第十二章抗肿瘤药物ChapterAntineoplasticDrugs讲解

第十二章抗肿瘤药物Chapter12AntineoplasticDrugs第四节抗肿瘤植物药有效成分

Section4ActiveIngredientsofAntitumorBotanicals第四节抗肿瘤植物药有效成分

Section4ActiveIngredientsofAntitumorBotanicals

(一)喜树碱和羟基喜树碱Camptothecinandhydroxycamptothecin是从中国特有珙桐科植物喜树中分离得到的两种生物碱，作用于DNA拓扑异构酶I，对肝癌、大肠癌、白血病等有效，但副作用较大。TheyaretwokindsofalkaloidsisolatedfromtheuniqueChinesenyssaceaeplant,camptothecaacuminata.ItactsonDNAtopoisomeraseI,andiseffectiveforlivercancer,colorectalcancer,leukemia,etc.,butthesideeffectsarerelativelylarge.喜树Camptothecaacuminata

(二)长春碱和长春新碱Vincaleukoblastinumandvincristine与微管蛋白结合阻止微管蛋白双微体聚合成为微管；又可诱导微管的解聚，使纺锤体不能形成，细胞停止于分裂中期，从而阻止肿瘤细胞分裂繁殖。Itiscombinedwithtubulintopreventtubulindoublemicrosomesfrompolymerizingintomicrotubules;itcanalsoinducethedepolymerizationofmicrotubules,sothatthespindlebodycannotbeformed,andthecellsstopinthemiddlestageofdivision,therebypreventingtumorcellsfromdividingandmultiplying.——天然的抗肿瘤生物碱，结构中含有吲哚环——Naturalanti-tumoralkaloidwithindoleringinitsstructure长春碱用于治疗各种实体瘤，长春新碱用于急性及慢性白血病等。对长春碱进行结构改造，合成长春地辛和长春瑞滨。Thevincaleukoblastinumisusedfortreatingvarioussolidtumors,acuteandchronicleukemia.Thestructureofthevincaleukoblastinumismodifiedtosynthesizevindesine

andvinorelbine.(三)鬼臼素及其衍生物Podophyllotoxinanditsderivatives鬼臼素是一种生物碱，具有抗癌活性，由于毒性大不能用于临床，它的半合成衍生物依托泊苷、替尼泊苷用于临床。Podophyllotoxinisanalkaloidwithanti-canceractivity.Itcannotbeusedclinicallyduetohightoxicity,Itssemi-syntheticderivatives,suchasetoposideandteniposidecanbeusedclinicallywith.

(四)紫杉醇Paclitaxel从红豆杉的树皮和树叶中提取的生物碱，为具有紫杉烯环的二萜类化合物，临床用于卵巢癌和乳腺癌的治疗。ThealkaloidsextractedfromthebarkandleavesofTaxuschinensisarediterpenoidcompoundswithataxanering,anditisclinicallyusedfortreatingovariancancerandbreastcancer.

Paclitaxel1.结构特点Structuralcharacteristics具有紫杉烷骨架的二萜类化合物Diterpenoidcompoundwithataxaneskeleton2.使用缺陷Usedefects(1)水溶性差，难制成制剂，生物利用度低Poorwatersolubility,difficulttomakepreparations,andlowbioavailability(2)含量低，来源受到限制Lowcontent,andlimitedsource紫杉醇是红豆杉属植物中的一种复杂的次生代谢产物,也是目前所了解的惟一一种可以促进微管聚合和稳定已聚合微管的药物。同位素示踪表明,紫杉醇只结合到聚合的微管上，不与未聚合的微管蛋白二聚体反应。细胞接触紫杉醇后会在细胞内积累大量的微管，这些微管的积累干扰了细胞的各种功能，特别是使细胞分裂停止于有丝分裂期，阻断了细胞的正常分裂。通过Ⅱ-Ⅲ临床研究，紫杉醇主要适用于卵巢癌和乳腺癌，对肺癌、大肠癌、黑色素瘤、头颈部癌、淋巴瘤、脑瘤也都有一定疗效。1963年，美国化学家瓦尼和沃尔首次从一种生长在美国西部大森林中称为太平洋杉树皮和木材中，分离到了紫杉醇的粗提物。PaclitaxelisacomplexsecondarymetaboliteinTaxusplant,anditisalsotheonlyknowndrugthatcanpromotemicrotubulepolymerizationandstabilizeaggregatedmicrotubules.Isotopetracinghasshowedthatpaclitaxelisonlycombinedwithpolymerizedmicrotubulesinsteadofreactingwithunpolymerizedtubulindimers.Afterthecellscontactwithpaclitaxel,alargenumberofmicrotubuleswillbeaccumulatedinthecells.Theaccumulationofthesemicrotubulesinterfereswithvariousfunctionsofthecells,especiallythecelldivisionstopsinthemitoticphaseandblocksthenormaldivisionofthecells.ThroughⅡ-Ⅲclinicalresearch,paclitaxelismainlysuitableforovariancancerandbreastcancer,andalsohascertainefficacyonlungcancer,colorectalcancer,melanoma,headandneckcancer,lymphomaandbraintumor.In1963,Americanchemists,VarneyandWallfirstisolatedacrudeextractofpaclitaxelfromthebarkandwoodofPacificfirthatgrowsinthegreatforestsofthewesternUnitedStates.价格昂贵：野生红豆杉一般散生在海拔2500-3000米的深山密林中，成材需50-250年，而1千克100年树龄的树皮，仅仅能获得50～100毫克的紫杉醇。据测算，即使将全世界的野生红豆杉全部砍伐用于提取紫杉醇，也只能挽救12.5万个生命。因此，紫杉醇售价昂贵，国际市场上每公斤售价在40万美元以上。Itisexpensive:thewildyewisgenerallyscatteredinthedeepmountainsanddenseforestsatanaltitudeof2500-3000m.Ittakes50-250yearstobecomeatree,and1kgof100-year-oldbarkcanonlyobtain50-100mgofpaclitaxel.Itisestimatedthatevenifallthewildyewtreesintheworldwerecutdownforextractingpaclitaxel,only125,000livescouldbesaved.Therefore,paclitaxelisexpensive,andthepriceperkilogramintheinternationalmarketismorethan400,000USdollars.紫杉醇同类药物——多西他赛（多烯紫杉醇）Similardrugsofpaclitaxel-docetaxel(taxotere)多烯紫杉醇的亲和力是紫杉醇的2倍，抑制微管解聚，促进微管二聚体形成的能力是紫杉醇的2倍。疗效更好，且水溶性比紫杉醇好。Theaffinityofdocetaxe