抗癌药的应用课件

抗癌药（Antineoplasticagents）

Overview

IntroductionMalignantdiseaseaccountsforahighproportionofdeathsinindustrialisedcountries.Thetreatmentofanticancerdrugistogivepalliation,induceremissionand,ifpossible,cure.OverviewIntroductionCanceroccursafternormalcellshavebeentransformedintoneoplasticcellsthroughalterationoftheirgeneticmaterialandtheabnormalexpressionofcertaingenes.Neoplasticcellsusuallyexhibitchromosomalabnormalitiesandthelossoftheirdifferentiatedproperties.Thesechangesleadtouncontrolledcelldivisionandmanyresultintheinvasionofpreviouslyunaffectedorgans,aprocesscalledmetastasis.AdvancesinCancerChemotherapyThetreatmentofapatientwithcancermayaimto:givepalliation,forexamplepromptreliefofunpleasantsymptomssuchassuperiorvenacavaobstructionfromamediastinaltumorinduce‘remission’sothatallmacroscopicandmicroscopicfeaturesofthecancerdisappear,thoughdiseaseisknowntopersistcure,forwhichallthecellsoftheclonemustbedestroyed.CancerChemotherapy

DiseaseName5YearsSurvivalRateChildhoodAcuteLymphoblasticLeukemia50~80%AdultAcuteLymphoblasticLeukemia20~60%ChildhoodAcuteMyeloblasticLeukemia20~60%AdultAcuteMyeloblasticLeukemia 10~20%BreastCancer（Premenopausal） 10~20%BreastCancer（Postmenopausal） 0~15%Hodgkin’slymphoma* 40~80%CancerChemotherapyDiseaseName5YearsSurvivalRateSmallCellLungCancer（LimitedStage） 10~20%

（ExtensiveStage）0~5%Non-Hodgkin’slymphoma* 40~65%OvarianCancer 40~60%ChildrenSolidTumor(Nephroblastoma,Rhabdomyosarcoma,Lymphoma，Osteosarcoma）* 60~90%Trophoblastoma（ChorionEpithelioma）**80~90%SeminomaofTestis** 60~90%EmbryonicCarcinomaofTestis 60~80%Note：*Combinationwithothertherapeutics **ChemotherapyLevelofourcountryishighTheClassificationofAnticancerDrugsAccordingtochemicalstructureandresourceofthedrug;Accordingtobiochemistrymechanismsofanticanceraction;Accordingtothecycleorphasespecificityofthedrug

TheClassificationofAnticancerDrugsAccordingtobiochemistrymechanismsofanticanceraction:BlocknucleicacidbiosynthesisDirectinfluencethestructureandfunctionofDNAInterferetranscriptionandblockRNAsynthesis

InterfereproteinsynthesisandfunctionInfluencehormonehomeostasisOthers沈阳最好的妇科医院/沈阳专业治疗男科的医院/沈阳专业治疗外阴白斑的医院/沈阳最专业的妇科医院/沈阳最好泌尿外科医院/沈阳最好性病医院/沈阳设施最好的性病医院/沈阳好的妇科医院/沈阳最权威妇科医院/沈阳最好的外阴白斑医院/沈阳最好男科医院/TheBasicConceptof

CellGenerationCycleThecycleofcellreplicationincludes:M（Mitosis）phaseG1（Gap1,periodbeforeS）phaseS（DNAsynthesis）phaseG2（Gap2,periodafterS）phase

GrowthFraction(GF）GrowthFraction(GF)GF＝ProliferatingcellgroupTotaltumorcellgroupCCNSA：drugsthatareactivethroughoutthecellcycle.CCSA:

drugsthatactduringaspecificphaseofthecellcycle.CCSAandCCNSACellCycleNonspecificAgents(CCNSA)

drugsthatareactivethroughoutthecellcycle

AlkylatingAgentsPlatinumCompoundsAntibiotics

CellCycleSpecificAgents(CCSA)

drugsthatactduringaspecificphaseofthecellcycle

SPhaseSpecificDrug:

Aantimetabolites,TopoisomeraseInhabitors

MPhaseSpecificDrug:

