General

Scientific Names: Cephalotaxus hainanensis

Common Names: Hai Nan Dao Jian Shan, Hai Nan Dao Cu Fei, Hai Nan Cu Fei.

 

BOTANICAL:

植物特征: 常绿乔木,树干通直,高 20-25米,胸径可达60-110厘米;树皮通常浅褐色或褐色 ,稀红紫色,裂成片状脱落。枝基部有宿存芽鳞,髓心中部具1树脂道。叶交互对生,两列 ,线形,质地较薄,中上部向上侧微弯或直,长2-4厘米,宽2.5-3.3毫米,先端急尖或渐尖 ,基部圆截形或圆形,几无柄,两面中脉隆起,上面绿色,下面有两条白色气孔带。雌雄异 株,偶有同株;雄球花6-8聚生,圆球状,腋生,直径6-9毫米,总梗长约4-5毫米,雌球 花具长梗,生于小枝基部苞腋,稀顶生,有数对交互对生的苞片,每苞腋着生2胚珠,胚珠 生于球托之上,通常2-8个发育。种子簇生于梗端,翌年成熟,下垂,全部包于肉质假种皮 中,倒卵状椭圆形、椭圆形或倒卵圆卵形,微扁,长2.2-3.2厘米,顶端有突尖,成熟时假 种皮常呈红色。

 

 

 

Pharmacology

化学成分: 海南粗榧 的根、茎、叶和果实中都含有生物碱,其主要 成分 异三尖杉酯、尖杉酯碱、脱氧三尖杉酯碱和高三尖杉酯碱。

海南粗榧,乃稀有珍贵的抗癌药物。全身含有抗癌生物碱,从它的树皮和树根中提取的总碱中,可分离出9种生物碱,其中有4种是具有抗癌活性的酯碱。这就是:异三尖杉酯、尖杉酯碱、脱氧三尖杉酯碱和高三尖杉酯碱。这些三尖杉酯碱治疗急、慢性细胞白血病有较好疗效。并且发现它们还含有其他药用价值更高的化学物质,不仅对治疗血癌有显著作用,而且能有效地抑制某些癌细胞的生长,对肺癌、恶性葡萄胎、食道癌、子宫平滑肌癌、胃癌、淋巴肉癌、上颌窦癌、何杰金氏病及其他恶性肿瘤等效果颇佳。 (source)

海南粗榧全株均含有抗癌生物碱,以树皮和树根含量高。由树皮中提取的总碱中分离出的九种生物碱中,有抗癌活性的酯碱有四种,其中的三尖杉酯碱治疗急性粗细胞白血病有良好的疗效。海南粗榧中还含有其它药用价值更高的化学物质。经肿瘤医院临床试用,证明能有效地抑制某些癌细胞的生长,不仅对治疗血癌有显著作用,而且对一些恶性肿瘤均有良好疗效。

 

 

 

Efficacy

Homoharringtonine (HHT) is an ester of cephalotaxine (CET), both of which derive from the Chinese coniferous tree Cephalotaxus hainanensis. HHT inhibited tumor cell growth at molar ranges comparable to established cytostatic drugs, whereas CET was 3-4 orders of magnitude less active. Inhibition concentration 50% (IC50) values of CET and HHT were significantly correlated to doxorubicin, vincristine, methotrexate, cisplatin, or camptothecin in 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute (NCI, Bethesda, Md., USA). We tested both drugs for resistance of cell lines which selectively overexpress the multidrug resistance (MDR)-conferring genes P-glycoprotein/ MDR1 (CEM/ADR5000), MDR-related protein 1 MRP1 (HL60/AR), and breast cancer resistance protein BCRP (MDA-MB-231-BCRP). A threefold and ninefold resistance to HHT and CET, respectively, was found in CEM/ADR5000 cells, while the other MDR cell lines did not show cross-resistance compared to their drug-sensitive counterparts. As the tumor suppressor p53 is another important factor of chemoresistance, we also analyzed the possibility that p53 affects the response of tumor cells to CET and HHT. Comparing the p53 mutational status of the 55 NCI cell lines (http://dtp.nci.nih.gov) with the IC50 values showed a significant correlation. Thus, CET and HHT were more active in cell lines without p53 mutation. We correlated the IC50 values of CET and HHT with the cell doubling times of the 55 NCI cell lines as proliferation parameter and observed that rapidly growing cells were more susceptible than slowly growing cell lines. We conducted a search mining the NCI's database for the mRNA expression of 465 genes in 55 cell lines and correlated the data with the IC50 values for CET and HHT. Of these genes 61 (=13%) correlated with the IC50 values for CET and 122 (=26%) with the IC50 values for HHT indicating the multifactorial mode of action of these drugs in cancer cells. We have chosen one example from these genes to test a causative role for drug response. U-87MG.DeltaEGFR cells transfected with an epidermal growth factor receptor ( EGFR) gene truncated in its extracellular domain through a deletion of exons 2-7 (Delta EGFR) were 14-fold more resistant to HHT than control cells transfected with mock expression vector or non-transfected cells. (source)

