抗癌藥英文課件

抗癌藥（Antineoplasticagents）

Overview

IntroductionMalignantdiseaseaccountsforahighproportionofdeathsinindustrialisedcountries.Thetreatmentofanticancerdrugistogivepalliation,induceremissionand,ifpossible,cure.OverviewIntroductionCanceroccursafternormalcellshavebeentransformedintoneoplasticcellsthroughalterationoftheirgeneticmaterialandtheabnormalexpressionofcertaingenes.Neoplasticcellsusuallyexhibitchromosomalabnormalitiesandthelossoftheirdifferentiatedproperties.Thesechangesleadtouncontrolledcelldivisionandmanyresultintheinvasionofpreviouslyunaffectedorgans,aprocesscalledmetastasis.

AdvancesinCancerChemotherapy

Treatmentoptionsofcancer:Surgery:before1955Radiotherapy:1955~1965Chemotherapy:after1965ImmunotherapyandGenetherapyAdvancesinCancerChemotherapyThetreatmentofapatientwithcancermayaimto: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

（Chorion

Epithelioma）**80~90%SeminomaofTestis** 60~90%EmbryonicCarcinomaofTestis 60~80%Note：*Combinationwithothertherapeutics **ChemotherapyLevelofourcountryishighTheClassificationofAnticancerDrugsAccordingtochemicalstructureandresourceofthedrug;Accordingtobiochemistrymechanismsofanticanceraction;Accordingtothecycleorphasespecificityofthedrug

TheClassificationofAnticancerDrugsAccordingtochemicalstructureandresourceofthedrug:

AlkylatingAgents,Antimetabolite,Antibiotics,PlantExtracts，Hormones，Others.TheClassificationofAnticancerDrugsAccordingtobiochemistrymechanismsofanticanceraction:BlocknucleicacidbiosynthesisDirectinfluencethestructureandfunctionofDNAInterferetranscriptionandblockRNAsynthesis

InterfereproteinsynthesisandfunctionInfluencehormonehomeostasisOthersTheClassificationofAnticancerDrugsAccordingtothecycleorphasespecificityofthedrug:

Cellcyclenonspecificagents(CCNSA)Cellcyclespecificagents(CCSA)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,Topoisomerase

Inhabitors

MPhaseSpecificDrug:

VincaAlkaloids,Taxanes

G2PhaseSpecificDrug:

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

inhibitdihydrofolate

reductase

(methotrexate)PyrimidineAntagonist:

inhibitthymidylate

synthetase

(fluorouracil);inhibitDNApolymerase(cytarabine)PurineAntagonist:

inhibitinterconversionofpurinenucleotide(mercaptopurine)Ribonucleoside

Diphosphate

ReductaseAntagonist:

(hydroxyurea)

InterfereProteinSynthesis

Antitubulin:

vincaalkaloids

and

taxanes;Interferethefunctionofribosome:

harringtonines；Influenceaminoacidsupply:

L-asparaginase

Bindtubulin,destroyspindletoproducemitoticarrest.InterfereTranscriptionandBlockRNASynthesisBindwithDNAtoblockRNAproduction.

doxorubicinInfluencetheStructureandFunctionofDNAAlkylatingAgent:

mechlorethamine,cyclophosphamideandthiotepaPlatinum:

cis-platiniumAntibiotic:

bleomycin

andmitomycinCTopoismeraseinhibitor:

camptothecineand

podophyllotoxin

InfluenceHormoneHomeostasis

Thesedrugsbindtohormonereceptorstoblocktheactionsofthesexhormoneswhichresultsininhibitionoftumorgrowth.EstrogensandestrogenantagonisticdrugAndrogensandandrogenantagonisticdrugProgestogendrugGlucocorticoiddruggonadotropin-releasinghormoneinhibitor:

leuprolide,goserelinaromataseinhibitor:

aminoglutethimide,anastrazoleTheLongRoadofaNewMedicineTheMainStepofAnticancerDrugResearch

