《抗肿瘤药PPT课件》由会员分享，可在线阅读，更多相关《抗肿瘤药PPT课件（60页珍藏版）》请在金锄头文库上搜索。
1、ANTINEOPLASTICAGENTS（抗肿瘤药）（抗肿瘤药）1SECTION1Introduction（概述）概述）SECTION2AgentsdirectlyactingonDNA（作用于（作用于DNA的药物）的药物）SECTION3AgentsinterferingwithDNAsynthesis（干扰（干扰DNA合成的药物）合成的药物）SECTION4Antimitoticagents（抗有丝分裂的药物）（抗有丝分裂的药物）SECTION5Newtargetsforantineoplasticagents（抗肿瘤药物的新靶点）（抗肿瘤药物的新靶点）2SECTON1Introducti
2、onneoplasm（肿瘤）（肿瘤）The medical term for cancer or tumor is neoplasm（肿瘤）肿瘤）, which means “a relatively autonomous growth of tissue.”Tumor is a general term indicating any abnormal mass or growth of tissue, not necessarily life-threatening. A “cancerous tumor” is a malignant neoplasm with potential dan
3、ger.3sarcoma In the early embryo of a multicellular organism before organs begin to form, cells arrange themselves in three layersectodermal, mesodermal, and endodermal. Mesodermal cells form bone, muscle, cartilage, and related tissues.A cancer that arises from mesodermal tissue is calledsarcoma. 4
4、carcinomaEctodermal cells form skin, its appendages, and nerve tissue. Endodermal cells form the intestinal system and its associated organsA cancer arises from ecto- or endodermal cells is called a carcinoma. 5BlastomaThe suffix-blastomais used to indicate certain types of tumors that have primitiv
5、e appearance resembling embryonic structures. CancersofbloodA cancer of the blood involving abnormal increase of leukocytesis calledleukemia.6CellgrowthcyclesInacellsnucleus,DNAreplicationoccursduringonlyonespecificpartofthecellcycle,calledSforsynthesis.BetweendivisionandSisaperiodcalledG1inwhichcel
6、lsgrow,butdonotmakeDNA.InG1,manymoleculessuchasenzymesaresynthesized.AnotherperiodcalledG2occursbetweenSandtheperiodcalledM,duringwhichthetwoDNAcopiesseparate.7Althougheachofthesefourmainperiodsofthecellcycle(G1,S,G2,M)isunique,allinproperorderarenecessaryfornewcellproduction.Normalandcancercellsbeh
7、avedifferently.Normalcell:G1G0G1Cancercell:G1,S,G2,M G0die89SECTON2AgentsdirectlyactingonDNA（作用于作用于DNA的药物）的药物）IAlkylatingagents（烷化剂）烷化剂）IIPlatinumComplex(金属铂配合物金属铂配合物)IIIBleomycin(博来霉素类博来霉素类) IV作用于作用于DNA拓扑异构酶拓扑异构酶(topoismerase)的药物的药物10IAlkylatingagentsAlkylatingagentsarereactivecompoundsthatactonDNA
8、,RNA,andcertainenzymes.1.Nitrogenmustards2.Aziridines3.Methanesulfonateestersandmultiplealcohols4.Nitrosoureas5.Triazemylimidazole6.Hydrazinederivatives）11IAlkylatingagents（烷化剂）烷化剂）1.Nitrogenmustards（氮芥类）氮芥类）载体部分载体部分烷基化部分烷基化部分12Mechanismofnitrogenmustards1314Manyderivativesofthenitrogenmustardshaveb
9、eensynthesizedwithvariousimprovements.Theseagentsarethoughttoreactwith7positionofguanineineachofthedoublestrandsofDNA,causingcross-linking,whichinterfereswithseparationofthestrandsandpreventsmitosis.15The principle use of mechlorethamine is in combination chemotherapy of Hodgkins disease and the non
10、-Hodgkins lymphomas. It has wide activity, but more recent agents are safer and easier to use. A major disadvantage ultimately carcinogenic, effect on bone marrow stem cells, culminating in a form of acute myelogenous leukemia.MechlorethamineHydrochloride(盐酸氮芥盐酸氮芥) MechlorethaminoxideHydrochloride(盐
