岩藻糖基化海参硫酸软骨素抑制肿瘤生长和转移作用及其机制的研究
|
摘要
海参自古以来被视为珍贵的滋补品,其体壁中含有多种生物活性物质,如海参多糖、海参皂苷、脂肪酸、多肽、海参神经节苷脂等。海参硫酸多糖是海参体壁的重要功效成分,占海参体壁干重的7%-10%,包括海参硫酸软骨素(Sea Cucumber Chondroitin Sufate, SC-CHS)和海参岩藻聚糖硫酸酯(Sea Cucumber Fucan,SC-FUC)。其中,SC-CHS是一种带有岩藻糖支链且高度硫酸酯化的多糖。本实验中,SC-CHS提取自美国肉参,采用红外光谱分析和核磁共振波谱分析对其结构进行研究;通过细胞和动物实验,探讨SC-CHS抑制肿瘤生长和转移的作用及其机制。主要研究结果如下:
美国肉参SC-CHS主要由葡萄糖醛酸(GlcUA)、氨基半乳糖(GalN)和岩藻糖(Fuc)组成,GlcUA、GalN和Fuc的摩尔比为1:0.7:0.9,岩藻糖支链95.9%为2,4-SO4取代;以多种肿瘤细胞株为研究对象,MTT法筛选出SC-CHS的敏感细胞株是人高转移肺癌细胞95D;流式细胞术分析证明SC-CHS可以诱导细胞早期凋亡;RT-PCR法研究证实SC-CHS促进了抑癌基因p53和p21 mRNA的表达,抑制了周期蛋白cycling B1和cdc2 mRNA的表达;下调细胞存活基因bcl-xl mRNA表达,提高半胱氨酸蛋白酶caspase-3 mRNA表达,提示SC-CHS能抑制95D细胞增殖,诱导细胞凋亡和G2/M期周期阻滞是其主要作用机制
采用细胞粘附、迁移、侵袭实验和RT-PCR实验,探讨了SC-CHS体外抑制肿瘤转移的作用。结果表明,SC-CHS显著降低了肿瘤细胞同基质、内皮细胞的粘附能力(P<0.05);显著降低了95D细胞的迁移和侵袭能力(P<0.05);抑制细胞基质金属蛋白酶MMP-1/2的表达,促进其相应的基质金属蛋白酶抑制剂TIMP-1/2 mRNA的表达,通过降低肿瘤细胞在细胞外基质的侵袭能力发挥抑制肿瘤转移的作用。
通过小管形成实验和鸡胚尿囊膜血管新生实验,发现SC-CHS具有抑制血管生成的作用。RT-PCR和Western Blot法检测表明SC-CHS可以降低细胞中血管内皮生长因子VEGF mRNA和蛋白的表达,提示SC-CHS通过抑制VEGF的活性,达到抑制血管新生作用。
通过建立小鼠Lewis肺癌自发肺转移模型,研究SC-CHS在体内抑制肿瘤生长和转移的作用。结果表明,SC-CHS可以显著抑制荷瘤小鼠肿瘤的生长,其平均抑制率为31.5%;可以显著减少肺表面转移灶结节数(P<0.01),平均抑制率为47.5%;显著提高血清中TNF-α和γ-IFN的含量(P<0.05);降低荷瘤小鼠肿瘤组织中HIF-1α、VEGF mRNA的表达(P<0.05)。提示SC-CHS能显著抑制肿瘤细胞在小鼠体内的生长和转移,通过下调转移相关因子HIF-1α、VEGF的表达,抑制肿瘤诱导血管新生。
通过建立建立小鼠B16人工肺转移模型,研究SC-CHS抑制B16实验性肺转移的作用。结果发现,SC-CHS可以显著降低小鼠的肺转移灶数量,平均转移抑制率为62.66%,并且改善了血清中肿瘤恶化的生化指标,减轻了肺脏的纤维化。提示SC-CHS可能通过影响B16细胞的活力,降低其粘附和侵袭能力来达到抑制肺转移的作用。
综上所述,本文从体内和体外系统地研究了岩藻糖基化海参硫酸软骨素抑制肿瘤生长和转移的作用,并对其机制进行了探讨,为更好的阐明海参硫酸软骨素抗肿瘤活性的构效关系提供依据,为海参硫酸软骨素的抗肿瘤药物开发提供实验依据。
Sea cucumber, an important food and medicine resource, has lots of bioactive substances, such as sea cucumber polysaccharide, saponins, collagen proteins and cerebrosides. The sea cucumber polysaccharide is one of the most important bioactive substance, and weight about 7%-10% of the body wall of the sea cucumber. There are sea cucumber chondroitin sulfate (SC-CHS) and the sulfated fucan of the sea cucumber polysaccharide. In this study, sea cucumber chondroitin sulfate (SC-CHS) was isolated from the Isostichopus badionotus, and its antitumor and antimetastasis effect was studied in tumor cells and animal models. Results are shown as follows:
The monosaccharide composition of the SC-CHS was similar to that of chondroitin sulfate, mainly with molar ratio 1:0.7:0.9 of glucuronic acid (GlcUA), galactosamine (GlaN) and fucose (Fuc). IR and NMR analysis of anomer hydrogen signals of sulfate fucose in SC-CHS shows that mainly 2, 4-SO4 disubstituted. It was proved that SC-CHS could significantly inhibit 95D cell proliferation most sensitively by MTT assay; induce 95D cell early apoptosis with flow cytometry; SC-CHS induced expression of the p53 tumor suppressor gene and the Cdk inhibitor p21; The anti-proliferative activity of SC-CHS was accompanied by inhibition of cycling B1and Cdc2 mRNA; Moreover, SC-CHS inhibited the expression of bcl-xl,and induced expression of caspase-3 clearly. The results showed that SC-CHS significantly inhibit 95D cell proliferation through apoptosis and G2/M arrest.