Non-clinicalResearch：1.AnticancerDrugScreen:

invitro：tumorcellculture,tumorinhibitor/killtest

invivo：animalxenograftmodele.g.Ehrlich

ascitestumor,S180lymphosarcoma2.Pharmacodynamics,pharmacokineticsandtoxicologytestTheMainStepofAnticancerDrugResearchClinicalResearch:

Phase1clinicaltrialPhase2clinicaltrialPhase3clinicaltrialPhase4clinicaltrialTheMainStepofAnticancerDrugResearchPhase1clinicaltrial

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

InPhase2clinicaltrials,thestudydrugortreatmentisgiventoalargergroupofpeople(40-100)toseeifitiseffectiveandtofurtherevaluateitssafety.

TheMainStepofAnticancerDrugResearchPhase3clinicaltrial

InPhase3studies,thestudydrugortreatmentisgiventolargegroupsofpeople(morethan200)tofurtherdetermineitseffectiveness,monitorsideeffects,compareittocommonlyusedtreatments,andcollectinformationthatwillallowthedrugortreatmenttobeusedsafely.TheMainStepofAnticancerDrugResearchPhase4clinicaltrial

Phase4studiesaredoneafterthedrugortreatmenthasbeenmarketed.Thesestudiescontinuetestingthestudydrugortreatmenttocollectinformationabouttheireffectinvariouspopulationsandanysideeffectsassociatedwithlong-termuse.

AnticancerDrugsAlkylatingAgentAntimetaboliteAntibioticsAlkaloid

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

alkylation.Afteralkylation,DNAisunabletoreplicateandthereforecannolongersynthesizeproteinsandotheressentialcellmetabolites.Consequently,cellreproductionisinhibitedandthecelleventuallydiesfromtheinabilitytomaintainitsmetabolicfunctions.ClassificationofAlkylatingAgentsBis

ChloroethylAmines：

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.ClassificationofAntimetabolites

Folicacid

Antagonists:MTX

PurineAntagonists:6MP6TG

PyrimidineAntagonists：5FU

araCHUAntimetabolites——

FolicAcidAntagonistMethotrexate

（MTX）MechanismofAction：

ThestructuresofMTXandfolicacidaresimilar.MTXisactivelytransportedintomammaliancellsandinhibitsdihydrofolate

reductase,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-FdUMPinhibitsthymidylate

synthetasesandpreventsthesynthesisofthymidine,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.Although

bleomycinintercalatesDNA,themajorcytotoxicityisbelievedtoresultfromironcatalyzedfreeradicalformationandDNAstrandbreakage.Indications:ItisusefulinHodgkin’sandnon-Hodgkin’slymphomas,testicularcancer,andseveralothersolidtumors.AdverseEffects:Bleomycinproducesverylittlemyelosuppression.ThemostserioustoxicitiesofBleomycinarepulmonaryandmucocutaneousreactions.Anti-CancerPlantAllaloidsTubulin-BindingAgents

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

Vinblastine,vincristin,vindesineandvinorelbineareallalkaloidsderivedfromtheperiwinkleplant(Vinca

rosea).Indications:VinblastineisusedincombinationwithBleomycinandCisplatinformetastatictesticulartumors.Vincristineisusedincombinationwithprednisonetoinduceremissioninchildhoodleukemia.Vinorelbineisusedtotreatnon-small-celllungcancerandbreastcancer.Anti-CancerPlantAllaloidsTubulin-BindingAgentsPaclitaxel:

Taxanesenhanceallaspectsoftubulinpolymerization,anactionthatistheoppositetothatofvincaalkaloids,buttheyarealsocytotoxic,emphasizingthedynamicimportanceoftubulinpolymerizationasatargetforcytotoxicdrugs.

Paclitaxel,TaxotereInterferetheFunctionofRibosome:CephalotaxusAlkaloids:

Harringtonine

HomoharringtonineAnti-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.Itismosteffectiveinpatientswhohaveestrogen