虎眼万年青总皂苷防治肝癌作用的初步实验研究
|
摘要
目的:探讨虎眼万年青总皂苷在肝损伤硬化,肝癌发生、发展中的防治作用及其影响。
方法:二乙基亚硝胺诱发大鼠肝癌变,虎眼万年青总皂苷干预,运用常规HE染色法观察肝组织病理形态改变;采用比色分析法检测丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)的活性;运用免疫组化方法观察并分析肝组织标本中增殖细胞核抗原(Ki67)、血管内皮生长因子受体-1(Flt-1)的表达。
结果:(1)12周肝硬化阶段模型组以出现增生结节,嗜碱性变,透明变,水变性为主;14周后模型组出现大量的“灶中灶”现象,18周模型组全部出现癌变。而虎眼万年青总皂苷预防组12周时减少嗜碱性细胞结节以出现少量假小叶、纤细纤维间隔、灶状变性为主。14周预防组假小叶、不规则纤维间隔、肝细胞灶状水变性、脂肪变性为主。14周治疗组以部分处肝硬化、变性轻度为特点。18周肝癌治疗组出现肝硬化、增生结节、灶状变性,同时癌周出现包裹性的囊肿。(2)在肝损伤硬化、肝癌的发生发展阶段MDA含量逐渐增高;SOD在12周模型组显著增高,与趋于正常组水平的模型14周、模型18周组均有统计学差异。SOD活力在虎眼万年青作用的12周预防组低于12周模型组,且有统计学差异。而在14周、18周虎眼万年青总皂苷作用组与相应模型组间,无显著差异。GSH-Px活力在模型组12周、14周、18周逐渐下降,相互间有显著性差异。虎眼万年青总皂苷作用组明显提高GSH-Px活力,并与相应的模型组间均有显著性差异。(3)肝癌变过程中以12周模型组Ki67LI表达最高,14周及18周模型组Ki67 LI逐渐降低,与12周模型组比较有统计学意义。虎眼万年青总皂苷作用的12周预防组Ki67 LI较低且与相应12周模型组有统计学意义。诱癌14周模型组Flt-1 LI表达最高,12周及18周模型组Flt-1 LI相对低下,与14周模型组比较有统计学意义。虎眼万年青总皂苷作用的14周预防组、治疗组Flt-1 LI降低,且与模型组有统计学意义。
结论:(1)虎眼万年青总皂苷以癌周出现囊肿阻断癌灶血液供应起到抑制肝癌发展,诱导肝癌细胞凋亡,起到治疗肝癌的作用。(2)虎眼万年青总皂苷具有降低MDA的生成作用,尤以肝损伤硬化阶段明显;虎眼万年青总皂苷干预SOD活力水平发生在肝损伤硬化阶段;虎眼万年青总皂苷在肝癌促进、发生发展阶段中能够增加GSH-Px的活力,提高抗氧化系统功能,降低对毒物的敏感性。(3)肝癌变过程中以肝损伤硬化阶段肝细胞增生活跃,而虎眼万年青总皂苷干预此阶段的肝细胞增生。肝癌变过程中在肝癌发生阶段Flt-1表达较高,虎眼万年青总皂苷干预此阶段Flt-1表达。
Objective:To study the anti-tumor effect of Ornithogalum Caudatum Ait total saponin(OCA-TS) on living diethylnitrosamine(DEN) induced hepatocarcinogenesis rat.
Methods:the OCA-TS was administeredto interfere the hepatocarcinogenesis induced with DEN in rats,and the dynamic expression of pathological evolution,antioxidative activities of SOD,GSH-Px and the content of MDA were investigated by the colorimetric method in rat serum. Ki67 and Flt-1 were observed with immunohistochemical staining respectively.
