedfromStreptomycesparvulus.Thechemicalstructureoftheantibioticsiscomposedofatricyclic,phenoxazin-3-onechromophoreandtwoidenticalpentapeptidelactonesgroup,aandb,attachedtothechromophore.ActinomycinbindswithDNAbyintercalationinsertionbetweenbasepairsasinasandwich,andperpendiculartothemainaxisofthehelix,asarethebasepairs.Becauseofitsflatrigidaromaticstructure,theoxazine（噁嗪）portionofactinomycincanbindnonconvalentlybetweentwosuccessivebasesinDNA,elongatingtheDNA.,43,p486,44,Doxorubicin(Adriamycin，多柔比星，阿霉素),45,*DaunorubicinEpirubicin(Daunomycin，柔红霉素)(表柔比星，表阿霉素),46,Anthracyclines（蒽环类抗肿瘤抗生素）representsamajorclassofantineoplasticdrugs.Doxorubicinisprobablythemostimportantanticancerdrugavailablebecauseofitsrelativelybroadspectrumofactivity,anddaunorubicinisanimportantagentinthetreatmentofacutelymphocyticandmyelocyticleukemia.Doxorubicinhasasignificantroleinthetreatmentofsolidtumorssuchascarcinomaofthebreast,lung,thyroid,andovary,aswellassofttissuesarcomas.,47,ZorubicinAclacinomycinA(佐柔比星)(阿柔比星，阿克拉霉素),48,*Mitoxantrone(Novantrone，米托蒽醌)1,4-dihydro-5,8-bis2-(2-hydroxyethyl)amino-ethyl-amino9,10-anthracenedinoneBisantrene(比生群)Twoanthracenederivativesshowedlowtoxicity,andespeciallylowcardiactoxicity.,49,SECTION3AgentsinterferingwithDNAsynthesis,IPyrimidineantagonistsIIPurinesantagonistsIIIFolicAcidAntagonists,50,IPyrimidineantagonists（嘧啶拮抗物）1.Uracilderivatives（尿嘧啶衍生物）,Fluorouracil(5-FU，氟脲嘧啶，5-氟尿嘧啶)5-fluoro-2,4(1H,3H)-pyrimidinedione,51,Fluorouracilmustbephosphorylatedtothenucleotidetobeactiveand,assuch,inhibitsthymidylate(胸苷酸)synthetase,akeyenzymeinthebiosynthesisofDNA.Ithasatleasttwobiochemicalactionsthatmayaccountforitscytotoxicity.Itisconvertedfirsttothemonophosphates5-FUMPand5-FdMP;thelatterbindstightlytothymidylatesynthetaseandinhibitstheeventualsynthesisofDNA.Ontheotherhand,5-FUMP,afterconversionto5-FUTP,isincorporatedintoRNAandinhibitsRNAprocessingofmRNAandrRNA,andmaycauseerrorsinbasepairingduringRNAtranscription.,52,AntitumorMechanismofFluorouracil.,53,HydrolysisofFluorouracil.,54,IIPurinesantagonists(嘌呤拮抗物),*6-MercaptopurineHypoxanthine,55,6-MPisin