CancerTherapyThespecificapproachusedtotreatcancerdependsuponthespecifictype,location,andstageofthecancerFundamentaltechniquesavailabletotreatcancer:SurgeryRadiationtherapyImmunologictreatmentChemicalbasedapproachesGenerally,eachhasitsownmerits,andacombinationofthesemethodsisusedSurgery:ThecancermuststillbeintheprimarytumorstageAhighdegreeofconfidencethattheentiretumorcanbeexcisedRemovingthetumorwithoutcausingsignificantdamagetovitalorgansRadiationtherapy:isusedtoshrinkordestroytumorsThisapproachrequiresthatthetumorbelocalizedX-rayradiationisusedbyfocusinganX-raybeamonthetumorImmunologicTherapy:UtilizetheimmunesystemtoeradicatethecancerThismethodologyattemptstoboostthelevelofT-cellandB-cellThemajorroleofT-cellistodestroyforeigncells,includingmalignantcellsB-cellisproducedinthebonemarrowandlymphnodes,makeantibodiesinresponsetoaforeignproteinSection2CancerChemotherapy一AlkylatingAgents（烷基化試劑）1Nitrogenmustards（氮芥）mechlorethamineMechanismofAction氮丙啶鎓AlkylationofguanineinDNAbyanalkylatingagentOncealkylationoccurs,thealkylatedsitesbecomepronetocleavage

鳥嘌呤2.Melphalan（美法倫）L-L-PhenylalaninemustardorL-PAML-PAMcanbepreferentiallytransportedintocells,withtheassistanceofL-aminoacidactivetransporter3.Cyclophosphamide（環(huán)磷酰胺）

Reducednucleophilicitybecauseoftheamide-likephosphoramidelinkageLesslikelytoformanaziridiniumionChemicallymorestableRequiresmetabolicactivation(pro-drug)SynthesisofCyclophosphamide（環(huán)磷酰胺的合成）AcidichydrolysisofcyclophosphamidepH4.0-6.0（環(huán)磷酰胺的酸性水解）氮芥磷酰二氯3-氨基丙醇OtherAlkylatingAgentsAziridineDerivativesLessreactiveagentsAziridineisathree-memberednitrogenheterocyclethatreactswithnucleophilesinordertorelieveringstain氮丙啶為三元雜環(huán)，和親核試劑或基團反應開環(huán)，可釋放環(huán)的張力三乙蜜胺替哌塞替哌氮丙啶衍生物，乙撐亞胺類提高抗腫瘤作用減少毒副作用白血病前藥P450作用下轉(zhuǎn)化為替哌乳腺癌最早用于臨床安徽阜陽大頭娃Thiotepa（塞替哌）anditsmetabolicproductTEPA（替哌）塞替哌pKa=6.0OtherAlkylatingAgentsQuinoneastransporterQuinonepartcanreducetheelectrondensity,decreasedtoxicity醌部分可降低電子云密度，降低藥物的毒性QuinonepartcaninterfereenzymaticRe-Ox,inhibittumorcelldivision醌類化合物干擾酶系統(tǒng)氧化-還原過程，抑制腫瘤細胞的有絲分裂癌抑散三亞胺醌卡波醌Metabolicactivationofquinoneaziridine還原單氫醌氫醌ActivationoftheaziridinepartOtherAlkylatingAgents-MitomycinC（絲裂霉素C）Quinonemoiety,theaziridinering,thecarbamatePoororalabsorption,administeredIVTreatpancreaticcancer,胰腺癌antibioticBio-reductiveactivationofmytomycinCandDNAalkylationStabilityofMitomycinC（三）Methylsulfonate（甲磺酸酯類）

Busulfan，

白消安，馬利蘭CH3SO3isaverygoodleavinggroup（甲磺酸基是很好的離去基團）對白血病療效顯著（四）Nitrosoureas（亞硝基脲類）Carmustine，卡莫司汀