Results,As a result the procession of hepatocarcinogenesis in this model included three stages-hepatic toxic lesion、hepatic proliferation/ cirrhosis and hepatic carcinogenesis.Hyperplasia node,Basophilic cell lesions,lucencied and watering denaturalization appeared in the 12 weeks model group;a lot of foci-in-foci phenomenon appeared in the 14 weeks model group;carcinoma node appeared in the 18 weeks model group.Sprinkle basophilic cell lesions and fake flocculi,fibre alternation,local denaturalization appeared in the 12 weeks prevent group with OCA-TS;fake flocculi,abnormity fiber alternation,local watering and fatting denaturalization appeared in the 14 weeks prevent group with OCA-TS; segment hepatocirrhosis and gently denaturalization appeared in the 14 weeks treated group with OCA-TS.Hepatocirrhosis,hyperplasia node,local denaturalization and wrap around carcinoma with cyst appeared in the 18 weekstreated group with OCA-TS.Under the electronic microscope,part of vacuole,lipid droplet,cristae rupture,swelling,and metamorphose in the mitochondrion and endoplasmic reticulum expanded appeared in the 14 weeks model group.Some part of mitochondrion-endoplasmic reticulum complex appeared in the 14 weeks prevent group.Some part of vacuole,lipid droplet and cristae rupture appeared in the 14 weeks treated group,but there were no metamorphose in the mitochondrion and endoplasmic reticulum expand.Nuclear cataclasm,chromatin gather in the board,mitochondrion contract,endoplasmic reticulum swelling,and pull off granule appeared in the 18 weeks model group.Mitochondrion swelling,vacuole,lipid droplet,cristae rupture,endoplasmic reticulum expand,nuclear membrane metamorphose and chromatin distributing odds appeared in the chemotherapy group.Mitochondrion swelling and vacuole,endoplasmic reticulum expand with a lot of granule,cell plasma loosen appeared in the 18 weeks group treated with OCA-TS.The level of MDA increased remarkably in the 12 weeks、14 weeks and 18 weeks model group,and the content of MDA decreased by OCA-TS,there has significance between the groups administered with OCA-TS and the model groups respectively.In the 12 weeks model group the activities of SOD increased remarkably,but it tend to normal group in the 14 weeks,18 weeks model group.The expression of SOD in the 12 weeks prevent group administered with OCA-TS were lower than the 12weeks model group,maybe it dependent the level of MDA.The expression of GSH-Px activities decreased gradually in the 12 weeks、14 weeks and 18 weeks model group,and there have significance among of them.The expression of GSH-Px increased in the group administered with OCA-TS,and there have significance between the same periods model group respectively.We found the expression of Ki67 labeling index(LI) were significantly higher in the group of experiment than the normal group.The expression of Ki67 LI were highest in the 12 weeks model group,the OCA-TS interfered the expression of Ki67 LI in this periods significantly.And the Ki67 LI decreased gradually in the 14 weeks and 18 weeks model group,there have significant correlation between the 12 weeks model group respectively. And in these periods the OCA-TS interfered the expression of Ki67 LI not too much.We also found the expression of F1t-1 labeling index(LI) were significantly higher in the group of experiment than the normal group. The expression of Flt-1 LI were highest in the 14 weeks model group,the OCA-TS.interfered the expression of Flt-1 LI in this periods significantly. And the Flt-1 LI decreased in the 12 weeks and I8 weeks model group relatively,there have significant correlation between the 14 weeks model group respectively.And in these periods the OCA-TS interfered the expression of Flt-1 LI not too much.
Conclusion:The procession of hepatocarcinogenesis interfered with OCA-TS appeared cyst wrap around carcinoma.OCA-TS interfered the hepatocarcinogenesis periods in the expression of the free radicals and antioxidants,and restrained the course of hepatocarcinogenesis.And the OCA-TS interfered the hepatocellular hyperplasia.The expression of Flt-1 were significantly high in the hepatocellular carcinoma occuring periods, and the OCA-TS interfered the expression of Flt-1 in this periods.
方法:二乙基亚硝胺诱发大鼠肝癌变,虎眼万年青总皂苷干预,运用常规HE染色法观察肝组织病理形态改变;采用比色分析法检测丙二醛(MDA)、超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)的活性;运用免疫组化方法观察并分析肝组织标本中增殖细胞核抗原(Ki67)、血管内皮生长因子受体-1(Flt-1)的表达。
结果:(1)12周肝硬化阶段模型组以出现增生结节,嗜碱性变,透明变,水变性为主;14周后模型组出现大量的“灶中灶”现象,18周模型组全部出现癌变。而虎眼万年青总皂苷预防组12周时减少嗜碱性细胞结节以出现少量假小叶、纤细纤维间隔、灶状变性为主。14周预防组假小叶、不规则纤维间隔、肝细胞灶状水变性、脂肪变性为主。14周治疗组以部分处肝硬化、变性轻度为特点。18周肝癌治疗组出现肝硬化、增生结节、灶状变性,同时癌周出现包裹性的囊肿。(2)在肝损伤硬化、肝癌的发生发展阶段MDA含量逐渐增高;SOD在12周模型组显著增高,与趋于正常组水平的模型14周、模型18周组均有统计学差异。SOD活力在虎眼万年青作用的12周预防组低于12周模型组,且有统计学差异。而在14周、18周虎眼万年青总皂苷作用组与相应模型组间,无显著差异。GSH-Px活力在模型组12周、14周、18周逐渐下降,相互间有显著性差异。虎眼万年青总皂苷作用组明显提高GSH-Px活力,并与相应的模型组间均有显著性差异。(3)肝癌变过程中以12周模型组Ki67LI表达最高,14周及18周模型组Ki67 LI逐渐降低,与12周模型组比较有统计学意义。虎眼万年青总皂苷作用的12周预防组Ki67 LI较低且与相应12周模型组有统计学意义。诱癌14周模型组Flt-1 LI表达最高,12周及18周模型组Flt-1 LI相对低下,与14周模型组比较有统计学意义。虎眼万年青总皂苷作用的14周预防组、治疗组Flt-1 LI降低,且与模型组有统计学意义。
结论:(1)虎眼万年青总皂苷以癌周出现囊肿阻断癌灶血液供应起到抑制肝癌发展,诱导肝癌细胞凋亡,起到治疗肝癌的作用。(2)虎眼万年青总皂苷具有降低MDA的生成作用,尤以肝损伤硬化阶段明显;虎眼万年青总皂苷干预SOD活力水平发生在肝损伤硬化阶段;虎眼万年青总皂苷在肝癌促进、发生发展阶段中能够增加GSH-Px的活力,提高抗氧化系统功能,降低对毒物的敏感性。(3)肝癌变过程中以肝损伤硬化阶段肝细胞增生活跃,而虎眼万年青总皂苷干预此阶段的肝细胞增生。肝癌变过程中在肝癌发生阶段Flt-1表达较高,虎眼万年青总皂苷干预此阶段Flt-1表达。
Objective:To study the anti-tumor effect of Ornithogalum Caudatum Ait total saponin(OCA-TS) on living diethylnitrosamine(DEN) induced hepatocarcinogenesis rat.