The effects of SC-CHS on adhesion, the invasion and metastasis ability of 95D cells were investigated through cell-base adhesion assay, migration assay, invasion assay and RT-PCR assay. The results showed that the SC-CHS could decrease the adhesion rate in dose dependent manner and inhibit the cellular motility(P<0.05); inhibited invsion of 95D cells in dose despondently(P<0.01); inhibited the expression of MMP-2/9, and induce expression of TIMP-1/2. The results suggested that the SC-CHS could inhibit the metastasis of 95D cell with protecting ECM under degradation by MMPs.
The chorioallntoic membrane assay and tube formation assay indicate that SC-CHS inhibit the generation of new blood vessels. And RT-PCR and Western Blot assay confirm that its antiangiogenic effect was that SC-CHS can inhibit the expression of VEGF.
The Lewis lung carcinoma models of C57BL/6J mice were established and the results showed that the tumor growth was suppressed significantly in SC-CHS groups, the average inhibition rate was 31.5% compared with control group. The metastatic foci occurrence rate of SC-CHS group was lower than control group, and the difference were significant(P<0.05). SC-CHS could significantly down-regulated the expression levels of HIF-1αand VEGF mRNA of the tumor than control. And SC-CHS also could increase amounts of TNF-αandγ-IFN in serum. The results suggested SC-CHS has inhibitory effect on growth and metastasis of Lewis lung carcinoma cell in mice, and may be through inhibiting solid tumor angiogenesis and improve the well-being of the immunity of the mice.
To observe the inhibitory effect of SC-CHS on lung metastasis of mouse melanoma cell line B16-F10. The results suggested that SC-CHS clearly suppressed lung metastasis by 65.26% in mice and could reduce the levels of serum saliva acid content andγ-GT energy clearly (P<0.01). Biochemical parameters such as hydroxyproline, hexosamines and uronic acid levels in the lung were also reduced clearly (P<0.01) in the SC-CHS treated animals. Therefore, the results indicate that SC-CHS can inhibit the metastasis of B16-F10 metastatic mouse melanoma cells and its mechanism is maybe that it can inhibit the B16-F10 cells adhering to the ECM and reduce the migration of B16-F10 cells.
In this study, we systemically investigated the antitumor and antimetastasis effect of a fucosylated chondroitin sulfate isolated from Isostichopus badionotus, furthermore we do lots of work to do that contribute to the illustration of the mechanism of its effect. Our works provide the scientific approvement for the research of the bioactive function of the sea cucumber polysaccharide and good use in food and medicine.
美国肉参SC-CHS主要由葡萄糖醛酸(GlcUA)、氨基半乳糖(GalN)和岩藻糖(Fuc)组成,GlcUA、GalN和Fuc的摩尔比为1:0.7:0.9,岩藻糖支链95.9%为2,4-SO4取代;以多种肿瘤细胞株为研究对象,MTT法筛选出SC-CHS的敏感细胞株是人高转移肺癌细胞95D;流式细胞术分析证明SC-CHS可以诱导细胞早期凋亡;RT-PCR法研究证实SC-CHS促进了抑癌基因p53和p21 mRNA的表达,抑制了周期蛋白cycling B1和cdc2 mRNA的表达;下调细胞存活基因bcl-xl mRNA表达,提高半胱氨酸蛋白酶caspase-3 mRNA表达,提示SC-CHS能抑制95D细胞增殖,诱导细胞凋亡和G2/M期周期阻滞是其主要作用机制
采用细胞粘附、迁移、侵袭实验和RT-PCR实验,探讨了SC-CHS体外抑制肿瘤转移的作用。结果表明,SC-CHS显著降低了肿瘤细胞同基质、内皮细胞的粘附能力(P<0.05);显著降低了95D细胞的迁移和侵袭能力(P<0.05);抑制细胞基质金属蛋白酶MMP-1/2的表达,促进其相应的基质金属蛋白酶抑制剂TIMP-1/2 mRNA的表达,通过降低肿瘤细胞在细胞外基质的侵袭能力发挥抑制肿瘤转移的作用。
通过小管形成实验和鸡胚尿囊膜血管新生实验,发现SC-CHS具有抑制血管生成的作用。RT-PCR和Western Blot法检测表明SC-CHS可以降低细胞中血管内皮生长因子VEGF mRNA和蛋白的表达,提示SC-CHS通过抑制VEGF的活性,达到抑制血管新生作用。
通过建立小鼠Lewis肺癌自发肺转移模型,研究SC-CHS在体内抑制肿瘤生长和转移的作用。结果表明,SC-CHS可以显著抑制荷瘤小鼠肿瘤的生长,其平均抑制率为31.5%;可以显著减少肺表面转移灶结节数(P<0.01),平均抑制率为47.5%;显著提高血清中TNF-α和γ-IFN的含量(P<0.05);降低荷瘤小鼠肿瘤组织中HIF-1α、VEGF mRNA的表达(P<0.05)。提示SC-CHS能显著抑制肿瘤细胞在小鼠体内的生长和转移,通过下调转移相关因子HIF-1α、VEGF的表达,抑制肿瘤诱导血管新生。
通过建立建立小鼠B16人工肺转移模型,研究SC-CHS抑制B16实验性肺转移的作用。结果发现,SC-CHS可以显著降低小鼠的肺转移灶数量,平均转移抑制率为62.66%,并且改善了血清中肿瘤恶化的生化指标,减轻了肺脏的纤维化。提示SC-CHS可能通过影响B16细胞的活力,降低其粘附和侵袭能力来达到抑制肺转移的作用。
综上所述,本文从体内和体外系统地研究了岩藻糖基化海参硫酸软骨素抑制肿瘤生长和转移的作用,并对其机制进行了探讨,为更好的阐明海参硫酸软骨素抗肿瘤活性的构效关系提供依据,为海参硫酸软骨素的抗肿瘤药物开发提供实验依据。