VincaAlkaloids,Taxanes

G2PhaseSpecificDrug:

BbleomycinCCSAandCCNSAMechanismofAnticancerDrugsBlocknucleicacid(DNA,RNA)biosynthesisDirectlydestroyDNAandinhibitDNAreproductionInterferetranscriptionandblockRNAsynthesisInterfereproteinsynthesisandfunctionInfluencehormonehomeostasisBlockNucleicAcid(DNA,RNA)BiosynthesisAntimetabolites:FolicAcidAntagonist:

inhibitdihydrofolatereductase(methotrexate)PyrimidineAntagonist:

inhibitthymidylatesynthetase(fluorouracil);inhibitDNApolymerase(cytarabine)PurineAntagonist:

inhibitinterconversionofpurinenucleotide(mercaptopurine)RibonucleosideDiphosphateReductaseAntagonist:

(hydroxyurea)

InterfereTranscriptionandBlockRNASynthesisBindwithDNAtoblockRNAproduction.

doxorubicinInfluencetheStructureandFunctionofDNAAlkylatingAgent:

mechlorethamine,cyclophosphamideandthiotepaPlatinum:

cis-platiniumAntibiotic:

bleomycinandmitomycinCTopoismeraseinhibitor:

camptothecineand

podophyllotoxin

TheLongRoadofaNewMedicineTheMainStepofAnticancerDrugResearch

Non-clinicalResearch：1.AnticancerDrugScreen:

invitro：tumorcellculture,tumorinhibitor/killtest

invivo：animalxenograftmodele.g.Ehrlichascitestumor,S180lymphosarcoma2.Pharmacodynamics,pharmacokineticsandtoxicologytestTheMainStepofAnticancerDrugResearchPhase1clinicaltrial

InPhase1clinicaltrials,researcherstestanewdrugortreatmentinasmallgroupofpeople(20-80)forthefirsttimetoevaluateitssafety,determineasafedosagerange,andidentifysideeffects.TOLERANCEPHARMACOKINETICSTheMainStepofAnticancerDrugResearchPhase2clinicaltrial

InPhase2clinicaltrials,thestudydrugortreatmentisgiventoalargergroupofpeople(40-100)toseeifitiseffectiveandtofurtherevaluateitssafety.

TheMainStepofAnticancerDrugResearchPhase3clinicaltrial

InPhase3studies,thestudydrugortreatmentisgiventolargegroupsofpeople(morethan200)tofurtherdetermineitseffectiveness,monitorsideeffects,compareittocommonlyusedtreatments,andcollectinformationthatwillallowthedrugortreatmenttobeusedsafely.AnticancerDrugsAlkylatingAgentAntimetaboliteAntibioticsAlkaloid

HormonesOthers（cis-platinum，carboplatin，lobaplatin）AlkylatingAgentsOneofthefrighteningdevelopmentsofWorldWarIwastheintroductionofchemicalwarfare.Thesecompoundswereknownasthenitrogenmustardgases.Thenitrogenmustardswereobservedtoinhibitcellgrowth,especiallyofbonemarrow.Shortlyafterthewar,thesecompoundswereinvestigatedandshowntoinhibitthegrowthofcancercells.AlkylatingAgentsMechanismofActionNitrogenmustardsinhibitcellreproductionbybindingirreversiblywiththenucleicacids(DNA).Thespecifictypeofchemicalbondinginvolvedis

alkylation.Afteralkylation,DNAisunabletoreplicateandthereforecannolongersynthesizeproteinsandotheressentialcellmetabolites.Consequently,cellreproductionisinhibitedandthecelleventuallydiesfromtheinabilitytomaintainitsmetabolicfunctions.ClassificationofAlkylatingAgentsBisChloroethylAmines：

Cyclophosphamide,Chlormethine,Chlorambucil,SarcolysineNithrosoureas：

Carmustine，LomustineEthyeneammoniumorAziridines：

Thiotepa，triethylenemelamineAlkysulfonates：BusulfanResistanceofAlkylatingAgents

Resistancetoalkylatingagentshasseveralcauses:

Membranetransportmaybedecreased.Thedrugmaybeboundbyglutathione(GSH)viaGSH-S-transferaseormetallothioneinsinthecytoplasmandinactivated.Thedrugmaybemetabolizedtoinactivespecies.AdverseEffectsofAlkylatingAgentsMyelosuppressionisthedose-limitingadverseeffectforalkylatingagents.Nauseaandvomitingarecommonasareteratogenesisandgonadalatrophy,althoughinthelattercasesthesearevariable,accordingtothedrug,itsschedule,androuteofadministration.Treatmentalsocarriesamajorriskofleukemogenesisandcarcinogenesis.AlkylatingAgents——MustineMustinemustbeinjectedintravenouslybecauseitishighlyreactive.Itdisappearsveryrapidlyfromtheblood,theactivityofMustinelastsonlyafewminutes.ThemainindicationforMustineisintreatmentofHodgkinsdiseaseandlymphomas,butitmayalsobeusefulinothermalignancies.AlkylatingAgents——CyclophosphamideCyclophosphamidecanalsobegivenorally.Indications：Itisusedinthetreatmentofchroniclymphocycticleukemia,non-Hodgkin’slymphomas,breastandovariancancer,andavarietyofothercancers.Itisalsoapotentimmunosuppressant,itisusedinthemanagementofrheumatoiddisordersandautoimmunenephritis.AdverseEffects:Alopecia,nausea,vomiting,myelosuppression,andhemorrhagiccystitis.AlkylatingAgents——NitrosoureasCarmustine,Lomustine,SemustinePharmacokinetics:Nitrosoureasarehighlylipophilicandreachcerebrospinalfluidconcentrationsthatareabout30%ofplasmaconcentrations.Indications:BecauseoftheirexcellentCNSpenetration,carmustineandlomustinehavebeenusedtotreatbraintumors.AlkylatingAgents——

PhenylalanineNitrogenMustardMelphalanisanitrogenmustardthatisprimarilyusedtotreatmultiplemyeloma(plasmacellmyeloma),breastcancer,andovariancancer.AlkylatingAgents——

AlkysulfonatesBusulfan[Myleran]Indications:Busulfanisadministeredorallytotreatchroicgranulocyticleukemiaandothermyeloproliferativedisorders.AdverseEffects:Busulfanproducesadverseffectsrelatedtomyelosuppression.Itonlyoccasionallyproducesnauseaandvomitting.Inhighdoses,itproducesararebutsometimesfatalpulmonaryfibrosis,”busulfanlung”.AlkylatingAgents——Thiotepa

Thiotepaisconvertedrapidlybylivermixed-functionoxidasestoitsactivemetabolitetriethylenephosphoramide(TEPA);itisactiveinbladdercancer.AntimetabolitesGeneralCharacteristics：AntimetabolitesareSphase-specificdrugsthatarestructuralanaloguesofessentialmetabolitesandthatinterferewithDNAsynthesis.Myelosuppressionisthedose-limitingtoxicityforalldrugsinthisclass.ClassificationofAntimetabolitesFolicacid

Antagonists:MTX

PurineAntagonists:6MP6TG

PyrimidineAntagonists：5FUaraCHUAntimetabolites——

FolicAcidAntagonistMethotrexate（MTX）MechanismofAction：

ThestructuresofMTXandfolicacidaresimilar.MTXisactivelytransportedintomammaliancellsandinhibitsdihydrofolatereductase,theenzymethatnormallyconvertsdietaryfolatetothetetrahydrofolateformrequiredforthymidineandpurinesynthesis.Antimetabolites——

FolicAcidAntagonistMethotrexate（MTX）Indications：TheuseofMTXinthetreatmentofchoriocarinoma,atrophoblastictumor,wasthefirstdemonstrationofcurativechemotherapy.Itisespeciallyeffectivefortreatingacutelymphocyticleukemiaandfortreatingthemeningealmetastasesofawiderangeoftumors.Antimetabolites——