Methods:the OCA-TS was administeredto interfere the hepatocarcinogenesis induced with DEN in rats,and the dynamic expression of pathological evolution,antioxidative activities of SOD,GSH-Px and the content of MDA were investigated by the colorimetric method in rat serum. Ki67 and Flt-1 were observed with immunohistochemical staining respectively.
Results,As a result the procession of hepatocarcinogenesis in this model included three stages-hepatic toxic lesion、hepatic proliferation/ cirrhosis and hepatic carcinogenesis.Hyperplasia node,Basophilic cell lesions,lucencied and watering denaturalization appeared in the 12 weeks model group;a lot of foci-in-foci phenomenon appeared in the 14 weeks model group;carcinoma node appeared in the 18 weeks model group.Sprinkle basophilic cell lesions and fake flocculi,fibre alternation,local denaturalization appeared in the 12 weeks prevent group with OCA-TS;fake flocculi,abnormity fiber alternation,local watering and fatting denaturalization appeared in the 14 weeks prevent group with OCA-TS; segment hepatocirrhosis and gently denaturalization appeared in the 14 weeks treated group with OCA-TS.Hepatocirrhosis,hyperplasia node,local denaturalization and wrap around carcinoma with cyst appeared in the 18 weekstreated group with OCA-TS.Under the electronic microscope,part of vacuole,lipid droplet,cristae rupture,swelling,and metamorphose in the mitochondrion and endoplasmic reticulum expanded appeared in the 14 weeks model group.Some part of mitochondrion-endoplasmic reticulum complex appeared in the 14 weeks prevent group.Some part of vacuole,lipid droplet and cristae rupture appeared in the 14 weeks treated group,but there were no metamorphose in the mitochondrion and endoplasmic reticulum expand.Nuclear cataclasm,chromatin gather in the board,mitochondrion contract,endoplasmic reticulum swelling,and pull off granule appeared in the 18 weeks model group.Mitochondrion swelling,vacuole,lipid droplet,cristae rupture,endoplasmic reticulum expand,nuclear membrane metamorphose and chromatin distributing odds appeared in the chemotherapy group.Mitochondrion swelling and vacuole,endoplasmic reticulum expand with a lot of granule,cell plasma loosen appeared in the 18 weeks group treated with OCA-TS.The level of MDA increased remarkably in the 12 weeks、14 weeks and 18 weeks model group,and the content of MDA decreased by OCA-TS,there has significance between the groups administered with OCA-TS and the model groups respectively.In the 12 weeks model group the activities of SOD increased remarkably,but it tend to normal group in the 14 weeks,18 weeks model group.The expression of SOD in the 12 weeks prevent group administered with OCA-TS were lower than the 12weeks model group,maybe it dependent the level of MDA.The expression of GSH-Px activities decreased gradually in the 12 weeks、14 weeks and 18 weeks model group,and there have significance among of them.The expression of GSH-Px increased in the group administered with OCA-TS,and there have significance between the same periods model group respectively.We found the expression of Ki67 labeling index(LI) were significantly higher in the group of experiment than the normal group.The expression of Ki67 LI were highest in the 12 weeks model group,the OCA-TS interfered the expression of Ki67 LI in this periods significantly.And the Ki67 LI decreased gradually in the 14 weeks and 18 weeks model group,there have significant correlation between the 12 weeks model group respectively. And in these periods the OCA-TS interfered the expression of Ki67 LI not too much.We also found the expression of F1t-1 labeling index(LI) were significantly higher in the group of experiment than the normal group. The expression of Flt-1 LI were highest in the 14 weeks model group,the OCA-TS.interfered the expression of Flt-1 LI in this periods significantly. And the Flt-1 LI decreased in the 12 weeks and I8 weeks model group relatively,there have significant correlation between the 14 weeks model group respectively.And in these periods the OCA-TS interfered the expression of Flt-1 LI not too much.
