General

Scientific Names: Camptotheca acuminata Decne.

Common Names: Xi Shu, Han Lian, Shui Tong Shu, Tian Zi Shu, Ye Ba Jiao, Han Lian Mu, Shui Mo Zi, Nanjing Wu Tong, Shui Dong Gua, Yuan Mu, Qian Zhang Shu.

BOTANICAL:

Camptotheca acuminata is a member of the family Nyssaceae (tupelo family) and is native only to China and Tibet, where it is known as xi shu ("happy tree"). Its primary anti-cancer ingredient is a quinoline alkaloid called camptothecin , which in turn has been modified to create a host of other anti-cancer drugs, including irinotecan, topotecan, 9-aminocamptothecin, and CPT-11. Camptothecin and these analogs are being investigated to treat a wide variety of cancers, but the compounds are quite toxic, and only topotecan (Hycamtin) and irinotecan HCl (Camptosar) have met with FDA approval; Hycamtin has been approved for ovarian cancer theray, and Camptosar is approved for metastatic colorectal cancers.

Western researchers (Dr. Monroe E. Wall of the USDA and Jonathon Hartwell of the National Cancer Institute) first discovered Camptotheca's anticancer properties in 1958. In 1966, after Wall joined the Research Triangle Institute , he and other researchers isolated camptothecin. A camptothecin analog (camptothecin sodium) was tested on gastrointestinal cancer patients in the early 70's, but the clinical trials were discontinued because the patients suffered severe side effects. Researchers continued to investigate camptothecin to develop drugs with fewer side effects, and their work began to bear fruit in the late 80's. In China, camptothecin has been used to treat leukemia and cancers ( carcinomas ) of the stomach and liver.

Camptotheca goes by many names in its native lands. Xi shu translates as "happy tree" and has been called this by people whom it cured of colds and other illnesses. Its other names include long shu (dragon tree), ,jia shu (fine tree), and tian zi shu (heaven wood tree). The Chinese have also used this tree for firewood and as an ornamental plant. All American specimens of the Camptotheca are descendants of two trees germinated from seeds brought from China in the 1930s.

The Chinese have used xi shu for traditional drug purposes for hundreds, and possibly thousands, of years. They have employed xi shu against psoriasis and in the treatment of diseases of the liver, gallbladder, spleen, and stomach. Xi shu has also been used to treat leukemia . In fact, one common name for Camptotheca is the "cancer tree". For treating cancer its primary constituent is camptothecin, which inhibits topoisomerase I, an enzyme linked with cell division and DNA replication. By inhibiting this enzyme, camptothecin appears to stunt tumor growth. A host of other anticancer drugs have been modified from camptothecin, two of which are approved by the U.S. Food and Drug Administration. Topotecan is used to treat ovarian and small lung cancers . Irinotecan is used to treat metastatic colorectal cancer , the second leading cause of cancer deaths in the United States. Other camptothecin related drugs are no longer in use because of their severe toxicity.

资源分布: 喜树果 Fructus seu Radix Camptothecae Acuminatae 产于江苏、浙江、福建、江西、湖北、湖南等地。主销上海、湖北等地。

生药材鉴定: 1.性状鉴别:果实披针形,长2-2.5cm,宽5-7mm,先端尖,有柱头残基;基部变狭,可见着生在花盘上的椭圆形凹点痕,两边有翅。表面棕色至棕黑色,微有光泽,有纵绉纹,有时可见数条角棱和黑色斑点。质韧,不易折断,断面纤维性,内有种子1粒,干缩成细条状。气微,味苦。 2.显微鉴别:果实横切面:外果皮为一列扁平细胞;中果皮为多列薄壁细胞,含红棕色物,维管束十数个,散列,外侧具纤维群,纤维壁厚,木化;内果皮为数列厚壁纤维。种皮细胞由棕色扁平细胞组成;鲜品的胚乳细胞和子叶细胞内充满内含物,干后萎缩。 3.理化鉴别:取样品粉末2g,用80%乙醇30ml回流30分钟,放冷,滤过,滤液减压蒸去乙醇,放冷,滤过,滤液用含有10%乙醇的氯仿溶液提取,浓缩提取液,作供试液,以喜树碱和10-羟基喜树碱制对照溶液。吸取二溶液,点于硅胶G板上,以氯仿-丙酮(7:3)为展开剂,展距13m,于紫外光灯下(254nm)观察,样品与对照品色谱在相对应的位置处显相同颜色的荧光斑点。