Sea cucumber, an important food and medicine resource, has lots of bioactive substances, such as sea cucumber polysaccharide, saponins, collagen proteins and cerebrosides. The sea cucumber polysaccharide is one of the most important bioactive substance, and weight about 7%-10% of the body wall of the sea cucumber. There are sea cucumber chondroitin sulfate (SC-CHS) and the sulfated fucan of the sea cucumber polysaccharide. In this study, sea cucumber chondroitin sulfate (SC-CHS) was isolated from the Isostichopus badionotus, and its antitumor and antimetastasis effect was studied in tumor cells and animal models. Results are shown as follows:
The monosaccharide composition of the SC-CHS was similar to that of chondroitin sulfate, mainly with molar ratio 1:0.7:0.9 of glucuronic acid (GlcUA), galactosamine (GlaN) and fucose (Fuc). IR and NMR analysis of anomer hydrogen signals of sulfate fucose in SC-CHS shows that mainly 2, 4-SO4 disubstituted. It was proved that SC-CHS could significantly inhibit 95D cell proliferation most sensitively by MTT assay; induce 95D cell early apoptosis with flow cytometry; SC-CHS induced expression of the p53 tumor suppressor gene and the Cdk inhibitor p21; The anti-proliferative activity of SC-CHS was accompanied by inhibition of cycling B1and Cdc2 mRNA; Moreover, SC-CHS inhibited the expression of bcl-xl,and induced expression of caspase-3 clearly. The results showed that SC-CHS significantly inhibit 95D cell proliferation through apoptosis and G2/M arrest.
The effects of SC-CHS on adhesion, the invasion and metastasis ability of 95D cells were investigated through cell-base adhesion assay, migration assay, invasion assay and RT-PCR assay. The results showed that the SC-CHS could decrease the adhesion rate in dose dependent manner and inhibit the cellular motility(P<0.05); inhibited invsion of 95D cells in dose despondently(P<0.01); inhibited the expression of MMP-2/9, and induce expression of TIMP-1/2. The results suggested that the SC-CHS could inhibit the metastasis of 95D cell with protecting ECM under degradation by MMPs.
The chorioallntoic membrane assay and tube formation assay indicate that SC-CHS inhibit the generation of new blood vessels. And RT-PCR and Western Blot assay confirm that its antiangiogenic effect was that SC-CHS can inhibit the expression of VEGF.
The Lewis lung carcinoma models of C57BL/6J mice were established and the results showed that the tumor growth was suppressed significantly in SC-CHS groups, the average inhibition rate was 31.5% compared with control group. The metastatic foci occurrence rate of SC-CHS group was lower than control group, and the difference were significant(P<0.05). SC-CHS could significantly down-regulated the expression levels of HIF-1αand VEGF mRNA of the tumor than control. And SC-CHS also could increase amounts of TNF-αandγ-IFN in serum. The results suggested SC-CHS has inhibitory effect on growth and metastasis of Lewis lung carcinoma cell in mice, and may be through inhibiting solid tumor angiogenesis and improve the well-being of the immunity of the mice.
To observe the inhibitory effect of SC-CHS on lung metastasis of mouse melanoma cell line B16-F10. The results suggested that SC-CHS clearly suppressed lung metastasis by 65.26% in mice and could reduce the levels of serum saliva acid content andγ-GT energy clearly (P<0.01). Biochemical parameters such as hydroxyproline, hexosamines and uronic acid levels in the lung were also reduced clearly (P<0.01) in the SC-CHS treated animals. Therefore, the results indicate that SC-CHS can inhibit the metastasis of B16-F10 metastatic mouse melanoma cells and its mechanism is maybe that it can inhibit the B16-F10 cells adhering to the ECM and reduce the migration of B16-F10 cells.