Harringtonine (HT) and homoharringtonine (HHT) are two alkaloids isolated from the bark of the evergreen tree Cephalotaxus hainanensis Li in the 1970s. They were found to have activity against murine leukemia, Lewis lung carcinoma and B16 melanoma, and used as anti-leukemia drugs clinically. Apoptosis is an active process of programmed cell suicide and now is believed to be an important target for tumor chemotherapy. In this report, the apoptosis inducing effect of HT and HHT in HL-60 cells were observed. The experiments demonstrated that 2 x 10(-7) mol.L-1 of HT and 10(-7) mol.L-1 of HHT could induce apoptosis in HL-60 cells when the cells were exposed to HT and HHT for 4 h. In agarose gel electrophoresis, DNA extracted from HL-60 cells treated with HT and HHT showed a typical internucleosomal DNA degradation, i.e., DNA ladder and parallel morphological changes as nuclear chromosome segmentation and condensation as well as cytoplasma vacuolation. This effect of HT and HHT was shown to appear in a concentration- and time-dependent manner. The efficacy of HT and HHT in inducing apoptosis of HL-60 cells was found to parallel with their cytotoxic activity in HL-60 cells. These results suggest that the mechanism of antitumor action of HT and HHT is related to their apoptosis inducing activity. (source)

海南粗榧(红壳松)树皮已提炼出21种单体生物碱,其中三尖杉酯碱、高山尖杉酯碱、异三尖杉酯碱、脱氧三尖杉酯碱具有抗癌作用,对自血病及恶性淋巴瘤也有较好的疗效。近年来,已经多家肿瘤医院临床试用,对治疗白血病有显著作用,对其他恶性肿瘤亦有一定的效果。 (source)

三种植物(三尖杉,中华粗榧,海南粗榧)的总生物碱对各个类型的白血病及恶性淋巴瘤均有较显著的疗效,对肺癌,绒癌,及恶性葡萄胎可能有一定疗效。对恶性淋巴瘤患者应用三尖杉总生物碱后发现,淋巴结中肿瘤细胞数减少,瘤细胞减少区域剩余者多为分化较好的成熟淋巴细胞核分裂基本找不到,提示三尖杉总碱有抑制肿瘤细胞增生的作用。对小鼠L1210白血病细胞杀伤动力学研究,认为本品属于周期非特异性药物对S期细胞杀伤较为明显。三尖属植物中的酯类生物碱对各类型白血病及恶性淋巴瘤有效,对急性粒细胞性白血病,急性单核细胞性白血病和急性早幼粒细胞性白血病的疗效较好,特别可用于白细胞数低的病例。 (source)

IN VITRO:

  1. Effetrth T, et al., Molecular modes of action of cephalotaxine and homoharringtonine from the coniferous tree Cephalotaxus hainanensis in human tumor cell lines. Naunyn Schmiedebergs Arch Pharmacol. 2003 Jan; 367(1):56-67. Epub 2002 Nov 5.
  2. Li L, et al., [Induction of apoptosis by harringtonine and homoharringtonine in HL-60 cells]. Yao Xue Xue Bao. 1994; 29(9):667-72. Chinese.
  3. Fang M, et al., [Apoptosis resistance and its reversal in harringtonine resistant cell line]. Yao Xue Xue Bao. 1994; 29(12):891-8. Chinese.
  4. Kato T, et al., [Antitumor activities and mechanisms of action of harringtonine and homoharringtonine]. Gan To Kagaku Ryoho. 1984 Nov; 11(11):2393-9. Japanese.
  5. [No authors listed]. [Chemical, pharmacological and clinical studies on the antitumor active principle of Cephalotaxus hainanensis Li (author's transl). Zhonghua Zhong Liu Za Zhi. 1979; 1(3):176-82. Chinese.




 

Safety

不良反应: 主要有头晕,乏力,恶心,呕吐,食欲不振,肌注局部疼痛。对造血系统有明显的抑制作用,可使白细胞明显下降,血小板亦可降低。部分病人发生心脏毒性,表现为心悸,胸闷,心动过速,心肌损害,极个别发生奔马律,房室传导阻滞,甚至心衰。


 
   
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