 

Pharmacology

Variations in camptothecin (CPT) content in relation to leaf characteristics namely leaf area, leaf biomass, and specific leaf area (leaf area divided by leaf biomass), and the influence of climatic factors on CPT content in saplings of Camptotheca acuminata Decne. were studied. Leaf area and CPT content showed a logarithmic relationship in young leaves similar to that between leaf biomass and CPT content, while CPT content was linearly correlated to specific leaf area. There was no apparent relationship between each leaf characteristic and CPT content in old leaves. CPT contents in sapling leaves showed large variation from May to September and were highly correlated to the variation in the level of climatic factors, where high average temperature, high evaporation capacity and low precipitation increased CPT content according to stepwise regression analysis. This suggests that adverse growing conditions can induce CPT accumulation to enhance chemical defense in C. acuminata . Young leaves with area of 70 cm 2 -100 cm 2 gave the highest quantity of CPT per leaf, thus the optimal harvest period would be when young leaves expanded to these sizes. In addition, sample collection on dry days is preferable as it increases CPT content in raw materials. (Source)

中药化学成分: 全株含喜树碱(Camptothecine),根中含率约0.008%,根、根皮、树皮、果实、树枝含量分别为1∶2∶1∶2.5∶0.4。根中尚含喜树次碱即印度鸭脚树碱Venoter-Pine),3,3',4-三甲基并没食子酸(3,3',4-Tri-o-methyl-ellagic acid)及谷甾醇。干木中还含羟基喜树碱(Hydrox-ycamptothecine), 甲氧基喜树碱Methoxycamptothe-cine)。果实中还含羟基喜树碱、去氧喜树碱(Deoxycam-ptothecine)、喜树次碱、白桦脂酸(Betulic acid)和喜果甙即长春甙内酰胺(Vincoside-lactam)。

