药理学英文版教学课件：Chapter 45 anticancer drugs

AnticancerDrugsAlsocalled:AntineoplasticDrugsCancerchemotherapeuticdrugs§1BasicPharmacologyofAnticancerDrugsI.Classificationofanticancerdrugs1.accordingtostructureAlkalytingagent(烷化剂)Antimetabolites（抗代谢药）AntitumorantibioticsPlantalkaloidsHormonalagentsOthers2.accordingtomechanismofactionDrugsaffectingbiosynthesisofnucleicacidDrugsdestroyingDNAstructureandfunctionDrugsinterferingwithtranscriptionandblockingRNAsynthesisDrugsaffectingproteinsynthesisHormonalagents3.AccordingtoEffectoncellproliferationkineticsTumorcellphaseG0phaseCellcycle:G1→S→G2→M growthfraction，GFAnticancerdrugsCellcyclenonspecificdrugs(CCNS)Cellcyclespecificdrugs(CCS)II.Mechanismsofanticancerdrugs1.mechanismofcytotoxicanticancerdrugsCellcyclenonspecificdrugs(CCNS)Cellcyclespecificdrugs(CCS)2.mechanismofnon-cytotoxicagentsBalancehormonesinthebodyInducecancercelldifferentiationInduceapoptosisofcancercellsSuppressthevasculargrowthofcancerIII.MechanismsofdrugresistanceG0cellP-glucoprotein§2Cytotoxicanticancerdrugs

I.

Drugsaffectingnucleicacidsynthesis(antimetabolites)Methothrexate(MTX,甲氨蝶呤)CCSSphaseMechanism:inhibitdihydrofolatereductase(DHFR，二氢叶酸还原酶),interferingsynthesisofthymidylate,purinenucleotidesClinicaluses:childhoodacutelymphoblasticleukemiaandchorioepithelioma（绒毛膜上皮癌）Toxicity:myelosuppression

Fluorouracil（5-Fu,氟尿嘧啶）PyrimidineantagonistsMechanism:convertto5F-dUMPandinhibitthynidylatesynthase,blockthesynthesisofdTMPClinicaluses:goodeffectoncancerofdigestivetract,breastcancerToxicity:myelosuppressionandmucositisMercaptopurine（6-MP,巯嘌呤）Mechanism:metabolizedbyHGPRTtothionosinate(T-IMP)andinhibitsynthesisofAMPandGMPfromIMPClinicaluses:childhoodacuteleukemiaToxicity:myelosuppressionandgastrointestinalsymptomsHydroyurea(Hu,羟基脲)InhibitribonucleotidereductaseClinicaluses:chronicgranulocyticleukemiaToxicity:bonemarrowdepression,nausea,vomitingCytarabine（Ara-C,阿糖胞苷）Ara-C→Ara-CMP→→Ara-CTP,competitivelyinhibitDNApolymeraseClinicaluses:acutegranulocyticleukemia,mononuclearcyteleukemiaToxicity:severemyelosuppression,nauseaetcII.DrugsdestroyingDNAstructure

andfunctionCCNSAlkylatingagentsAntitumorantibioticsCisplatin（顺铂）andcarbaplatinCamptothecins(喜树碱)1.AlkylatingagentsCyclophosphamide(CTX，环磷酰胺)CTX→aldophosphamide→phosphoramidemustardClinicaluses:malignantlymphoma,acuteleukemiaToxicity:bladderitis（膀胱炎）,alopecia（脱发）,nausea,vomiting,myelosuppressionThiotepa(TSPA,噻替派)Clinicaluses:breastcancer,ovariancancer,livercanceretcToxicity:myelosuppressionBusulfan(myleran,白消安)GoodeffectonchronicgranulocyticleukemiaToxicity:myelosuppressionNitrosoureas(亚硝基脲)Drugs:carmustine(BCNU,卡氮芥),lomustine(CCNU,)Highlylipid-soluble,cancrossBBBTreatmentofbraintumor2.Cisplatin(顺铂)&CarbaplatinClinicaluses:Genitourinarycancers,particularovarianandbladdercancerTesticularcancer:incombinationwithvinblastineandbleomycinToxicityAcutetoxicity:nausea,vomitingRenaltoxicity:hydrationwithsalineinfusion&diureticsMyelosuppression

3.AntitumorantibioticsBleomycin（BLM,博莱霉素）Clinicaluses:treatmentofsquamouscellcarcinomaoftheneck,cervix,skin,penis,rectumandincombinationtherapyforlymphomasToxicity:Severe:pulmonaryfibrosisCommon:anorexia,alopecia,blisteringandhyperkeratosisofpalmsMitomycinC(丝裂霉素)Clinicaluses:adenocarcinomasofthestomach,pancreas,lungandbreastToxicitySevere:myelosuppressionCommon:nausea,vomitingandanorexia4.Topoisomeraseinhibitors(拓扑异构酶抑制剂)