In this study, we systemically investigated the antitumor and antimetastasis effect of a fucosylated chondroitin sulfate isolated from Isostichopus badionotus, furthermore we do lots of work to do that contribute to the illustration of the mechanism of its effect. Our works provide the scientific approvement for the research of the bioactive function of the sea cucumber polysaccharide and good use in food and medicine.
引文
[1] Hickman J A. Apoptosis induced by anticancer drugs[J]. Cancer Metastasis Rev, 1992, 11(2): 121-139.
[2]吴志敏,袁克厚. Caspase蛋白酶的结构及其在CNS损伤中的作用[J].中国临床神经外科杂志, 2003, 8(2): 152-156.
[3] Stennicke H R, Salvesen S. Properties of the caspases[J]. Biochimica et Biophysica Aeta, 1998, 1387: 17-31.
[4] W oo R A, Mclure K G, Lees Miller S P, et al. DNA dependent protein kinase acts upstream o f p53 in response to DNA damage[J]. Nature, 1998, 394( 6694): 700-704.
[5] Balin t E, Vousden K H. Activities of the p53 tumor suppressor protein[J]. Br J Cancer, 2002, 85: 1813-1823.
[6] Salomons G S, Brady H J, Verwijs-Janssen M, et al. The Bax/Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemic[J]. In J Cancer, 1997, 71(6): 959-965.
[7] Pepper C, Thomas A, Hidalgo de Quintana J, et al. Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia-the role of Bcl-2 family dysregulation[J]. Leuk Res, 1999, 23(11): 1007-1014.
[8] Deng G, Lane C, Kornblau S, et al. Ratio of Bcl-x short to Bcl-x long is different in good and poor prognosis subsets of acute myeloid leukemia[J]. Mol Med, 1998, 4(3):158-164.
[9] Pantaxis P, Chatterjee D, Han Z, et al. Differentiation and synethesis of proteins associated with apoptosis in human leukemia U937 cells acquiring resistance to vincristine[J]. Eur J Haematol, 1996, 57(1): 79-86.
[10] D Ari R. Cycle-regulated genes and cell cycle regulation[J]. Bioessays, 2001, 23(7): 563-565.
[11] Herwig S, Stranss M. The retinoblastoma protein: a master of cell cycle, differentiation and apoptosis[J]. Eur J Biochem, 1997, 246(3): 581-601.
[12] Sanchez I, B D Dynlaeht. New insights inio cyclins, CDK, and cell cycle[J]. Semin Cell Dev Biol, 2005, 16(3): 311-321.
[13]纪欣,布立民,陈刚,等.穿琥宁对人大肠癌HCT-8细胞生长的影响[J].现代消化及介入诊疗, 2003, 8(2): 72-73.
[14]吴永平,孔庆充,刘莹.三氧化二砷引起人结肠癌LoVo细胞S期及G/M期阻滞[J].徐州医学院学报, 2001, 21(6): 437-439.
[15]崔映字,王宏斌,谢衡,等.马尾松树皮提取物体外抑制人大肠癌细胞生长机理初探[J].中国农业大学学报, 2007, 12(4): 7-14.
[16] Liotta L A, Stetler-Stevenson W G. Tumor invasion and metastasis: an imbalance of positive and negative regulation[J]. Cancer Research, 1991, 51(18): 5054-5059.
[17]张彩莲.多西环素对肺癌细胞的作用及其机制的研究:[博士学位论文].西安:第四军医大学, 2007.
[18] Hanahan D, Weinberg R A. The hallmarks of cancer cell[J]. Science, 2000, 100: 57-70.
[19] Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis[J]. Seminars in Cancer Biology, 2000, 10(6): 415-433.
[20] Starnenkovic I. Extracellular matrix remodeling: the role of matrix metalloproteinases[J]. The Journal of Pathology, 2003, 200(4): 448-464.
[21] Vlodvas I, Eldor A, Haimovitz Firedman A, et al. Expression of heparanase by platelets and circulating cells of the immune system: Possible involvement in diapedesis and extrvaasation[J]. Invasion Metastasis, 1992, 12(2): 112-127.
[22] Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J]. Clin Invest, 2001, 108: 341-347.
[23] Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases[J]. Nature, 2000, 407(6801): 249-257.
[24] Kim E S, Serur A, Huang J, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma[J]. Proc Natl Acad Sci, 2002, 99(17): 11399-11404.
[25] Tian X , Song S , Wu J , et al. Vascular endothelial growth factor: acting as an autocrine growth factor for human gastric adeno carcinoma cell MGC803[J]. Biochem Biophys Res Commun, 2001, 286(3): 505-512.
[26]孙军,李岩.姜黄素对人肝癌细胞BEL-7402中HIF-1α表达的影响[J].中国药理学通报, 2006, 22(11): 1379-83.
