抗肿瘤药版.ppt

AnticancerDrugs,Dr.QamarBarakzaiDepartmentofPharmacologyZiauddinMedicalUniversityKarachi.Pakistan,“CANCER”ReferstoaMalignantneoplasm(Newgrowth)Cancercellscanmanifest:UncontrolledProliferation.Lossoffunctionduetolackofabilitytodifferentiate.Invasiveness.Theabilitytometastasize.Cancerarisesasaresultofaseriesofgeneticchangesinthecell,themaingeneticlesionsbeing:Inactivationoftumorsuppressorgenes.Theactivationofoncogenes.,AntineoplasticagentsArecytotoxicnottumoricidalOnlykillcellsduringmitosis,andNotallcancercellsaredividingatthesametime.SUCCESSDEPENDSON:StageofcancerattimeofdiagnosisTypeofcancerDevelopmentofdrugresistanceOverallhealthofpatient.,R,TumorSuppressorGenes-ve(p53)GrowthFactorsOncogenes+ve,SDNASynthesis,G2PremitoticInterval,M,PROPHASEMETAPHASEANAPHASETELOPHASE,MITOSIS,G0,G1,SPHASESPECIFICCytosineArbinosideHydroxyureaSPHASESPECIFICSELFLIMITING6-MercaptpurineMethotrexate.,MPHASESPECIFICvincristinevinblastinepaclitaxel,PHASENONSPECIFICalkylatingagents,cis-platinumnitrosoureas,dacarbazineantibioticsprocarbazine,G0,Differentiation,CELLGROWTHCYCLE5DISTINCTPHASESOFMITOSIS1.G0-Resting-nomitosis2.G1-Postmitotic-firstgrowth3.S-DNAsynthesisphase4.G2-Premitotic-secondgrowth5.M-MitosisphaseGENERATIONTIME-onecompletecycledifferentinalltumors,fromhourstodays,PENTOSTATIN,InhibitsadenosineDeaminase,PALA,InhibitsPyrimidineBiosynthesis,Purinesynthesis,Pyrimidinesynthesis,Ribonucleotides,Deoxyribonucleotides,DNA,HYDROXYUREA,InhibitRibonucleotideReductase,6-MERCAPTOPURINE6-THIOGAUNINE,InhibitPuringringbiosynthesis,InhibitNeocleotideinterconversions,5-FLOUROURACIL,InhibitTMPSynthesis,METHOTREXATE,Inhibitdihydrofolatereduction,blocksTMPandPurinesynthesis,DNA,RNA,(Transfer,messenger,ribosomal),CYTARABINEFLUDARABINE2-CHLORODEOXYADENOSINE,InhibitDNASynthesis,ALKYLATINGAGENTSMITOMYCETINCISPLATINPROCARBAZINEDACARBAZINE,Formadductsw/DNA,BLEOMYCINETOPOSIDETENIPOSIDE,DamageDNAandPreventrepair,DACTINOMYCINEDAUNORUBICINDOXORUBICINMITOXANTRONE,IntercalatewithDNAInhibitRNAsynthesis,PROTEINS,Enzymes,Microtubules,A-ASPARAGINASE,Deaminateasparagine,Inhibitsproteinsynthesis,PACLITAXELVINCAALKALOIDSCOLCHICINE,InhibitfunctionofMicrotubules,ANTINEOPLASTICAGENTSDEFINITIONS:ALKYLATION-chemicalreactionthatcleavesDNAandinterfereswithmitosisBIFUNCTIONALALKYLATINGAGENTS-have2alkylgroupsandalkalate2DNAstrandsDOSE-LIMITEDSIDEEFFECTS-adverseeffectsthatpreventanagentfrombeinggiveninhigherdosesEMETICPOTENTIAL-potentialofanagenttocauseN&V,ANTINEOPLASTICAGENTSADVERSEEFFECTS:KillsallfastgrowingcellsHairfolliclesGItractmucosaBonemarrowsuppression(BMS)causinganemiaandleukopeniaAllarepregnancycategoryD!Mostarenephro-hepato-andototoxicExtravasationofIVcanresultinlossoflimb,AntineoplasticAgentsADVERSEEFFECTS:(Contd)AllhaveaBMSandemeticindexAllhavewideinteractionwithotherdrugs.SpecialtrainingrequiredfornursingMostagentscanbeharmfultonurseadministeringthem,DEFINITIONS:GROWTHFRACTION%ofcellsinmitosisatanygiventimeLEUCOVORINRESCUE-useofleucovorintoreversemethotrexate-inducedtoxicityMITOTICINDEXnumberofcellsperunitundergoingmitosisduringagiventimeNADIRlowestpoint(asinbloodcount)afterbeingdepressedbychemotherapyPARANEOPLASTICSYNDROME(PNS)S/Sofcancerlocateddistantfromtumororitsmetastaticsites,ANTINEOPLASTICAGENTS2MAINGROUPSOFAGENTS:CELLCYCLE-NONSPECIFIC(CCNS)ALKYLATINGAGENTScytotoxicinanyphaseofcellcycleeffectiveagainstslowlygrowingtumorsCELLCYCLE-SPECIFIC(CCS)3TYPESANTIMETABOLITES-cytotoxicisSphaseMITOTICINHIBITORS-cytotoxicinMphaseCYTOTOXICANTIBIOTICS(someareCCNS)effectiveagainstrapidlygrowingtumors,ALKYLATINGAGENTSNITROGENMUSTARDSfirstdevelopedin1940sCCNSkillingabilitymechlorethamineistheprototypicalagentUSES:Hodgkinsdisease&lymphomas.leukemias,CANCERSOFlung,breast,ovary,testes,brain,bladder,Mostwidelyusedagent,oftenincombinationwithotheragents.,ALKYLATINGAGENTSSELECTEDAGENTS:Mechlorethamine(Mustine,Mustargen)IVonly(adultuseonly)Cyclophosphamide(Cytoxan,Neosar)IVandPO,adultsandpediatricuseCarmustine(BiCNU)IV,adultonly,cancrossblood-brainbarrier,thereforeusedtotreadbrainlesionsOTHERAGENTS:Chlorambucil,Streptozotocin,HepaticcytochromeP4500 xidase4-HydroxycyclophosphamideAldophosphamideEnzymaticNonenzymaticHepaticaldehydeoxidase4-Ketocyclophosphamide(Inactive).AcroleinCytotoxicPhosphamideMustardCytotoxic.Carboxyphosphamide(Inactive).Responsibleforunwantedeffects,Cyclophosphamide(Inactive),Cyclophosphamide(Inactive),HepaticcytochromeP4500 xidase,4-Hydroxycyclophosphamide,Aldophosphamide,Enzymatic,Nonenzymatic,Hepaticaldehydeoxidase,4-Ketocyclophosphamide(Inactive).,AcroleinCytotoxicPhosphamideMustardCytotoxic,Carboxyphosphamide(Inactive).,Responsibleforunwantedeffects,ANTIMETABOLITESACTIONS:Antagonismoffolate,purines,andpyrimidinesneededforsynthesisofnucleicacids-stopscellreplicationUSES:Solidtumors(breast,lung,liver,brain,colon.Stomach,pancreas)Lymphomas,leukemias.Someagentsalsoimmunosuppressive,Usefulintreatingimmune-mediateddiseases,ANTIMETABOLITESSELECTEDAGENTS:(FOLICACIDANALOG)METHOTREXATE(Folex,Rheumatrex,MTx)FolicacidantagonistPO&IM,adultandpediatricuseAlsousedtotreatimmune-mediateddiseases,UsedincombinationwithmisoprostolfortherapeuticabortionCausesprofoundanemia(folatedepletion)Thereforeleucovorin“rescue”oftenusedtocounteract,ANTIMETABOLITESSELECTEDAGENTS:PURINEANALOG-MERCAPTOPURINE(6-MP,Purinethol)-Purineantagonist-POonly,adultandpediatricusePYRIMIDINEANALOG-CYTARABINE(Ara-C,Cytosar-U)-Pyrimidineantagonist-IVandintrathecal(withinspinalcanal),MITOTICINHIBITORSACTIONS:Plantalkaloids(periwinkle,yewtree,mandrakeplant,etc.)BindtoanddisruptmitoticspindlesUSES:Lymphomas(Hodgkinsandnon-Hodgkins),NeuroblastomaKaposissarcoma,Solidtumors(breast,testicular,etc.),MITOTICINHIBITORSSELECTEDAGENTS:ETOPOSIDE(VP-16,VePesid)IVandPO,adultuseonlyPACLITAZEL(Taxol)IVonly,adultuseonlydrugofchoiceforovaryandbreastcaVINCRISTINE(LCR,VCR,Oncovin)IVonly,adultandpediatricusedrugofchoiceforacuteleukemia,CYTOTOXICANTIBIOTICSACTIONS:Source:Streptomycesmold-workbyintercalation(insertionofdrugmoleculebetweenthe2DNAstrandscausingitto(“unwind”)KillsomebacteriaandvirusesbutaretootoxictouseforinfectionsIVextravasationconstantdanger!USES:widevarietyofsolidtumors,alwaysusedincombinationwithotheragents,CYTOTOXICANTIBIOTICSSELECTEDAGENTS:DOXORUBICIN(ADR,Rubex,Doxil)IVonly,adultuseonlyBLEOMYCIN(BLM,Blenoxane)IM,IV,SQ,adultuseonlyverytoxicagents!,MISCELLANEOUSANTINEOPLASTICSVariousactions,BothCCNSandCCSUsedincombinationswithother