11、酸氧氮芥盐酸氧氮芥)*16ChlorambucilChlorambucilisusedchieflyinchroniclymphocyticleukemia,usuallyorallybecauseofitsfavorableaqueoussolubilityasthesodiumsaltandrapidconversiontothefreedrug.Sideeffectsareanorexia厌食,nausea,andvomiting.17*MelphalanItiseffectiveinmultiplemyeloma(骨髓瘤)andhashadaroleinthetreatmentofbr
12、eastandovariancancers.*Formylmerphalan()-N-Formyl-4-bis-(b b-chloroethyl)amino-phenylalanine（国产）降低毒性18Syntheticrouteofnitrogenmustards19*Cyclophosphamide(环磷酰胺环磷酰胺)N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxidemonohydrate20Ifosfamide(异环磷酰胺异环磷酰胺)Trofosfamide(曲磷胺曲磷胺)212.Aziri
13、dines（乙撑亚胺类）（乙撑亚胺类）TretamineHexamethylmelamine(Triethylenemelamine,(HMM,六甲蜜胺六甲蜜胺)TEM,三曲他胺三曲他胺,三乙蜜胺三乙蜜胺)p47222Tepa*Thiotepa(替哌替哌)(塞替哌塞替哌)23*MitomycinC(丝裂霉素丝裂霉素C)MitomycinCcontainsthreegroupsthatcandamagecells:thequinonethatcanparticipateinfreeradicalreactionsgeneratingsuperoxides,andaziridinylanduret
14、hane（乌拉坦,氨基甲酸乙酯）.24ReactionschemeforbioreductiveactivationofmitomycinCandthesubsequentinterstrandcross-linkingofDNA.253.Methanesulfonateestersandmultiplealcohols（甲磺酸酯及多元醇类）甲磺酸酯及多元醇类）*Busulfan(白消安，马利兰白消安，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双功能的烷化剂，临床对于慢性粒细胞白血病的疗效显著著26DibromomannitolDibromodulcilol(二溴甘露醇二溴甘露醇
15、)(DBD,二溴卫矛醇二溴卫矛醇)Dianhydrogalactitol(DAG,脱水卫矛醇脱水卫矛醇):R=HDiacetyldianhydrogalactitol(DADAG,脱水卫矛醇双乙酰化物脱水卫矛醇双乙酰化物):R=-COCH327*Carmustine, BCNU（卡莫司汀卡莫司汀,卡氮芥）卡氮芥）N,N-Bis(2-chloroethyl)-N-nitrosourea4.Nitrosoureas（亚硝基脲类）亚硝基脲类）28*SyntheticrouteofCarmustine(BCNU,卡莫司汀卡莫司汀,卡氮芥卡氮芥)29Lomustine(CCNU,洛莫司汀洛莫司汀):R=
16、Semustine(Me-CCNU,司莫司汀司莫司汀):R=Nimustine(ACNU,盐酸尼莫司汀盐酸尼莫司汀):R=Ranimustine(雷莫司汀雷莫司汀):R=30Decompositionofchloroethylnitrosoureas.氨甲酰化31Streptozotocin(链左托星链左托星):R=CH3Chlorozotocin(DCNU,氯脲霉素氯脲霉素):R=CH2CH2Cl325.Triazemylimidazole（三氮烯咪唑类）三氮烯咪唑类）*Dacarbazine(DTIC,达卡巴嗪达卡巴嗪)5-(3,3-dimethyl-1-triazemyl)-imidaz
17、ole-4-carboxamide临床用于黑色素病，何杰金氏病的治疗33Bioactivationofdacarbazine.346.Hydrazinederivatives（肼类）肼类）*ProcarbazineHydrochloride(丙卡巴肼，甲基苄肼丙卡巴肼，甲基苄肼)N-isopropyl-(2-methyl-hydrazino-p-toluamide hydrochloride)35BioactivationofProcarbazinehydrochloridein vivo.p47936IIPlatinumComplex(金属铂配合物金属铂配合物)*Cisplatin(顺铂顺铂
18、)Cisplatinisthemostactivesingleagentagainstnonseminomatous(非精原细胞瘤的)testicularcancer,andcombinatedwithvinblastineandbleomycin,itisusuallycurative.Itisalsothemostactivesingleagentagainstovariancancer.Otherapplicationincludetreatmentofsquamousandtransitionalcellcarcinomas,andtreatmentofsmall-celllungca
19、ncer.37IIIBleomycin(博来霉素类博来霉素类)Bleomycinisagroupofglycopeptides,withantitumoractivity,isolatedfromStreptomycesverticillus（放线菌）（放线菌）.TheclinicalpreprationisamixtureofbleomycinA2,A2I,B1-4,etc,withA2thepredominantcomponent.BleomycincausesstrandscissionandfragmentofDNA.Itactsintheformofacupriccomplex,in
20、hibitingDNAligase.Bleomycin hs been used in basal cell carcinoma and pericardial sclerotherapy, as well as in combination therapies, especially because it lacks bone marrow toxicity and immune suppression. It has modest activity in a variety of squamous cell cancer.38BleomycinA2:X=BleomycinB2:X=Bleo
21、mycinA5:X=p48239AntitumormechanismofBleomycin.p484402.AgentsactingonTopoII(作用于作用于TopoII的抗肿瘤药物的抗肿瘤药物)嵌入型抗肿瘤药物嵌入型抗肿瘤药物L-苏氨酸苏氨酸D-缬氨酸缬氨酸L-脯氨酸脯氨酸N-甲基甘氨酸甲基甘氨酸L-N-甲基缬氨酸甲基缬氨酸放线菌素放线菌素Dp485(ActinomycinD,Dactinomycin)吩噁嗪环41ActinomycinisthemostactiveofaseriesofcyclicpentapeptidesisolatedfromStreptomycesparvulus