Camptothecins(喜树碱类)Drugs:topotecan(TPT),irinotecan(CPT-11)Mechanism:interferewiththeactivityoftopoisomeraseⅠClinicaluses:canceroflung,stomach,colonetcNocrossresistancewithotheranticancerdrugsToxicityCommon:nausea,vomiting,alopeciaDose-limitingeffect:neutropenia,thrombocytopeniaCPT-11:diarrheaPodophyllotoxins(鬼臼毒素衍生物)Etopsid(vepesid,VP-16,鬼臼乙叉苷)Combinedwithmicrotubuleproteinandinhibittheirpolymerization,CCSTeniposide(VM-26,特尼泊苷)InhibittheactivityoftopoisomeraseII,CCNSIII.DrugsinterferingwithtranscriptionDactinomycin(放线菌素D)Doxorubicin(ADM,多柔比星)Darnorubucin(DNR,柔红霉素)Dactinomycin(放线菌素D)Mechanismbindtightlytodouble-strandedDNAthroughinteractionbetweenadjacentguanine-cytosinebasepair,andinhibitallformsofDNA-dependentRNAsynthesisClinicaluses:narrow-spectrumIncombinationwithsurgeryandvincristine(长春新碱）intheadjuvanttreatmentofWilm’stumorToxicity:evidentmyelosuppressionDoxorubicin(ADM,多柔比星

)&Daunorubicin(DNR,柔红霉素)MechanismBindwithhighaffinitytoDNAthroughintercalationandthenblockthesynthesisofDNAandRNAClinicalusesADM:oneofthemostimportantanticancerdrugs,treatmentofcarcinomaofthebreast,endometrium,ovary,testicle,thyroid,lungandmanysarcoma,acuteleukemia,Hodgkin’sdiseaseDaunorubicin:acuteleukemiaAdversereactionsCardiactoxicity:mostsevereandirreversiblySevereortotalalopecia:atstandarddosageMyleosuppression:shortdurationandrapidrecoveryIV.DrugsaffectingproteinsynthesisVinblastine(VLB)&Vincristine(VCR)Podophyllotoxins:teniposide（VM-26）andetoposide（VP-16）Taxanes:taxol&taxotereHarringtonine&HomoharringtonineL-asparaginaseVinblastine（VLB,长春碱）&vincristine（VCR,长春新碱）Mechanismofactionbindspecificallytothemicrotubularproteintubulin（微管）indimericform,terminateassemblyofmicrotubules（抑制微管聚集）andresultinmitoticarrest（有丝分裂阻滞）atmetaphase（中期）,causedissolutionofthemitoticspindle（纺锤体溶解）andfinallyinteferewithchromosomesegregationClinicalusesVLB:systemicHodgkin’sdiseaseandotherlymphomaVCR:acuteleukemiainchildren(combinationwithpredinisone)ToxicityVLB:nausea,vomiting,alopecia（脱发）,myelosuppressionVCR:neurotoxicity,includemuscleweakness,peripheralneuritisandareflexia（无反射）Etoposide（VP-16）

MechanismInhibittopoisomeraseⅡ,resultinDNAdamagethroughstrandbreakageClinicalusesVP-16:lungandtesticularcancerVM-26:braincancerandlymphomaToxicitynausea,vomiting,alopeciaandmyelosuppressionTaxol(紫杉醇)&taxotereMechanismEnhancetubulinpolymerizationandpromotemicrotubuleassemblyClinicaluses:

Firstchoiceforovarianandadvancedbreastcancer

ToxicityHypersensitivityPeripheralneuropathyNeutropenia（WBC减少）,thrombocytopeniaHarringtonine(三尖杉生物碱类)&HomoharringtonineMechanismInhibitthestartstageofproteinsynthesis,decomposetheribosomeClinicaluse:AcutegranulocyticleukemiaandacutemononuclearleukemiaToxicityNausea,vomiting,leukopeniaandhearttoxicityL-asparaginase（门冬酰胺酶）MechanismDepletionofserumasparagineandinhibitproteinsynthesisinneoplasticcellsClinicalusesChildhoodacuteleukemia§3RationaleforcombinationofantineoplasticdrugsCellproliferatingkineticsThemechanismofthedrugsToxicityofthecombinationaldrugsAnti-cancerspectrumMethodofadministeringdrugsToxicityoftheanticancerdrugsAcutetoxicityCommontoxicityMyleosuppressionGastrointestinaldisturbanceAlopeciaSpecifictoxicityCardiactoxicity:daunorubicinLivertoxicity:CTX,dactinomycinBladdertoxicity:CTXNeurotoxicity:VCRHypersensitivity:taxolChronictoxicity:infertility,teratogenesis,carcinogenesis§4Non-cytotoxicdrugsI.HormonalagentsAdrenalcorticosteroidsActueleukemia,lymphomaandmyelomaPredisone,prednisolone,dexamethasoneSexhormonesCanca