Conclusion:The procession of hepatocarcinogenesis interfered with OCA-TS appeared cyst wrap around carcinoma.OCA-TS interfered the hepatocarcinogenesis periods in the expression of the free radicals and antioxidants,and restrained the course of hepatocarcinogenesis.And the OCA-TS interfered the hepatocellular hyperplasia.The expression of Flt-1 were significantly high in the hepatocellular carcinoma occuring periods, and the OCA-TS interfered the expression of Flt-1 in this periods.
引文
[1]丁景和,曾万章.药用植物学[M].上海:上海科学技术出版社,1985:225.
[2]TANG Yuping.YU Biao.The chemical constituentsfrom bulbsoornithogalum caudatum[J].Journal ofChinese Pharmaceuticeal Sciences.2001,10(4):26-28.
[3]SHI Lei,LI Juan,LIU Wenxiang,et al.Chemicalcharacteristic of bioactive pOlysaccharides isolatedfrom ornithogalum caudatum ait [J].Chem Res Chi—nese U,2003,19(3):286-289.
[4]Julian E.Selenium and the prevention of cancer(part I:Evidence for the carcinostatie activityofSecompounds)[J].BulISelenium-Tellurium Dev ASSOC,2001:5:I-6.
[5]Kraizer Y,Mawasi N,Seagal J,et al.Vascular endothelial growth factor and angiopoietin in liver regeneration.Biochem Biophys Res Commun,2001,287(1):209-215.
[6]Forster Y,Meye A,Krause S,et al.Antisense-mediated VEGF suppression in bladder and breast cancer cells[J].Cancer Left,2004,212(1):95,103
[7]Takei Y,Kadomatsu Ko YuzawaY,et al.A small interfering RNA targeting vascularendothelial growth factorascancer therapeutics[J].Cancer Res,2004,64(10):3365-3370
[8]Joseph B.Kearney,Nicholas C.Kappas,Catharina Ellerstrom,et al.The VEGF receptor fit-1(VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis.Blood,2004;103(7):4527-4535.
[9]Adini A,Kornaga T,Firoozbakht F,et al.Placental growth factor is a survival factor for tumor endothelial cells and macrophages.Cancer Res 2002:62:2749-2752
[10]肖冲,鱼红闪.虎眼万年青皂苷的分离提取[J]。大连轻工业学院学报,2006;25(2):93-95。
[11]徐墩海,徐雅娟,刘大有,等.虎眼万年青的化学成分[J].药学学报,2000,35(1):32-36.
[12]KUBO S,MIMAKI Y,SASHIDA Y,et al.New cholestanebisdesmosides from the bulbs of omithogalum thyrsoides[J].Bull Chem Soc Jpn,1992,65:1120.
[13]KUBOS,MIMAKI Y,TERAOM,et al.hcylated cholestaneglycosides from the bulbs of omithogalum saundersiae[J].Phytochemistry,1992,31:3969.
[14]KUBO S,MIMAKI Y,SASHIDA Y,et al.New po]yhydroxy—lated cholestane glycosides from the bulbs of omithoga]umsaundersiae[J].Chem Pham Bull,1992,40:2469.
[15]JANG K,YU P,YU B,et al.The chemicM constituents from the bulbsof omithogalum caudatum[J].J Chin Pharmaceut Sci,2001,I0(4):169-171.
[l6]MIMAKI Y,KUROD AM,KAMEYAM AA,et al.Cholestaneglycosides from omithogalum saundersiae and their potentcytotoxic activity on various malignant tumor cells[J].Tlen—nen Yuki Kagobutsu Toronkai Koen Yoshishu,1996,38:313-318.
[17]MIMAKI Y,KUROD AM,SASHIDA AY,et al.Cholestaneglycosides with potent cytostatic activities onva~oustumorcellsfromomithogalumsaundersiae bulbs[J].Bioorg MedChem Lett,1997,7:633-636.
[18]MIMAKI Y,KUROD AM,SASHIDA Y,et al.A new rear ranged cholestane glycosidefromomithogalumsaundersiaebulbsexhibitinpotentcytostati c activities on leukemia HL—60 and MOIJT-4 ceHs[J].Bioorg Med Chem Lett,1996,6:2635-2638.
[19]王晓明,王宝恩,王泰龄等.实验性肝细胞癌变过程中嗜碱性小细胞病灶的癌变趋势.中华肝脏病杂志2006;14(7):495-498
[20]姜幼纯,董奇男,肖邦良,等.非坏死剂量二乙基亚硝胺诱发大鼠肝癌模型的研究[J].华西医科大学学报,2001:32(4):555
[21]Roberts LJ,Morrow JD.Measurement of F2-isoprostanes as an index of oxidative stress in vivo[J].Free Radical Biology & Medicine,2000;28(4):505
[22]Zhang Z,Yu CX.Effect of melatonin learing and memory impairment induced by aluminum chloride and its mechanism.Yao Xue Xue Bao,2002;37:682-686
[23]丁书茂,杨旭.超氧化物歧化酶及其模拟化合物研究进展[J].高等函授学报(自然科学版),2004;17(1):1-5.