FolicAcidAntagonist

Methotrexate（MTX）AdverseEffects：MTXismyelosuppressive,producingsevereleukopenia,bonemarrowaplasia,andthrombocytopenia.Thisagentmayproduceseveregastrointestinaldisturbances.Renaltoxicitymayoccurbecauseofprecipitation(crystalluria)ofthe7-OHmetaboliteofMTX.Antimetabolites——

PurineAntagonists6-Mercapapurine（6-MP）

Thedrugsarebelievedtoactsimilarlytoinhibitpurinebasesynthesis,althoughtheirexactmechanismsofactionarestilluncertain.Indications:MercaptopurineisusedprimarilyforthemaintenanceofremissioninpatientswithacutelymphocyticleukemiaandisgivenincombinationwithMTXforthispurpose.AdverseEffects:Welltolerate.Myelosuppressionisgenerallymildwiththioguanine.Long-termmercaptopurineusemaycausehepatotoxicity.Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)MechanismofAction：Fluorouracilisananalogueofthymineinwhichthemethylgroupisreplacedbyafluorineatom.Ithastwoactivemetabolites:5-FdUMPand5-FdUTP.5-FdUMPinhibitsthymidylatesynthetasesandpreventsthesynthesisofthymidine,amajorbuildingblockofDNA.5-FdUTPisincorporatedintoRNAbyRNApolymeraseandinterfereswithRNAfunction.Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)Indications：Fluorouracilisexclusivelyusedtotreatsolidtumors,especiallybreast,colorectal,andgastrictumorsandsquamouscelltumorsoftheheadandneck.Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)AdverseEffects：Fluorouracilmaycausenauseaandvomiting,myelosuppression,andoralandgastrointestinalulceration.Nauseaandvomittingareusuallymild.Withfluorouracil,myelosuppressionismoreproblematicafterbolusinjections,whereasmucosaldamageisdose-limitingwithcontinuousinfusions.Antimetabolites——

PyrimidineAntagonistsCytarabineIndications：Cytarabinehasanarrowclinicalspectrumandisprimarilyusedincombinationwithdaunorubicinorthioguanineforthetreatmentofacutenonlymphocyticleukemia.AdverseEffects:Highdosesofcytarabinecandamagetheliver,heart,andotherorgans.

AntibioticsClassificationofAntibiotics:Adriamycin(AnthracyalineAntibiotics)MitomycinCBleomycinActinomycinDAntibioticsAdriamycinandDaunorubicin：Properties:AdriamycinandDaunorubicinaretetracyclineringswiththesugardaunosamine.TheyareDNAintercalatingagentsthatblockthesynthesisofDNAandRNA.TheseagentsareprimarilytoxicduringtheSphaseofcellcycle.Theseagentsimpartsaredtingetotheurine.Adramycinisusedtotreatacuteleukemias,lymphoma,andanumberofsolidtumors.AntibioticsMitomycinC:Mechanism:MitomycinCisanantineoplasticantibioticthatalkylatesDNAandtherebycausesstrandbreakageandinhibitionofDNAsynthesis.Indications:Itisprimarilyusedincombinationwithvinvristineassalvagetherapyforbreastcancer.AdverseEffects:Mitomycinproducesdelaysandprolongedmyelosuppressionthatpreferentiallyaffectsplateletsandleukocytes.AntibioticsActinomycinD:ActinomycinDintercalatesDNAandtherebypreventsDNAtranscriptionandmessengerRNAsynthesis.Thedrugisgivenintravenously,anditsclinicaluseislimitedtothetreatmentoftrophoblastic(gestational)tumorsandthetreatmentofpediatrictumors,suchasWilms’tumorandEwing’ssarcoma.AntibioticsBleomycin:Mechanism:ThedrughasitsgreatesteffectonneoplasticcellintheG2phaseofthecellreplicationcycle.AlthoughbleomycinintercalatesDNA,themajorcytotoxicityisbelievedtoresultfromironcatalyzedfreeradicalformationandDNAstrandbreakage.Indications:ItisusefulinHodgkin’sandnon-Hodgkin’slymphomas,testicularcancer,andseveralothersolidtumors.AdverseEffects:Bleomycinproducesverylittlemyelosuppression.ThemostserioustoxicitiesofBleomycinarepulmonaryandmucocutaneousreactions.Anti-CancerPlantAllaloidsTubulin-BindingAgents