[27] Damert A, Machein M, Breier G, et al. Up-regulation of vascular endothelial growth factor exp ression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms[J]. Cancer Res, 1997, 57(17): 3860-3864.
[28]孙鹏,胡君艳,李瑞强.螺旋藻多糖的结构及生物学活性研究[J].中国生化药物杂志, 2005, 26(3): 185-187.
[29]徐宝顺,程爱斌,宋勇春,等.海洋真菌YS4108抗肿瘤多糖YCP发酵条件的优化[J].中国生化药物杂志, 2006, 27(5): 257-261.
[30]王海生,范廷英,任青华,等.壳聚糖对小鼠微循环及移植性肿瘤的影响[J].中国生化药物杂志, 2006, 26(5): 301-302.
[31]黄芳,蒙义文.活性多糖的研究进展[J].天然产物研究与开发, 1998, 11(5): 90-98.
[32]郑维发,陈才法,程启平.隐杆藻胞外多糖抗肿瘤活性研究[J].中草药, 2005, 6(7): 1026-1030.
[33]郑尧,何景华,高建华,等.甘草多糖对小鼠巨噬细胞吞噬功能的影响[J].中医药学刊, 2003, 21(2): 254.
[34]顾笑梅,孔健,王富生,等.一株乳酸菌所产胞外多糖对荷瘤小鼠机体免疫功能影响的研究[J].微生物学报, 2003, 42(3): 251.
[35]季宇彬,高世勇,张秀娟.羊栖菜多糖诱导肿瘤细胞凋亡的研究[J].中国中药杂志, 2004, 29(3): 166.
[36]魏小龙,茹祥斌.低分子质量地黄多糖体外对Lewis肺癌细胞p53基因表达的影响[J].中国药理学通报, 1998, 14(3): 245.
[37] Koyangi S, Tanigawa N, Nakagawa H, et al. Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities [J]. Biochem pharmaco, 2003, 65(2): 173-179.
[38]张惟杰.唾液酸[J].中国生物化学与分子生物学报, 1986, 2(5): 1.
[39]咚丽,黄添友,梁谋,等.植物多糖对5180细胞膜脂肪酸组成的影响[J].第一军医大学学报, 1995, 15(4): 305-307.
[40] Zhang LN, Chen L , Xu X J, et a1. Comparison on chain stiffncss of a water_insoluble (1-3) -α-D-glucan isolated from Poria cocosmycelia and its sulfated derivative[J]. Carbohydrate Polymers, 2005, 59: 257.
[41]史宝军,聂小华,许泓渝.灰树花多糖硫酸酯的制备及其抗肿瘤活性[J].中国医药工业杂志, 2003, 34(8): 383-385.
[42]高贵珍,陈雷,李绪亮.硫酸化茯苓多糖急性毒性实验研究[ J].生物学杂志, 2004, 21(1): 34-37.
[43]范曼芳,陈琼华.褐藻淀粉和褐藻淀粉硫酸酯的制取,分析及生物活性比较[ J].中国药科大学学报, 1998, 19(1): 30-34.
[44]赖萍,林跃鑫.天然多糖分子修饰研究进展[J].生命的化学, 2003, 23(3): 183-187.
[45] Yoshida O, Nakashim aH, Yosh idaT, et al. Sulfation of the immune om odulating polysa-ccharide lentinan: A noval strategy for antivirals to hum an immunode ficiency virus (HIV) [J]. Biochem Pharm, 1998, 37(7): 2887-2889.
[46]董浦江,姚榛祥,涂刚. LAMS对肝癌细胞株的Bcl-2、Bax基因蛋白影响[J].重庆医科大学学报, 2002, 27(1): 26-31.
[47]翟振国,蒋捍东,秦筱梅,等.海藻硫酸多糖对肺癌增殖的抑制作用及其机制[J].中华结核和呼吸杂志, 2004, 27(2): 97-100.
[48]盛玉青,尹鸿萍,李海涛,等.螺旋藻多糖硫酸酯化修饰前后抗肿瘤及免疫活性的研究[J].药物生物技术, 2006, 13(2): 107-111.
[49] Soeda S, Kozako T, Iwata K, et al. Oversulfated fucoidan inhibits the basic fibroblast growth factor-2 induced tube formation by human umbilical vein endothelial cells: its possible mechanism of action[J]. Biochim BiophysActa, 2000, 1497(1) :127-134.
[50]徐中平,李福川,王海仁,等.昆布多糖硫酸酯的抑制血管生成和抗肿瘤作用[J].中草药, 1999, 30(1): 551-553.
[51]廖玉麟,我国的海参[J].生物学通报, 2001, 36(009): 1-3.
[52] Cui F, Xue C, Li Z, Zhang Y, et al. Characterization and subunit composition of collagen from the body wall of sea cucumber Stichopus japonicus[J]. Food Chemistry, 2007, 100(3):1120-1125.
[53] Zou Z, Yi Y, Wu H, et al. Intercedensides AC, three new cytotoxic triterpene glycosides from the sea cucumber Mensamaria intercedens Lampert[J]. J Nat Prod, 2003, 66(8): 1055-1060.