[24]魏文树,曾昭全,刘锡钧.超氧化物歧化酶模拟物研究进展[J].药物生物技术,2003;10(4):256-260.
[25]Ayene IS,Benbard EJ,Mckenna WG.DNA as an important target in radiation induced apoptosis of and plus transfected rat embryo fibroblasts[J].int J Radiat Biol,2000;76(3):343
[26]Buolamwini JK.Novel anticancer drug discovery.Curt Opin Chem Biol,1999;3:500-509.
[27]韩圣华,黄建福.肝细胞癌Ki-67抗原丧达及其意义[J].中国普通外科杂志,2001;9(1):42-45
[28]Morsi HM,Leers MP,Jager W,et al.The patterns of expression of an apoptosis-related CK18 neoepitope,the bcl-2 protooncogene,and the Ki67 proliferation marker in normal,hyperplasic,and malignant endometrium[J].Int J Gynecol Pathol,2000;9:118-126
[29]杜滂,魏经国.VEGF及其受体的表达与肝癌的生物学特性关系.放射学实践,2002:17(6):542-545
[30]Kanno S,Oda N,Abe M,et al.Roles of two VEGF receptors,Flt-1 and KDR,in the signal transduction of VEGF effects in human vascular endothelial cells.Oncogene 2000;19:2138-2146
[31]Joseph B.Kearney,Nicholas C.Kappas,Catharina Ellerstrom,et al.The VEGF receptor flt-1(VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood, 2004; 103(7): 4527 - 4535.
[32] Deng L, Wu H, Yu B, etal. Synthesis of OSW-1 analogs with modified side chains and their antitumor activities. Bioorg Med Chem Lett, 2004; 14:2781-2785.
[1]任剑,朱丽娟.中医药为主治疗中晚期原发性肝癌30例临床观察[J].江西中医药,1999;30(5):21.
[2]陈力,王广良,陈成彬,等.细胞周期相关基因微阵列在中药抑制肝癌细胞增殖作用机理研究中的作用[J].中国中药杂志,2005;30(1):S0-53.
[3]Feakim R M,Niekols C D,Bidd H,d.Abnonml expression of pRb,p16,and eydin Dll in gastric adenoearcinoma and its lymph nodemetastases:relationship with pathological features and survival.Hum Pathol,2003:34(12):1276.
[4]Gooder N M,Cannon J,HuntTetal.(n cycle regulatory protein—san overview with relevance tO oral cancer.Oral Oncol,1997,33(2):61.
[5]翁景宁,张惠蓉.增殖细胞核抗原反义寡核苷酸对牛晶状体上皮细胞增殖的影响.中华眼科杂志,2003;39(02):98.
[6]谆振球、朱梅菊.抗纤灵对人体癌细胞HePGP21 waft/cipI蛋白表达的影响[J].湖南中医学院学报,1999,19(4)7
[7]闰智勇,王再漠,张天娥,等癌肿宁对荷肝癌(H22)小鼠的抑瘤作用及其对IL.2和NK细胞活性的影响[J].中西医结合肝病病杂志.1999,9(7):24
[8]朱梅菊,郭振球.唐发清.新制抗癌方对肝癌荷瘤鼠的治疗作用[J].中医药研究,2000.16(1):36.
[9]朱梅菊,郭振球.唐发清.新制抗癌方对裸鼠移植性人肝癌细胞的体内抑制作用及形态学的影响[J]中国中医药科技,2000,7(4):219
[10]黄炜,黄挤群,张东方,等.全反式维甲酸、18甘草次酸和甘草酸诱导人肝癌细胞分化和凋亡的研究[J].中西医结合肝病杂志,2003,13(3):148-150.
[11]胡兵,安红梅,李新民.龙力胶囊对人肝癌细胞诱导分化及机理研究[J].成 都中医药大学学报,2000;2(1):46-48.
[12]刘平,周建锋,胡义扬,等.益气养阴诱导SMMC-7721肝癌细胞分化作用与意义[J].中国中医基础医学杂志,2000;6(8):29-34.
[13]胡兵,安红梅,李新民.龙力胶囊对人肝癌细胞诱导分化及机理研究[J]成都中医药大学学报,2000,23(I):46
[14]黄育华.张建军.吴雪生,等富硒绿条对人肝癌细胞株BEI-7402的诱导分化作用[J]中医药研究,1999,15(5):43
[15]姜浩,樊光华.人参皂甙-Rh2诱导人肝癌Bcl-7404细胞增殖和凋亡的影响[J]。中国肿瘤临床与康复,2004;11(4):289-292.