MechanismofActionReactivespeciesReactivespeciesReactivespeciesReactivespeciesFormationofavinylcationfromcarmustineTextbook,page544,圖21-1廣譜抗腫瘤活性，可通過BBBSynthesisofNirosoureas（亞硝基脲類）CarmustineOtherNitrosoureaanalogs洛莫司汀司莫司汀尼莫司?。ㄎ澹┤┻溥蝾愌苌顳acarbazine（DTIC）達卡巴嗪Proposedmetabolismandmechanismofactionofdacarbazine5-Amino-4-carboxamide5-（3，3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamideDTIC主要用于治療黑色素病、霍杰金氏病鳥嘌呤烷基化鳥嘌呤被DTIC（diazomethane）烷基化六：肼類，Procarbazine（丙卡巴肼）MetabolicactivationofprocarbazineProdrug偶氮甲基肼二、Cisplatin（順鉑）MechanismofActionofCisplatin與鳥嘌呤堿基N7配位形成五元環(huán)，擾亂DNA的正常雙螺旋，使局部變性失活DNA的復制停止Note:onlythecis-isomerisactive三、Bleomycin,DactinomycinD,Homoharringtonine博來霉素、放線菌素D和高三尖杉酯堿Bleomycins:antitumorantibiotic，糖肽類discoveredin1966IsolatedfromStreptomycesverticillus放線菌Thetwosugarring:possiblecellrecognitionanduptakesiteTheimidazole,amideandtheamine:Iron2+(Fe2+)chelatingsiteThethiazolerings（二噻唑環(huán)）:DNAbindingsites主要用于治療皮膚癌二噻唑糖咪唑嘧啶2、DactinomycinD,放線菌素DIsolatedfromStreptomycesparvullusThisringsystemisaromatic,planar,canintercalateorinsertintoDNAbetweenbasepairstepsHomoharringtonine,高三尖杉酯堿Alkaloid,生物堿Isolatedfromhomoharringtonineplant，三尖杉植物

Inhibitproteinsynthesis;DNAsynthesis中國協(xié)和醫(yī)科院，黃量院士，國家科技進步一等獎四、Antitumorreagents–Topoisomeraseastargets作用于DNA拓撲異構(gòu)酶的藥物TopoisomerasescatalyzeandguidetheunknottingofDNAbycreatingtransientbreaksintheDNAusingaconservedTyrosineasthecatalyticresidueTopIandTopII:differentfunction（一）Camptothecin（喜樹堿）,Hydroxycamptothecin（羥基喜樹堿）TopisomeraseIinhibitors

CamptothecinisanaturalproductAdditionofthehydroxylanddimethylaminomethylgroupsimprovedwatersolubilityandreducedtheoccurrenceofunpredictablesideeffects

MechanismofAction:causesinglestrandbreaksinDNA（二）Anthracyclines（阿霉素類屬蒽醌類）TopoisomeraseIIinhibitors

Atetracyclic

quinonecontainingringnucleustowhichisattachedauniquedaunosaminesugarReddishincolorFirstisolatedfromthefermentationbrothsofStreptomyces

peucetiusMechanismofAction:1)TheflattopographyoftheanthroquinonenucleusresultsintheabilityoftheanthracyclinestointercalatewithDNAperpendiculartoitslongaxis.2)Theanthroquinoneringsystemarecapableofgeneratingreactiveoxygenspecies,thefreeradicalsmayproducedestructiveeffectsuponthecellwhichmayincludedamagetotheDNATheaminosugarconfersaddedstabilitytothisbindingthroughitsinteractionwiththesugarphosphatebackboneofDNA阿霉素柔毛霉素表柔比星，表阿霉素OtherAnthracyclinesAnalogsSectionIIIAntimetaboliteantitumoragents第三節(jié)干擾ＤＮＡ合成的藥物