VincaAlkaloids:Thecellularmechanismofactionofvincaalkaloidsisthepreventionofmicrotubuleassembly,causingcellstoarrestinthelateG2phasebypreventingformationofmitoticfilamentsfornuclearandcelldivision.Anti-CancerPlantAllaloidsTubulin-BindingAgentsVincaalkaloids:

Vinblastine,vincristin,vindesineandvinorelbineareallalkaloidsderivedfromtheperiwinkleplant(Vincarosea).Indications:VinblastineisusedincombinationwithBleomycinandCisplatinformetastatictesticulartumors.Vincristineisusedincombinationwithprednisonetoinduceremissioninchildhoodleukemia.Vinorelbineisusedtotreatnon-small-celllungcancerandbreastcancer.Anti-CancerPlantAllaloidsTubulin-BindingAgentsPaclitaxel:

Taxanesenhanceallaspectsoftubulinpolymerization,anactionthatistheoppositetothatofvincaalkaloids,buttheyarealsocytotoxic,emphasizingthedynamicimportanceoftubulinpolymerizationasatargetforcytotoxicdrugs.

Paclitaxel,TaxotereInterferetheFunctionofRibosome:CephalotaxusAlkaloids:

HarringtonineHomoharringtonineAnti-CancerPlantAllaloidsPlatinumCompoundCisplatin:MechanismofAction:CisplatinbindstoguanineinDNAandRNA,andtheinteractionisstabilizedbyhydrogenbonding.ThemolecularmechanismofactionisunwindingandshorteningoftheDNAhelix.PlatinumCompoundCisplatin:Indications:Cisplatinhasefficacyagainstawiderangeofneoplasms.Itisgivenintravenouslyasafirst-linedrugfortesticular,ovarian,andbladdercancer,anditisalsousefulinthetreatmentofmelanomaandanumberofothersoildtumors.AdverseEffect:Cisplatinproducesrelativelylittlemyelosuppressionbutcancauseseverenausea,vomiting,andnephrotoxicity.PlatinumCompoundCarboplatin:Indication:Carboplatinhasasimilarspectrumofactivity,butitisapprovedonlyasasecond-linedrugforovariancancer.HormonesSeveraltypesofhormone-dependentcancer(especiallybreast,prostate,andendometrialcancer)respondtotreatmentwiththeircorrespondinghormoneantagonists.Estrogenantagonistsareprimarilyusedinthetreatmentofbreastcancer,whereasandrogenantagonistsareusedinthetreatmentofprostatecancer.Corticosteroidsareparticularlyusefulintreatinglymphocyticleukemiasandlymphomas.HormonesEstrogens:Estrogensinhibittheeffectsofendogenousandrogensandandrogen-dependentmetastaticprostaticcarcinoma.Diethylstilbestrolisusuallytheagentofchoice.Cardiacandcerebrovascularcomplicationsandcarcinomaofthemalebreastarepotentialadverseeffects.HormonesProgenstins:Progestinsareusefulinthemanagementofendometrialcarcinomaandback-uptherapyformetastatichormone-dependentbreastcancer.

HormonesAntiestrogen:

TamoxifenTamoxifenisthedrugofchoiceinpostmenopausalwomenwithorrecoveringfrommetastaticbreastcancer.Itismosteffectiveinpatientswhohaveestrogenreceptor-positivetumors.Tamoxifenisalsousedasadjunvctivetherapytooophorectomytoleuprolideorgoserelininpremenopausalwomenwithestrogenreceptor-positivetumors.沈阳最好的妇科医院/沈阳专业治疗男科的医院/沈阳专业治疗外阴白斑的医院/沈阳最专业的妇科医院/沈阳最好泌尿外科医院/沈阳最好性病医院/沈阳设施最好的性病医院/沈阳好的妇科医院/沈阳最权威妇科医院/沈阳最好的外阴白斑医院/沈阳最好男科医院/HormonesAndrogens:Androgenactivityinbreastcancerissimilartothatofes