[16]刘华,毛小玲,钟海波.晚癌康2号对原发性肝癌细胞凋亡基因Bct-2、Bax 和Fas表达的影响[J].中医药学刊.2005;23(8):1409-1410.
[17]肖正明,宋景贵,徐晖,等.黄芪水提取物对体外培养人肝癌细胞增殖及代谢的影响[J].世界华人消化杂志2000 8(1):46.
[18]白锦雯.张颖.吴青。青椒碱对DEN诱发大鼠肝癌抑制作用的流式细胞光度术分析[J].北京中医药大学学报,1999、22(6):34.
[19]粱永红、侯华新、黎丹戎,等板蓝根 二酮B体外抗癌活性研究[J]中草药、2000.31(7):531.
[20]叶向荣,张素芬,张丹,等艾灸神阙穴抗癌的实验研究[J]山东中医药大学学报,2000,24(3):229.
[21]周延峰,刘朝霞,贺会江.扶正消瘤合刹抗肿瘤肺转移的实验研究[J]山东中医药大学学报,1999,23(5):391
[22]王志学,焦中华.消瘤平移合剂抗肿瘤术后转移的临床及实验研究[J].山东中医药大学学报,1999,23(4):213.
[23]刁风声,张丽秋,孔力,等当归补血汤对小鼠肝癌淋巴道转移和脾细胞凋亡的影响[J]中药药理与临床,1999,15(2):7
[24]郭伟剑,于尔辛,郑颂国,等.健脾理气药诱导人肝细胞SMMC-7221凋亡的研究[J].世界华人消化杂志,2000;8(21):52-55.
[25]汤钊猷.现代肿瘤学[M].上海:上海医科大学出版社,1993.391.
[26]梁爱华.近年来国内抗痛中草药药理研究.中草药研究,1991;5:55.
[50] Yan Zhou, Celia Garcia-Prieto, Dennis A. Carney, etal. OSW-1: a Natural Compound With Potent Anticancer Activity and a Novel Mechanism of Action[J]. Journal of the National Cancer Institute, 2005; 97(23) :1781-1785
[51] Wensheng Yu and Zhendong Jin. Total Synthesis of the Anticancer Natural Product OSW-1 [J]. J. Am. Chem. Soc. 2002; 124(23):6576 -6583
[52] Jianbei Zhu, Lei Xiong, Biao Yu, etal. Apoptosis Induced by a New Member of Saponin Family Is Mediated through Caspase-8-Dependent Cleavage of Bcl-2. [J] Mol Pharmacol, 2005; 68 (23) :1831-1838
[53] Mimaki Y, Kuroda M, Kameyama A, et al. Cholestane glycosides with potent cytostatic activities on various tumor cells from Ornithogalum saundersiae bulls. [J] Bioorg Med Chem Lett, 1997; 7(5) 633-636.
[2]TANG Yuping.YU Biao.The chemical constituentsfrom bulbsoornithogalum caudatum[J].Journal ofChinese Pharmaceuticeal Sciences.2001,10(4):26-28.
[3]SHI Lei,LI Juan,LIU Wenxiang,et al.Chemicalcharacteristic of bioactive pOlysaccharides isolatedfrom ornithogalum caudatum ait [J].Chem Res Chi—nese U,2003,19(3):286-289.
[4]Julian E.Selenium and the prevention of cancer(part I:Evidence for the carcinostatie activityofSecompounds)[J].BulISelenium-Tellurium Dev ASSOC,2001:5:I-6.
[5]Kraizer Y,Mawasi N,Seagal J,et al.Vascular endothelial growth factor and angiopoietin in liver regeneration.Biochem Biophys Res Commun,2001,287(1):209-215.
[6]Forster Y,Meye A,Krause S,et al.Antisense-mediated VEGF suppression in bladder and breast cancer cells[J].Cancer Left,2004,212(1):95,103
[7]Takei Y,Kadomatsu Ko YuzawaY,et al.A small interfering RNA targeting vascularendothelial growth factorascancer therapeutics[J].Cancer Res,2004,64(10):3365-3370
[8]Joseph B.Kearney,Nicholas C.Kappas,Catharina Ellerstrom,et al.The VEGF receptor fit-1(VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis.Blood,2004;103(7):4527-4535.
[9]Adini A,Kornaga T,Firoozbakht F,et al.Placental growth factor is a survival factor for tumor endothelial cells and macrophages.Cancer Res 2002:62:2749-2752
[10]肖冲,鱼红闪.虎眼万年青皂苷的分离提取[J]。大连轻工业学院学报,2006;25(2):93-95。
[11]徐墩海,徐雅娟,刘大有,等.虎眼万年青的化学成分[J].药学学报,2000,35(1):32-36.
[12]KUBO S,MIMAKI Y,SASHIDA Y,et al.New cholestanebisdesmosides from the bulbs of omithogalum thyrsoides[J].Bull Chem Soc Jpn,1992,65:1120.