[54] Vieira R, Mourao P. Occurrence of a unique fucose-branched chondroitin sulfate in the body wall of a sea cucumber[J]. Journal of Biological Chemistry, 1988, 263(34): 18176-18183.
[55] Mulloy B, Ribeiro A, Alves A, et al. Sulfated fucans from echinoderms have a regular tetrasaccharide repeating unit defined by specific patterns of sulfating at the 0-2 and 0-4 positions. Journal of Biological Chemistry, 1994, 269(35): 22113-22123.
[56]樊绘曾,陈菊娣.一种刺参酸性粘多糖分离提纯的新方法[J].中国中药杂志, 1982, (04).
[57]樊绘曾,陈菊娣,吕培宏,等.玉足海参酸性多糖的研究[J].药学导报, 1983, (03).
[58] Vieira R, Mulloy B, Mourao P. Structure of a fucose-branched chondroitin sulfate from sea cucumber. Evidence for the presence of 3-O-sulfo-beta-D-glucuronosyl residues[J]. Journal of Biological Chemistry, 1991, 266(21): 13530-13536.
[59] Kariya Y, Sakai T, Kaneko T, et al. Enhancement of t-PA-mediated plasminogen activation by partially defucosylated glycosaminoglycans from the sea cucumber Stichopus japonicus[J]. J Biochem, 2002, 132(2): 335-343.
[60]尹力昂,陈士国,薛长湖,等. 4种海参中含岩藻糖支链的硫酸软骨素化学组成差异的分析[J].中国海洋大学学报, 2009, 39: 63-68.
[61] Suzuki N, Kitazato K, Takamatsu J, Saito H. Antithrombotic and anticoagulant activity of depolymerized fragment of the glycosaminoglycan extracted from Stichopus japonicus Selenka[J]. Thromb Haemost, 1991, 65(4):369-73.
[62] li G. Basic and clinical study on the antithrombotic mechanism of glycosaminoglycan extracted from sea cucumber[J]. Chinese medical journal, 2000, 113(8): 706-711.
[63]杨晓光,陈关珍. Sjamp对纤溶系统影响的初步观察[J].中国医学科学院学报1990, 12(03): 187-192.
[64] Mourao P A, Boisson-Vidal C, Tapon-Bretaudiere J, et al. Inactivation of thrombin by a fucosylated chondroitin sulfate from echinoderm[J]. Thromb Res, 2001, 102(2): 167-176.
[65] Glauser B, Pereira M, Monteiro R, Mourao P. Serpin-independent anticoagulant activity of a fucosylated chondroitin sulfate[J]. Thromb Haemost, 2008, 100(3):420-428.
[66] Borsig L, Wang L, Cavalcante M C, et al. Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. effect on tumor metastasis and neutrophil recruitment[J]. J Biol Chem, 2007, 282(20): 14984-14991.
[67]王颖.刺参黏多糖对人宫颈癌Hela细胞caspase表达影响[J].齐鲁医学杂志, 2008,23(3).
[68] Chen S G, Xue C H, Ying L A, et al. Comparison of structures and anticoagulant activities of fucosylated chondroitin sulfates from different sea cucumbers[J]. Carbohydrate Polymers, 2011, 83: 688-696.
[69] Tapon Bretaudiere J, Chabut D, Zierer M, et al. A fucosylated chondroitin sulfate from echinoderm modulates in vitro fibroblast growth factor 2-dependent angiogenesis. Mol Cancer Res, 2002, 1 (2): 96-102.
[70] Mourao P A, Pereira M S, Pavao M S, et al. Structure and anticoagulant activity of a fucosylated chondroitin sulfate from echinoderm Sulfated fucose branches on the polysaccharide account for its high anticoagulant action[J]. J Biol Chem, 1996, 271(39): 73-84.
[71]樊绘曾,陈菊娣,林克忠.刺参酸性粘多糖的分离及其理化性质[J].药学学报, 1980, 15(5): 263-269.
[72] Millau J F, Bastien N, Drouin R. p53 transcriptional activities: a general overview and some thoughts[J]. Mutat Res, 2009, 681(23): 118-133.
[73] Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy[J]. Clin Cancer Res, 2009, 15(4): 1126-1132.
[74]陈乃耀,汪静,王雪明,等. STI571联合三氧化二砷对K562细胞增殖、凋亡及Caspase-3、Bcl-xL表达的影响[J].中国实验血液学杂志, 2010, 18(4): 882-886.
[75]邹明畅,崔飞伦,盛玉,等.昆布多糖硫酸酯对PC-3细胞PTEN和p27kip1基因表达的影响[J].中华男科学杂志, 2010, 16(6): 498-503.
[76] Liotta L A, Steeg P S, Stetler-Stevenson W G. Cancer metastasis and angiogensis: imbalance of positive and negative regulation[J]. Cell,1991, 64(2): 327-336.
[77] Stetler-Stevenson W G. Type N collagenases in tumor invasion and metastasis[J]. Cancer Metastasis Rev, 1990, 9(4): 289-303.