Antimetabolitesarecompoundsthatpreventthebiosynthesisofnormalcellularmetabolites.Usually,thissuggestsaclosechemicalsimilaritybetweenthenaturalmetaboliteandtheantimetabolite.NarrowAntitumorSpectrum,normallyeffectiveforleukemia（白血?。┮?、PyrimidineAntimetabolites（嘧啶拮抗物）5-Fluorouracil,5-FU.ApyrimidinewithringmodificationsSometumorspreferentiallyuseuracilforpyrimidinebiosynthesisKeyintermediatesinthesynthesisofdeoxythymidylicacidfromdeoxyuridylicacid胸腺嘧啶脫氧核甙酸5-FdUMPbindstothymidylatesynthetasetogiveanintermediatethatresemblestheintermediateformedwithuridylicacid,however,thisintermediatecannotbreakdownandtheenzymeisinhibited胸腺嘧啶脫氧核甙酸合成酶

Metabolismof5-fluorouracilSynthesisof5-FUbaseRingopenproductStabilityinNaHSO3

（二）Cytarabine（ARA-C,阿糖胞苷）

Pyrimidineantimetaboliteinwhichsugarismodified

胞嘧啶衍生物

胞嘧啶阿拉伯糖Thenormal2’configurationisα主要用于治療急性粒細胞白血病MetabolicactivationandinactivationofARA-C阿糖胞苷在體內(nèi)的代謝激活與失活InactivespeciesMechanismofActionforARA-C

ARA-CTPinhibitstheconversionofcytidylicacidto2’-deoxycytidylicacid

ARA-CTP抑制磷酸胞苷轉(zhuǎn)換為脫氧磷酸胞苷ARA-CTPalsoinhibitsDNA-dependentDNApolymerase

抑制依賴DNA的DNA多聚酶

ARA-CcausesmiscodingafterbeingincorporatedintoDNA

摻入DNA后編碼錯誤，DNA合成終止SynthesisofCytarabineD-阿拉伯糖氰胺2-氨基-D-阿糖噁唑啉cyclocytidine氯代丙烯氰二、PurineAntimetabolites（嘌呤拮抗劑）巰嘌呤Poorwatersolubility主要用于各種急性白血病的治療Na2SO3/H2ONa+6-MPMPinhibitsseveralkeyenzymesinvolvedinthebiosynthesisofpurineTheoverallactionof6-MPisinhibitionofthedenovosynthesisofpurinesMechanismofActionof6-mercaptopurineSynthesisofMercaptopurine硫脲三、Folicacidantimetabolites（葉酸拮抗劑）Folicacid,葉酸FolicacidisanessentialcomponentforthebiosynthesisofDNAandRNA葉酸是核酸生物合成的關(guān)鍵組分Animportantfactorforredcelldevelopment是紅細胞發(fā)育生長的重要因子Pterine，Pteridoxamine，碟呤MTXcompeteswiththenormalsubstratefolicacid,inhibitsDNAsynthesis

Folicacidantimetabolites（葉酸拮抗劑）葉酸氨基碟呤，白血寧甲氨碟呤，MTXOtherAnticancerDrugs1.Taxol,orPaclitaxel（紫杉烷）AntimicrotubleAgentTaxolpromotestheassemblyofmicrotubulesfromtubulindimersFormula：C47H51NO14。MW：853.92，1971年

PacificYew，1967紅豆杉Ovarian,breast,lungandcoloncancerMonroeE.WallTaxol?CamptothecinTMRTI，NCMansukhC.Wani2008，KetteringPrize--thehighesthonorinthefieldofcancerresearch1992年美國政府將專利轉(zhuǎn)讓給施貴寶（BMS），紫杉醇面世。1994年紫杉醇創(chuàng)世界抗癌藥物全球銷量冠軍。2000年紫杉醇銷量創(chuàng)百億（后受原料供應未有進一步上升）2004年施貴寶專利到期，全球更多藥廠介入紫杉醇生產(chǎn)。2005年中央再次發(fā)文，全國普查紅豆杉資源，鼓勵種植。2005年此項目接受個人投資者投資。2.Antiapoptoticproteininhibitors—ABT737Abott