第十七章抗肿瘤药（AntineoplasticAgents

1ANTINEOPLASTICAGENTS（抗肿瘤药）2SECTION1Introduction（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）3SECTON1Introductionneoplasm（肿瘤）•Themedicaltermforcancerortumorisneoplasm（肿瘤）,whichmeans“arelativelyautonomousgrowthoftissue.”•Tumorisageneraltermindicatinganyabnormalmassorgrowthoftissue,notnecessarilylife-threatening.•A“canceroustumor”isamalignantneoplasmwithpotentialdanger.4sarcoma•Intheearlyembryoofamulticellularorganismbeforeorgansbegintoform,cellsarrangethemselvesinthreelayers—ectodermal,mesodermal,andendodermal.•Mesodermalcellsformbone,muscle,cartilage,andrelatedtissues.Acancerthatarisesfrommesodermaltissueiscalledsarcoma..5carcinoma•Ectodermalcellsformskin,itsappendages,andnervetissue.Endodermalcellsformtheintestinalsystemanditsassociatedorgans•Acancerarisesfromecto-orendodermalcellsiscalledacarcinoma.6Blastoma•Thesuffix-blastomaisusedtoindicatecertaintypesoftumorsthathaveprimitiveappearanceresemblingembryonicstructures.Cancersofblood•Acancerofthebloodinvolvingabnormalincreaseofleukocytesiscalledleukemia.7Cellgrowthcycles•Inacell’snucleus,DNAreplicationoccursduringonlyonespecificpartofthecellcycle,calledSforsynthesis.BetweendivisionandSisaperiodcalledG1inwhichcellsgrow,butdonotmakeDNA.InG1,manymoleculessuchasenzymesaresynthesized.AnotherperiodcalledG2occursbetweenSandtheperiodcalledM,duringwhichthetwoDNAcopiesseparate.8•Althougheachofthesefourmainperiodsofthecellcycle(G1,S,G2,M)isunique,allinproperorderarenecessaryfornewcellproduction.Normalandcancercellsbehavedifferently.•Normalcell:G1→G0→G1•Cancercell:G1,S,G2,M→G0→die910SECTON2AgentsdirectlyactingonDNA（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11IAlkylatingagentsAlkylatingagentsarereactivecompoundsthatactonDNA,RNA,andcertainenzymes.1.Nitrogenmustards2.Aziridines3.Methanesulfonateestersandmultiplealcohols4.Nitrosoureas5.Triazemylimidazole6.Hydrazinederivatives）12IAlkylatingagents（烷化剂）1.Nitrogenmustards（氮芥类）载体部分烷基化部分NCH2CH2ClCH2CH2ClRSCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClH13MechanismofnitrogenmustardsNCH2CH2ClCH2CH2ClRN+CH2CH2CH2ClRH2CN+CH2CH2CH2XRH2CX-NCH2CH2XCH2CH2ClR-Cl--Cl-Y-NCH2CH2XCH2CH2YR14NNNNNH2HadenineHNNNNOHH2NguanineHNNOHOHNNOHCH3ONNNH2HOcytosineuracilthymine15Manyderivativesofthenitrogenmustardshavebeensynthesizedwithvariousimprovements.Theseagentsarethoughttoreactwith7positionofguanineineachofthedoublestrandsofDNA,causingcross-linking,whichinterfereswithseparationofthestrandsandpreventsmitosis.16TheprincipleuseofmechlorethamineisincombinationchemotherapyofHodgkin’sdiseaseandthenon-Hodgkin’slymphomas.Ithaswideactivity,butmorerecentagentsaresaferandeasiertouse.Amajordisadvantageultimatelycarcinogenic,effectonbonemarrowstemcells,culminatinginaformofacutemyelogenousleukemia.HClNCH2CH2ClCH2CH2ClCH3HClNCH2CH2ClCH2CH2ClCH3OMechlorethamineHydrochloride(盐酸氮芥)MechlorethaminoxideHydrochloride(盐酸氧氮芥)*17ChlorambucilChlorambucilisusedchieflyinchroniclymphocyticleukemia,usuallyorallybecauseofitsfavorableaqueoussolubilityasthesodiumsaltandrapidconversiontothefreedrug.Sideeffectsareanorexia厌食,nausea,andvomiting.N(CH2CH2Cl)2(CH2)3HOOC18*MelphalanItiseffectiveinmultiplemyeloma(骨髓瘤)andhashadaroleinthetreatmentofbreastandovariancancers.*Formylmerphalan(±)-N-Formyl-4-[bis-(b-chloroethyl)amino]-phenylalanine（国产）降低毒性N(CH2CH2Cl)2CH2CHHOOCNH2CH2NCHCOOHNHCHOClCH2CH2ClCH2CH219SyntheticrouteofnitrogenmustardsNRCH2CH2ClCH2CH2ClSOCl2NRCH2CH2OHCH2CH2OH20*Cyclophosphamide(环磷酰胺)N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxidemonohydrateH2OPNClCH2CH2ClCH2CH2ONOH21Ifosfamide(异环磷酰胺)Trofosfamide(曲磷胺)PO(ClCH2CH2)2NCH2CH2ClNOPOClCH2CH2NHCH2CH2ClNO222.Aziridines（乙撑亚胺类）TretamineHexamethylmelamine(Triethylenemelamine,(HMM,六甲蜜胺)TEM,三曲他胺,三乙蜜胺)NNNNNNCH2H2CH2CH2CCH2CH2NNNNNNCH3H3CCH3CH3H3CH3Cp47223Tepa*Thiotepa(替哌)(塞替哌)PSNNNPONNN24*MitomycinC(丝裂霉素C)MitomycinCcontainsthreegroupsthatcandamagecells:thequinonethatcanparticipateinfreeradicalreactionsgeneratingsuperoxides,andaziridinylandurethane（乌拉坦,氨基甲酸乙酯）.OOH2NCH3NOCNH2NHOCH3O25ReactionschemeforbioreductiveactivationofmitomycinCandthesubsequentinterstrandcross-linkingofDNA.DNA-CH3OH2H+e-,Enzyme[H]etcHO2+OOH2NCH3NNHDNAO2DNAOHOHH2NCH3NNHOHOHH2NCH3NOCNH2NHOOHOHH2NCH3NOCNH2NHOCH3OO-O-H2NCH3NOCNH2NHOCH3OOOH2NCH3NOCNH2NHOCH3O263.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SOCH3OO(CH2)4OSOOCH327DibromomannitolDibromodulcilol(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=-COCH3H2CCOHCHCORHOROCH2CCCBrCH2HOHCHOHHOHCCH2BrOHHCCBrCH2HOHCOHHHOHCCH2BrHOH28*Carmustine,BCNU（卡莫司汀,卡氮芥）CNHNCH2CH2ClClH2CH2CNOON,N’-Bis(2-chloroethyl)-N-nitrosourea4.Nitrosoureas（亚硝基脲类）29*SyntheticrouteofCarmustine(BCNU,卡莫司汀,卡氮芥)NCClCH2CH2NONHCH2CH2ClOHCOOHNaNO2DMFH2NCH2CH2OHNHOOCH2NH2NOHOCH2CH2NHCONHCH2CH2OHSOCl2HOCH2CH2NH2+CClCH2CH2NHClCH2CH2NHO30Lomustine