从喜树的果实中分得下列化合物:喜树碱(camptothecine),10-羟基喜树碱(10-hydroxy camptothecine),11-甲氧基喜树碱(11-methoxycamptothecine),去氧喜树碱(deoxy-camptothecine),喜树次碱(venoterpine),白桦脂酸(betulic acid),长春花甙内酰胺(vincoside-lactam),11-羟基喜树碱(11-hy-droxycamptothecine),10-甲氧基喜树碱(10-methoxycamp-tothecine),3,4-O,O-亚甲基并没食子酸(3,4-O,O-methyleneel-lagic acid),3',4'-O-二甲基-3,4-O,O-亚甲基并没食子酸(3',4'-O-dimethyl-3,4-O,O-methyleneellagic acid),3,4-O,O-亚甲基-3',4'-O-二甲基-5'-甲氧基并没食子酸(3,4-O,O-methlene-3',4'-O-dimethyl-5'-methoxyellagic acid),3,4-O,O-亚甲基-3',4'-O-二甲基-5'-羟基并没食子酸(3,4-O,O-methylene-3',4'-O-dimethyl-5'-hydroxyellagic acid),3,4'-O-二甲基并没食子酸(3,4'-O-dimethylellagic acid),3,4,3'-O-三甲基并没食子酸(3,4,3'-O-trimethylellagic acid),3'-O-甲基-3,4-O,O-次甲基并没食子酸(3'-O-methyl-3,4-O,O-methylidyneellagic acid),3,4-O,O-次甲基并没食子酸(3,4-O,O-methylidyneellagic acid),3,4-O,O-次甲基-3',4'-O-二甲基并没食子酸(3',4'-O-dimethyl-3,4-O,O-methyli-dyneellagic acid),3,4-O,O-次甲基-3,4'-O-二甲基-5'-甲氧基并没食子酸(5'-methoxy-3',4'-O-dimethyl-3,4-O,O-methyli-dyneellagic acid),3,3',4,4'-O-四甲基-5'-甲氧基并没食子酸(3,3',4,4'-O-tetramethyl-5'-methoxyellagic acid),5'-羟基-3',4'-O-二甲基-3,4-O,O-次甲基并没食子酸(5'-hydroxy-3',4'-O-dimethyl-3,4-O,O-methylidyneellagic acid),丁香酸(syringicacid),10-羟基脱氧喜树碱(10-hydroxydeoxycamptothecine),喜树矛因碱(camptacumothine),喜树曼宁碱(camptacumanine),乌檀费新碱(naucleficine),牛眼马钱托林碱(angustoline),二氢异喹胺(dihydroipouinamine),长梗马兜铃素(pedunculagin),19-O-甲基牛眼马钱托林碱(19-O-methylangustoline),22-羟基旱莲木碱(22-hydroxyacuminatine),19-羟基臭马比木碱(19-hy-droxymappicine),氧代儿茶钩藤丹宁碱(oxogambirtannine),18-羟基喜树碱(18-hydroxycamptothecin),吕宋果内酯(strychno-lactone),水杨酸(salicylic acid),壬二酸(nonandioic acid),止权酸(d-abscisic acid),丁香树脂酚(syringaresinol),β-谷甾醇(β-siiosterol),咖啡酸乙酯(ethyl caffeate),熊果酸(ursolic acid),肌醇(inositol)。 从喜树的根中分得喜树碱,并没食子酸-3,4,3'-三甲醚(3,4,3'-tri-O-methylellagic acid),喜树次碱,β-谷甾醇及β-谷甾醇3-β-D-葡萄糖甙(β-sitosterol 3-β-D-glucoside)。根皮中含有20-去氧喜树碱(20-dooxycamptothecin),20-己酰喜树碱(2O-hexanoylcamptothecine),20-己酰基-10-甲氧基喜树碱(20-hexanoyl-10-methoxy camptothecin)。 从喜树的木质部中分得喜树碱,1O-甲氧基喜树碱,11-羟基-(20s)-喜树碱。

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Efficacy

主治: 食道癌,贲门癌,胃癌,肠癌,肝癌,白血病.

抗肿瘤作用:喜树果、根皮的醇提取物对动物移植性肿瘤,均有一定抑制作用。喜树果或根皮中所含喜树碱及其衍生物,具有较强的抗癌活性。喜树碱体外对白血病L1210有明显的抑制作用,ID50为1.36 ×l0(-4)μm/ml;对HeLa细胞和多种肿瘤细胞均有抑制作用。喜树碱0.25-25mg/kg腹腔注射,连续7-10天,可延长白血病L1210、L5178Y、K1946、P388小鼠的生存时间1倍以上。对白血病L615和腹水型肝癌小鼠也可延长其生存时间。对小鼠Lewis肺癌、黑色素瘤B16、脑瘤B22、艾氏腹水癌及大鼠W256癌肉瘤及吉田肉瘤等多种实体瘤,均有明显抑制作用。喜树碱对小鼠白血病L1210和P388的各种耐药瘤株,也有抑制作用。10-羟基喜树碱1-2mg/kg,腹腔注射,连续7-9天,可明显延长白血病L1210、P388、艾氏腹水癌、腹水肝癌、网织细胞肉瘤腹水型小鼠和吉田肉瘤腹水型大鼠等的生存时间119%-280%。对小鼠肉瘤180、肉瘤37、宫颈癌U14、大鼠W256癌肉瘤等实体瘤生长均能抑制。喜树碱主要肢坏瘤细胞DNA结构,又抑制DNA聚合酶而影响DNA的复制。对细胞周期中S期有明显抑制作用,对G1期和G2期细胞亦有影响,对G0期细胞没有作用。喜树碱1mg/ml体外培养,能抑制HeLa细胞和L5178Y等细胞的DNA和RNA的合成,但在相同的浓度作用下,对大鼠肝、脑细胞的线粒体并不抑制,表明喜树碱对肿瘤细胞的作用大于对正常细胞的作用。喜树碱多相脂质体腹腔注射对小鼠肝癌细胞具有抑制增殖的效应,其对肝癌细胞DNA合成的最高抑制率为73.7%,作用时间约4小时,对癌细胞RNA合成抑制率达82.9%。对肉瘤S180及肝癌腹水型细胞(Heps)的抑制率可达74%及82%。可使艾氏腹水癌(EAC)小鼠的生命延长126%;喜树碱钠盐对S180及Heps的抑制率可达52%及53%,可使荷EAC小鼠的生命延长54%。