22、.Thechemicalstructureoftheantibioticsiscomposedofatricyclic,phenoxazin-3-onechromophoreandtwoidenticalpentapeptidelactonesgroup,aandb,attachedtothechromophore.ActinomycinbindswithDNAbyintercalationinsertionbetweenbasepairsasinasandwich,andperpendiculartothemainaxisofthehelix,asarethebasepairs.Becaus
23、eofitsflatrigidaromaticstructure,theoxazine（噁嗪）portionofactinomycincanbindnonconvalentlybetweentwosuccessivebasesinDNA,elongatingtheDNA.42p48643Doxorubicin(Adriamycin，多柔比星，阿多柔比星，阿霉素霉素)44*DaunorubicinEpirubicin(Daunomycin，柔红霉素柔红霉素)(表柔比星，表阿霉素表柔比星，表阿霉素)45Anthracyclines（蒽环类抗肿瘤抗生素）蒽环类抗肿瘤抗生素）representsama
24、jorclassofantineoplasticdrugs.Doxorubicinisprobablythemostimportantanticancerdrugavailablebecauseofitsrelativelybroadspectrumofactivity,anddaunorubicinisanimportantagentinthetreatmentofacutelymphocyticandmyelocyticleukemia.Doxorubicinhasasignificantroleinthetreatmentofsolidtumorssuchascarcinomaofthe
25、breast,lung,thyroid,andovary,aswellassofttissuesarcomas.46ZorubicinAclacinomycinA(佐柔比星佐柔比星)(阿柔比星，阿克拉霉素阿柔比星，阿克拉霉素)47*Mitoxantrone(Novantrone，米托蒽醌米托蒽醌)1,4-dihydro-5,8-bis2-(2-hydroxyethyl)amino-ethyl-amino9,10-anthracenedinoneBisantrene(比生群比生群)Twoanthracenederivativesshowedlowtoxicity,andespeciallylow
26、cardiactoxicity.48SECTION3AgentsinterferingwithDNAsynthesisIPyrimidineantagonistsIIPurinesantagonistsIIIFolicAcidAntagonists49IPyrimidineantagonists（嘧啶拮抗物）嘧啶拮抗物）1.Uracilderivatives（尿嘧啶衍生物）尿嘧啶衍生物）Fluorouracil(5-FU，氟脲嘧啶，氟脲嘧啶，5-氟尿嘧啶氟尿嘧啶)5-fluoro-2,4(1H,3H)-pyrimidinedione50Fluorouracilmustbephosphoryla
27、tedtothenucleotidetobeactiveand,assuch,inhibitsthymidylate(胸苷酸)synthetase,akeyenzymeinthebiosynthesisofDNA.Ithasatleasttwobiochemicalactionsthatmayaccountforitscytotoxicity.Itisconvertedfirsttothemonophosphates5-FUMPand5-FdMP;thelatterbindstightlytothymidylatesynthetaseandinhibitstheeventualsynthesi
28、sofDNA.Ontheotherhand,5-FUMP,afterconversionto5-FUTP,isincorporatedintoRNAandinhibitsRNAprocessingofmRNAandrRNA,andmaycauseerrorsinbasepairingduringRNAtranscription.51AntitumorMechanismofFluorouracil.52HydrolysisofFluorouracil.53IIPurinesantagonists(嘌呤拮抗物嘌呤拮抗物)*6-MercaptopurineHypoxanthine546-MPisin
29、activeuntilmetabolizedtotheirrespectivemonophosphateribonucleotides,whichresultfromactionoftheenzymehypoxanthine-guaninephosphoribosyltransferase(HGPRTase).Themonophosphatescaninhibitdenovopurinesynthesis,i.e.,theformationofadenylicandguanylicacidesfrominosinicacid.Furtherphosphorylationgivesthetrip
30、hosphatenucleotides.55SulfomercaprineSodium(磺巯嘌呤钠，溶癌呤磺巯嘌呤钠，溶癌呤)Sodium6-mercaptopurine-S-sulfonatedihydrate56磺巯嘌呤钠与巯嘌呤的合成路线磺巯嘌呤钠与巯嘌呤的合成路线57Azathioprine6-ThioguaninePentostatin(6-AP,硫唑嘌呤硫唑嘌呤)(6-TG,硫鸟嘌呤硫鸟嘌呤)(喷司他喷司他丁丁)口服吸收良好对腺苷酸脱氨酶有抑制作用58IIIFolicAcidAntagonists(叶酸拮抗物叶酸拮抗物)FolicAcid(叶酸叶酸)Aminopterin(氨基蝶呤
31、，白血宁氨基蝶呤，白血宁)59*Methotrexate(MTX,甲氨蝶呤甲氨蝶呤)N-4-2,4-diamino-6-pteridinylmethylmethyl-amino-benzoyl-L-glutamicacidMethotrexate acts as an antifolate by binding almost irreversibly to the enzyme dihydrofolatereductase and preventing the formation of the coenzyme tetrahydrofolic acids, essential for DNA synthesis and for replication of animal cells.60