[78] Eccles S A. Heparanase: breaking down barriers in tumors[J]. Nat Med, 1999, 5:735-736.
[79] Hulett M D, Freeman C, Hamdorf B J, et al. Cloning of mammlian heparanase, an important enzyme in tumor invasion and metestasis[J]. Nat Med, 1999, 5(7): 803.
[80] Voldavsky I, Friedman Y, Elkin M, et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis[J]. Nat Med, 1999, 5(7):793-802.
[81] Parish C R, Freeman C, Brown K J, et al. Identification of sulfatde oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity[J]. Cancer Res, 1999, 59: 3433-3441.
[82] Baraz B, Haupt Y, Elkin M, et al. Tumor suppressor p53 regulates heparanase gene expression. Oncogene, 2006, 25: 3939-3947.
[83] Folkman J. Tumor angiogenesis: therapeutic implicatiotions[J]. N Engl J Med, 1971, 285(21): 1182-1186.
[84] Vlahakis NE, Young BA, Atakilit A, et al. Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGFA- induced angiogenesis[J]. J Biol Chem, 2007, 282: 15187-15196.
[85] Fang J, Zhou Q, Liu L Z, et al. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression[J]. Carcinogenesis, 2007, 28: 858-864.
[86] A Wellstein, G Zugmaier, J A. Califano III, et al. Tumor growth dependent on kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate[J]. J Natl Cancer Inst,1991, 83(10): 716-720.
[87]陈伟,乔田奎,袁素娟,等.分次剂量卡铂联合X线对Lewis肺癌小鼠免疫功能的影响[J].中国癌症杂志, 2008, 18(7): 492-495.
[88] Dong J, Kukula A K, Toyoshima M, et al. Genomic organizationand chromosome localization of the newly identified human heparanase gene[J]. Gene, 2000, 253(2): 171-178.
[89] Miao H Q, Kelly T, Freeman C, et al. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bonemetastases[J]. Cancer Res, 2005, 65(13): 5778-5784.
[90]李墨林,李传刚,舒晓宏.美法仑治愈荷瘤小鼠的过程与TNF-α的关系[J].细胞与分子免疫学杂志, 2007, 23(4): 320-323.
[91]方瑜.山仙颗粒对lewis肺癌小鼠模型抑制作用的影响[J].陕西中医学院学报, 2007, 30(2): 44-45.
[92]孙伟,张逊,韩兴鹏.肺癌患者γ-IFN和TNF-α免疫因子检测及其临床意义[J].细胞与分子免疫学杂志, 2010, 26(9): 891-892.
[93] Elson, L.A, Morgan W.T. A lorimetric method for determination of glucosamine[J]. Journal of Biochemistry, 1933, 27:1824-1828.
[94] Bitter T, Muir H.M. A modified uronic acid carbazole reaction[J]. Analytical Biochemistry, 1962, (4): 330-334.
[95]王俏梅,林永前.血清唾液酸在恶性肿瘤中的诊断价值[J].中国热带医学, 2006, 6(9): 1616-1617.
[96]张天泽,徐光炜.肿瘤学[M].天津:天津科学技术出版社, 2006, 780-816.
[97]袁效涵,黄霞,徐立然,等.不同方剂对肺纤维化模型小鼠的比较研究[J].中成药, 2009, 31(12): 1827-1829.
[98] Richard D. Price M.G, Berry, Harshad A, Navsaria. Hyaluronic acid: the scientific and clinical evidence[J]. Journal of Plastic, Reconstructive & Aesthetic Surgery, 2007, 60: 1110-1119.
[99]曾益新.肿瘤学[M].人民卫生出版社, 2003, 1(2): 267-293.
[100]周春辉,张宝憬,孙立娟,等.血清唾液酸的测定及其对恶性肿瘤的诊断价值[J].大连医科大学学报, 1999, 20(1): 22-26.
[101] Prezioso J A, Wang N, Duty L, et al. Enhancement of pulmonary metastasis formation and gamma- glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro[J]. Clinical and Experimental Metastasis. 1993, 11(3): 263-274.
[102]韦仕高,韦霞,韦忠理.血清肿瘤标志物联合检测对原发性肝癌的诊断价值[J].现代预防医学, 2010, 37(13): 2598-2599.
[103]魏路清,刘斌,李振华,等.阿托伐他汀减轻博莱霉素诱导大鼠实验性肺纤维化[J].基础医学与临床, 2009, 29(11): 1198-1202.
[104]王胜霞,李俊,刘勇.玉屏风多糖对大鼠肺纤维化的干预作用及部分机制研究[J].安徽医科大学学报, 2009, 44(5): 586-589.
[105] Kikuchi S, Griffin C T, Wang S S, et al. Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6[J]. J Biol Chem, 2005, 280(15): 15398-15404.
[106] Mark E. Mummert, Mansour Mohamadzadeh, et al. Development of a peptide inhibitor of hyaluronan- mediated leukocyte trafficking[J]. J. Exp. Med. 2000, 192(6): 769-779.
