第十二章抗腫瘤藥物Chapter12AntineoplasticDrugs第四節(jié)抗腫瘤植物藥有效成分

Section4ActiveIngredientsofAntitumorBotanicals第四節(jié)抗腫瘤植物藥有效成分

Section4ActiveIngredientsofAntitumorBotanicals

(一)喜樹堿和羥基喜樹堿Camptothecinandhydroxycamptothecin是從中國特有珙桐科植物喜樹中分離得到的兩種生物堿，作用于DNA拓?fù)洚悩?gòu)酶I，對肝癌、大腸癌、白血病等有效，但副作用較大。TheyaretwokindsofalkaloidsisolatedfromtheuniqueChinesenyssaceaeplant,camptothecaacuminata.ItactsonDNAtopoisomeraseI,andiseffectiveforlivercancer,colorectalcancer,leukemia,etc.,butthesideeffectsarerelativelylarge.喜樹Camptothecaacuminata

(二)長春堿和長春新堿Vincaleukoblastinumandvincristine與微管蛋白結(jié)合阻止微管蛋白雙微體聚合成為微管；又可誘導(dǎo)微管的解聚，使紡錘體不能形成，細(xì)胞停止于分裂中期，從而阻止腫瘤細(xì)胞分裂繁殖。Itiscombinedwithtubulintopreventtubulindoublemicrosomesfrompolymerizingintomicrotubules;itcanalsoinducethedepolymerizationofmicrotubules,sothatthespindlebodycannotbeformed,andthecellsstopinthemiddlestageofdivision,therebypreventingtumorcellsfromdividingandmultiplying.——天然的抗腫瘤生物堿，結(jié)構(gòu)中含有吲哚環(huán)——Naturalanti-tumoralkaloidwithindoleringinitsstructure長春堿用于治療各種實(shí)體瘤，長春新堿用于急性及慢性白血病等。對長春堿進(jìn)行結(jié)構(gòu)改造，合成長春地辛和長春瑞濱。Thevincaleukoblastinumisusedfortreatingvarioussolidtumors,acuteandchronicleukemia.Thestructureofthevincaleukoblastinumismodifiedtosynthesizevindesine

andvinorelbine.(三)鬼臼素及其衍生物Podophyllotoxinanditsderivatives鬼臼素是一種生物堿，具有抗癌活性，由于毒性大不能用于臨床，它的半合成衍生物依托泊苷、替尼泊苷用于臨床。Podophyllotoxinisanalkaloidwithanti-canceractivity.Itcannotbeusedclinicallyduetohightoxicity,Itssemi-syntheticderivatives,suchasetoposideandteniposidecanbeusedclinicallywith.

(四)紫杉醇Paclitaxel從紅豆杉的樹皮和樹葉中提取的生物堿，為具有紫杉烯環(huán)的二萜類化合物，臨床用于卵巢癌和乳腺癌的治療。ThealkaloidsextractedfromthebarkandleavesofTaxuschinensisarediterpenoidcompoundswithataxanering,anditisclinicallyusedfortreatingovariancancerandbreastcancer.

Paclitaxel1.結(jié)構(gòu)特點(diǎn)Structuralcharacteristics具有紫杉烷骨架的二萜類化合物Diterpenoidcompoundwithataxaneskeleton2.使用缺陷Usedefects(1)水溶性差，難制成制劑，生物利用度低Poorwatersolubility,difficulttomakepreparations,andlowbioavailability(2)含量低，來源受到限制Lowcontent,andlimitedsource紫杉醇是紅豆杉屬植物中的一種復(fù)雜的次生代謝產(chǎn)物,也是目前所了解的惟一一種可以促進(jìn)微管聚合和穩(wěn)定已聚合微管的藥物。同位素示蹤表明,紫杉醇只結(jié)合到聚合的微管上，不與未聚合的微管蛋白二聚體反應(yīng)。細(xì)胞接觸紫杉醇后會在細(xì)胞內(nèi)積累大量的微管，這些微管的積累干擾了細(xì)胞的各種功能，特別是使細(xì)胞分裂停止于有絲分裂期，阻斷了細(xì)胞的正常分裂。通過Ⅱ-Ⅲ臨床研究，紫杉醇主要適用于卵巢癌和乳腺癌，對肺癌、大腸癌、黑色素瘤、頭頸部癌、淋巴瘤、腦瘤也都有一定療效。1963年，美國化學(xué)家瓦尼和沃爾首次從一種生長在美國西部大森林中稱為太平洋杉樹皮和木材中，分離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.價(jià)格昂貴：野生紅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年樹齡的樹皮，僅僅能獲得50～100毫克的紫杉醇。據(jù)測算，即使將全世界的野生紅豆杉全部砍伐用于提取紫杉醇，也只能挽救12.5萬個(gè)生命。因此，紫杉醇售價(jià)昂貴，國際市場上每公斤售價(jià)在40萬美元以上。Itisexpensive:thewildyewisgenerallyscatteredinthedeepmountainsanddenseforestsatanaltitudeof2500-3000m.Ittakes50-250yearstobecomeatree,and1kgof100-year-oldbarkcanonlyobtain50-100mgofpaclitaxel.Itisestimatedthatevenifallthewildyewtreesintheworldwerecutdownforextractingpaclitaxel,only125,000livescouldbesaved.Therefore,paclitaxelisexpensive,andthepriceperkilogramintheinternationalmarketismorethan400,000USdollars.紫杉醇同類藥物——多西他賽（多烯紫杉醇）Similardrugsofpaclitaxel-docetaxel(taxotere)多烯紫杉醇的親和力是紫杉醇的2倍，抑制微管解聚，促進(jìn)微管二聚體形成的能力是紫杉醇的2倍。療效更好，且水溶性比紫杉醇好。Theaffinityofdocetaxe