抗肿瘤药 课件

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 cellsarrangethemselvesinthreelayers ectodermal mesodermal andendodermal Mesodermalcellsformbone muscle cartilage andrelatedtissues Acancerthatarisesfrommesodermaltissueiscalledsarcoma 5 carcinomaEctodermalcellsformskin itsappendages andnervetissue EndodermalcellsformtheintestinalsystemanditsassociatedorgansAcancerarisesfromecto orendodermalcellsiscalledacarcinoma 6 BlastomaThesuffix blastomaisusedtoindicatecertaintypesoftumorsthathaveprimitiveappearanceresemblingembryonicstructures CancersofbloodAcancerofthebloodinvolvingabnormalincreaseofleukocytesiscalledleukemia 7 Cellgrowthcycles Inacell snucleus DNAreplicationoccursduringonlyonespecificpartofthecellcycle calledSforsynthesis BetweendivisionandSisaperiodcalledG1inwhichcellsgrow butdonotmakeDNA InG1 manymoleculessuchasenzymesaresynthesized AnotherperiodcalledG2occursbetweenSandtheperiodcalledM duringwhichthetwoDNAcopiesseparate 8 Althougheachofthesefourmainperiodsofthecellcycle G1 S G2 M isunique allinproperorderarenecessaryfornewcellproduction Normalandcancercellsbehavedifferently Normalcell G1 G0 G1Cancercell G1 S G2 M G0 die 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 TheprincipleuseofmechlorethamineisincombinationchemotherapyofHodgkin sdiseaseandthenon Hodgkin slymphomas 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 ActinomycinbindswithDNAbyintercalation insertionbetweenbasepairsasinasandwich 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 bis 2 2 hydroxyethyl amino ethyl amino 9 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 MPisina