[13]KUBOS,MIMAKI Y,TERAOM,et al.hcylated cholestaneglycosides from the bulbs of omithogalum saundersiae[J].Phytochemistry,1992,31:3969.
[14]KUBO S,MIMAKI Y,SASHIDA Y,et al.New po]yhydroxy—lated cholestane glycosides from the bulbs of omithoga]umsaundersiae[J].Chem Pham Bull,1992,40:2469.
[15]JANG K,YU P,YU B,et al.The chemicM constituents from the bulbsof omithogalum caudatum[J].J Chin Pharmaceut Sci,2001,I0(4):169-171.
[l6]MIMAKI Y,KUROD AM,KAMEYAM AA,et al.Cholestaneglycosides from omithogalum saundersiae and their potentcytotoxic activity on various malignant tumor cells[J].Tlen—nen Yuki Kagobutsu Toronkai Koen Yoshishu,1996,38:313-318.
[17]MIMAKI Y,KUROD AM,SASHIDA AY,et al.Cholestaneglycosides with potent cytostatic activities onva~oustumorcellsfromomithogalumsaundersiae bulbs[J].Bioorg MedChem Lett,1997,7:633-636.
[18]MIMAKI Y,KUROD AM,SASHIDA Y,et al.A new rear ranged cholestane glycosidefromomithogalumsaundersiaebulbsexhibitinpotentcytostati c activities on leukemia HL—60 and MOIJT-4 ceHs[J].Bioorg Med Chem Lett,1996,6:2635-2638.
[19]王晓明,王宝恩,王泰龄等.实验性肝细胞癌变过程中嗜碱性小细胞病灶的癌变趋势.中华肝脏病杂志2006;14(7):495-498
[20]姜幼纯,董奇男,肖邦良,等.非坏死剂量二乙基亚硝胺诱发大鼠肝癌模型的研究[J].华西医科大学学报,2001:32(4):555
[21]Roberts LJ,Morrow JD.Measurement of F2-isoprostanes as an index of oxidative stress in vivo[J].Free Radical Biology & Medicine,2000;28(4):505
[22]Zhang Z,Yu CX.Effect of melatonin learing and memory impairment induced by aluminum chloride and its mechanism.Yao Xue Xue Bao,2002;37:682-686
[23]丁书茂,杨旭.超氧化物歧化酶及其模拟化合物研究进展[J].高等函授学报(自然科学版),2004;17(1):1-5.
[24]魏文树,曾昭全,刘锡钧.超氧化物歧化酶模拟物研究进展[J].药物生物技术,2003;10(4):256-260.
[25]Ayene IS,Benbard EJ,Mckenna WG.DNA as an important target in radiation induced apoptosis of and plus transfected rat embryo fibroblasts[J].int J Radiat Biol,2000;76(3):343
[26]Buolamwini JK.Novel anticancer drug discovery.Curt Opin Chem Biol,1999;3:500-509.
[27]韩圣华,黄建福.肝细胞癌Ki-67抗原丧达及其意义[J].中国普通外科杂志,2001;9(1):42-45
[28]Morsi HM,Leers MP,Jager W,et al.The patterns of expression of an apoptosis-related CK18 neoepitope,the bcl-2 protooncogene,and the Ki67 proliferation marker in normal,hyperplasic,and malignant endometrium[J].Int J Gynecol Pathol,2000;9:118-126
[29]杜滂,魏经国.VEGF及其受体的表达与肝癌的生物学特性关系.放射学实践,2002:17(6):542-545
[30]Kanno S,Oda N,Abe M,et al.Roles of two VEGF receptors,Flt-1 and KDR,in the signal transduction of VEGF effects in human vascular endothelial cells.Oncogene 2000;19:2138-2146
[31]Joseph B.Kearney,Nicholas C.Kappas,Catharina Ellerstrom,et al.The VEGF receptor flt-1(VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood, 2004; 103(7): 4527 - 4535.
[32] Deng L, Wu H, Yu B, etal. Synthesis of OSW-1 analogs with modified side chains and their antitumor activities. Bioorg Med Chem Lett, 2004; 14:2781-2785.
[1]任剑,朱丽娟.中医药为主治疗中晚期原发性肝癌30例临床观察[J].江西中医药,1999;30(5):21.
[2]陈力,王广良,陈成彬,等.细胞周期相关基因微阵列在中药抑制肝癌细胞增殖作用机理研究中的作用[J].中国中药杂志,2005;30(1):S0-53.
[3]Feakim R M,Niekols C D,Bidd H,d.Abnonml expression of pRb,p16,and eydin Dll in gastric adenoearcinoma and its lymph nodemetastases:relationship with pathological features and survival.Hum Pathol,2003:34(12):1276.
[4]Gooder N M,Cannon J,HuntTetal.(n cycle regulatory protein—san overview with relevance tO oral cancer.Oral Oncol,1997,33(2):61.