喜树碱1.0、2.0 mg/kg腹腔注射连续7天,对小鼠脑瘤-22有抑制是作用;0.7、1.5 mg/kg腹腔注射连续7天,对大鼠瓦克癌(W250)有抑制作用;1mg/kg腹腔注射,连续10天,对小鼠艾氏腹水癌实体型有抑制作用;2.0、3.0 mg/kg腹腔注射,7-10天,可延长吉田肉瘤大鼠的生命;5、10、20 mg/kg腹腔注射,可明显抑14C-腺嘌噙对小鼠腹水型肝癌细胞DNA及RNA的掺入。喜树碱40 mg/kg腹腔注射对小鼠白血病L5178y、K1964等均有抑制作用。喜树碱25 mg/kg,每四天给L1210小鼠注射1次,能明显延长生存时间,1次剂量后,药物在腹水中的半衰期为35分钟,但对合成脱氧核糖核酸产生的抑制作用达24小时,对核糖核酸也有抑制影响。对培养人食管癌109细胞的作用。喜树碱5μg/ml现加高温(43.5℃)处理,有协同杀伤癌细胞的作用,喜树碱5μg/ml有诱导Hela细胞核仁分离现象,接触3小时,即出现核仁明显改变,交织紧密的颗粒与纤维成分分离。羟基喜树碱1.0 mg/kg腹腔注射,连续10天,可延长艾氏腹水癌小鼠的生命;1.0、2.0 mg/kg腹腔注射器,连续19天,可抑制小鼠子宫颈癌U14;6.0 mg/kg灌胃,连续8天,可抑制小鼠肉瘤-180(S150);2.0 mg/kg腹腔注射,连续10天,对小鼠肉瘤-37(S37)有抑制作用。羟基喜树碱10、20 mg/kg腹腔注射,给药后2及6小时观察其对小鼠腹水型肝癌细胞超微结构的影响,发现羟基喜树碱对癌细胞与肝细胞的超微结构变化是相近的,最后导致细胞破裂、核溶解,只是肝细胞要比癌细胞的受捐程度略轻。

免疫抑制作用:喜树碱小鼠小剂量(1mg/kg)腹腔注射,连续9次,对肿瘤相伴免疫性有明显的抑制作用;大剂量40mg/kg 1次冲击,对免疫抑制较小。喜树碱引起的免疫抑制是暂时的,停药9天免疫功能得以恢复。但也有报道,每日腹腔注射喜树碱前体多相脂质体0.5mg/kg,连续9天,对小鼠肿瘤相伴免疫没有明显影响。用兔眼球结膜体外细胞培养和活体兔结膜下埋线并用喜树碱对埋线周围成纤维细胞的增殖进行抑制实验,结果证明,喜树碱无论在体内还是体外,均有显著的抑制成纤维细胞增生的作用。

IN VITRO:

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CLINICAL:

临床运用: 喜树制剂治疗胃癌及结肠、直肠癌,据部分病例观察,有效病例多在用药2-4周后症状改善,如食欲增进,体重增加,肿块缩小或钡餐检查病灶变小等。对肺癌、食道癌、淋巴肉瘤、膀胱癌、恶性葡萄胎及绒毛膜上皮癌、头颈部癌肿中的圆柱瘤型腺癌、白血病等也有一定疗效。对肝癌的有效率低,大剂量使用时又易引起肝出血等不良后果。可惜用药后的近期疗效虽较显著,但缓解期很短,重复用药时疗效差,且因其毒性反应大,往往有些患者不能使用较长疗程而被迫停药。 因此,在用药后当肿块缩小到不能再进一步缩小时,应争取进行放射治疗或手术切除,以期达到根治目的。制剂、用法及用量: 1.1.喜树碱:静脉注射--常规剂量为5-10mg,加生理盐水20ml,每日1次;或15-2Omg,加生理盐水20ml,隔日1次,总量均以100mg为一疗程。大剂量用20mg,加生理盐水20ml,每日1次,以总量300mg为一疗程。动脉注射--少数肝癌或头颈部肿瘤患者,采用动脉插管注射;少数胃癌患者在手术时注射于胃网膜动脉内;每次5-10mg,加入生理盐水10-20ml;或加入生理盐水250ml中行动脉滴注,每日1次。胸腹腔注射--用于癌性胸水与腹水患者。抽水后(胸水尽量抽出,腹水抽出部分),用10-20mg或30mg加入生理盐水20或30ml中注入,每周2次。肿瘤局部注射--每次用5-10mg直接注射于转移性肿块内,每日或隔日1次。膀腕灌注--用20或3Omg加入生理盐水20或30ml中,排空小便后进行膀胱灌注。每日1次,一般连用3次;或每周2-3次。此外,尚有肌肉注射、穴位注射等用法。 1.2.喜树果浸膏:每日量约相当于生药2-3钱,分3-4次服。注射液--每2ml含生药8g。每日用2-8ml,肌肉注射、静脉注射或静脉滴注。喜树碱有相当的毒性反应,主要表现在消化系、泌尿系,及造血功能的抑制等。如食欲不振,恶心呕吐,血尿,白细胞下降等。有些病例有严重的脱发,皮疹,难以控制的腹泻(若不及时采取措施,有致命危险)及期外收缩,心悸,神经精神症状等。喜树果浸膏制剂的副作用较喜树碱为小,主要是消化道反应,膀胱炎反应则比较少见,骨髓抑制亦不严重,在一定剂量下可以长期用药达3个月以上。

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Safety

用药忌宜: 内服不宜过量。 1.《浙江民间常用草药》:“忌用铁器煎煮、调制。” 2.上海《中草药学》:“一般认为果的作用较根皮佳,但毒性也大。”

毒理学: 喜树碱腹腔注射对小鼠的半数致死量为±83.6±6.2 mg/kg。羟基喜树碱腹腔注射对小鼠的半数致死量为104±11 mg/kg。喜树碱钠盐对动物的毒性,灌胃较静脉注射为大,大鼠半数致死量静脉注射为234.1 mg/kg,灌胃为153.2 mg/kg;小鼠半数致死量静脉注射为57.3 mg/kg,灌胃为26.9 mg/kg。喜树碱钠盐给狗一次胸脉注射20-80 mg/kg,可致严重的出血性肠炎并致死;每日给药0.15-1.9 mg/kg,连续14天,对狗的亚急性毒性可出现中性白细胞、淋巴细胞和血小板减少,并有轻度贫血及中度的肝损害。喜树碱对胃肠道的毒性较大,对肾结扎的大鼠试验表明,静脉注射0.4-400 mg/kg,90分钟内胆囊内的喜树碱钠盐量达到注射量的一半以上,胆汁内的浓度300倍于血浆内浓度,说明喜树碱胃肠道毒性反应较突出的原因。

 

 

   
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