[5]翁景宁,张惠蓉.增殖细胞核抗原反义寡核苷酸对牛晶状体上皮细胞增殖的影响.中华眼科杂志,2003;39(02):98.
[6]谆振球、朱梅菊.抗纤灵对人体癌细胞HePGP21 waft/cipI蛋白表达的影响[J].湖南中医学院学报,1999,19(4)7
[7]闰智勇,王再漠,张天娥,等癌肿宁对荷肝癌(H22)小鼠的抑瘤作用及其对IL.2和NK细胞活性的影响[J].中西医结合肝病病杂志.1999,9(7):24
[8]朱梅菊,郭振球.唐发清.新制抗癌方对肝癌荷瘤鼠的治疗作用[J].中医药研究,2000.16(1):36.
[9]朱梅菊,郭振球.唐发清.新制抗癌方对裸鼠移植性人肝癌细胞的体内抑制作用及形态学的影响[J]中国中医药科技,2000,7(4):219
[10]黄炜,黄挤群,张东方,等.全反式维甲酸、18甘草次酸和甘草酸诱导人肝癌细胞分化和凋亡的研究[J].中西医结合肝病杂志,2003,13(3):148-150.
[11]胡兵,安红梅,李新民.龙力胶囊对人肝癌细胞诱导分化及机理研究[J].成 都中医药大学学报,2000;2(1):46-48.
[12]刘平,周建锋,胡义扬,等.益气养阴诱导SMMC-7721肝癌细胞分化作用与意义[J].中国中医基础医学杂志,2000;6(8):29-34.
[13]胡兵,安红梅,李新民.龙力胶囊对人肝癌细胞诱导分化及机理研究[J]成都中医药大学学报,2000,23(I):46
[14]黄育华.张建军.吴雪生,等富硒绿条对人肝癌细胞株BEI-7402的诱导分化作用[J]中医药研究,1999,15(5):43
[15]姜浩,樊光华.人参皂甙-Rh2诱导人肝癌Bcl-7404细胞增殖和凋亡的影响[J]。中国肿瘤临床与康复,2004;11(4):289-292.
[16]刘华,毛小玲,钟海波.晚癌康2号对原发性肝癌细胞凋亡基因Bct-2、Bax 和Fas表达的影响[J].中医药学刊.2005;23(8):1409-1410.
[17]肖正明,宋景贵,徐晖,等.黄芪水提取物对体外培养人肝癌细胞增殖及代谢的影响[J].世界华人消化杂志2000 8(1):46.
[18]白锦雯.张颖.吴青。青椒碱对DEN诱发大鼠肝癌抑制作用的流式细胞光度术分析[J].北京中医药大学学报,1999、22(6):34.
[19]粱永红、侯华新、黎丹戎,等板蓝根 二酮B体外抗癌活性研究[J]中草药、2000.31(7):531.
[20]叶向荣,张素芬,张丹,等艾灸神阙穴抗癌的实验研究[J]山东中医药大学学报,2000,24(3):229.
[21]周延峰,刘朝霞,贺会江.扶正消瘤合刹抗肿瘤肺转移的实验研究[J]山东中医药大学学报,1999,23(5):391
[22]王志学,焦中华.消瘤平移合剂抗肿瘤术后转移的临床及实验研究[J].山东中医药大学学报,1999,23(4):213.
[23]刁风声,张丽秋,孔力,等当归补血汤对小鼠肝癌淋巴道转移和脾细胞凋亡的影响[J]中药药理与临床,1999,15(2):7
[24]郭伟剑,于尔辛,郑颂国,等.健脾理气药诱导人肝细胞SMMC-7221凋亡的研究[J].世界华人消化杂志,2000;8(21):52-55.
[25]汤钊猷.现代肿瘤学[M].上海:上海医科大学出版社,1993.391.
[26]梁爱华.近年来国内抗痛中草药药理研究.中草药研究,1991;5:55.
[50] Yan Zhou, Celia Garcia-Prieto, Dennis A. Carney, etal. OSW-1: a Natural Compound With Potent Anticancer Activity and a Novel Mechanism of Action[J]. Journal of the National Cancer Institute, 2005; 97(23) :1781-1785
[51] Wensheng Yu and Zhendong Jin. Total Synthesis of the Anticancer Natural Product OSW-1 [J]. J. Am. Chem. Soc. 2002; 124(23):6576 -6583
[52] Jianbei Zhu, Lei Xiong, Biao Yu, etal. Apoptosis Induced by a New Member of Saponin Family Is Mediated through Caspase-8-Dependent Cleavage of Bcl-2. [J] Mol Pharmacol, 2005; 68 (23) :1831-1838
[53] Mimaki Y, Kuroda M, Kameyama A, et al. Cholestane glycosides with potent cytostatic activities on various tumor cells from Ornithogalum saundersiae bulls. [J] Bioorg Med Chem Lett, 1997; 7(5) 633-636.