[107] Mark E, Mummert, Diana I. Mummert, et al. Functional roles of hyaluronan in B16-F10 melanoma growth and Experimental Metastasis in Mice[J]. Molecular Cancer Therapeutics, 2003, 3(2):295-300.
[2]吴志敏,袁克厚. Caspase蛋白酶的结构及其在CNS损伤中的作用[J].中国临床神经外科杂志, 2003, 8(2): 152-156.
[3] Stennicke H R, Salvesen S. Properties of the caspases[J]. Biochimica et Biophysica Aeta, 1998, 1387: 17-31.
[4] W oo R A, Mclure K G, Lees Miller S P, et al. DNA dependent protein kinase acts upstream o f p53 in response to DNA damage[J]. Nature, 1998, 394( 6694): 700-704.
[5] Balin t E, Vousden K H. Activities of the p53 tumor suppressor protein[J]. Br J Cancer, 2002, 85: 1813-1823.
[6] Salomons G S, Brady H J, Verwijs-Janssen M, et al. The Bax/Bcl-2 ratio modulates the response to dexamethasone in leukaemic cells and is highly variable in childhood acute leukaemic[J]. In J Cancer, 1997, 71(6): 959-965.
[7] Pepper C, Thomas A, Hidalgo de Quintana J, et al. Pleiotropic drug resistance in B-cell chronic lymphocytic leukaemia-the role of Bcl-2 family dysregulation[J]. Leuk Res, 1999, 23(11): 1007-1014.
[8] Deng G, Lane C, Kornblau S, et al. Ratio of Bcl-x short to Bcl-x long is different in good and poor prognosis subsets of acute myeloid leukemia[J]. Mol Med, 1998, 4(3):158-164.
[9] Pantaxis P, Chatterjee D, Han Z, et al. Differentiation and synethesis of proteins associated with apoptosis in human leukemia U937 cells acquiring resistance to vincristine[J]. Eur J Haematol, 1996, 57(1): 79-86.
[10] D Ari R. Cycle-regulated genes and cell cycle regulation[J]. Bioessays, 2001, 23(7): 563-565.
[11] Herwig S, Stranss M. The retinoblastoma protein: a master of cell cycle, differentiation and apoptosis[J]. Eur J Biochem, 1997, 246(3): 581-601.
[12] Sanchez I, B D Dynlaeht. New insights inio cyclins, CDK, and cell cycle[J]. Semin Cell Dev Biol, 2005, 16(3): 311-321.
[13]纪欣,布立民,陈刚,等.穿琥宁对人大肠癌HCT-8细胞生长的影响[J].现代消化及介入诊疗, 2003, 8(2): 72-73.
[14]吴永平,孔庆充,刘莹.三氧化二砷引起人结肠癌LoVo细胞S期及G/M期阻滞[J].徐州医学院学报, 2001, 21(6): 437-439.
[15]崔映字,王宏斌,谢衡,等.马尾松树皮提取物体外抑制人大肠癌细胞生长机理初探[J].中国农业大学学报, 2007, 12(4): 7-14.
[16] Liotta L A, Stetler-Stevenson W G. Tumor invasion and metastasis: an imbalance of positive and negative regulation[J]. Cancer Research, 1991, 51(18): 5054-5059.
[17]张彩莲.多西环素对肺癌细胞的作用及其机制的研究:[博士学位论文].西安:第四军医大学, 2007.
[18] Hanahan D, Weinberg R A. The hallmarks of cancer cell[J]. Science, 2000, 100: 57-70.
[19] Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis[J]. Seminars in Cancer Biology, 2000, 10(6): 415-433.
[20] Starnenkovic I. Extracellular matrix remodeling: the role of matrix metalloproteinases[J]. The Journal of Pathology, 2003, 200(4): 448-464.
[21] Vlodvas I, Eldor A, Haimovitz Firedman A, et al. Expression of heparanase by platelets and circulating cells of the immune system: Possible involvement in diapedesis and extrvaasation[J]. Invasion Metastasis, 1992, 12(2): 112-127.
[22] Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis[J]. Clin Invest, 2001, 108: 341-347.
[23] Carmeliet P, Jain R K. Angiogenesis in cancer and other diseases[J]. Nature, 2000, 407(6801): 249-257.
[24] Kim E S, Serur A, Huang J, et al. Potent VEGF blockade causes regression of coopted vessels in a model of neuroblastoma[J]. Proc Natl Acad Sci, 2002, 99(17): 11399-11404.
[25] Tian X , Song S , Wu J , et al. Vascular endothelial growth factor: acting as an autocrine growth factor for human gastric adeno carcinoma cell MGC803[J]. Biochem Biophys Res Commun, 2001, 286(3): 505-512.
[26]孙军,李岩.姜黄素对人肝癌细胞BEL-7402中HIF-1α表达的影响[J].中国药理学通报, 2006, 22(11): 1379-83.
[27] Damert A, Machein M, Breier G, et al. Up-regulation of vascular endothelial growth factor exp ression in a rat glioma is conferred by two distinct hypoxia-driven mechanisms[J]. Cancer Res, 1997, 57(17): 3860-3864.
[28]孙鹏,胡君艳,李瑞强.螺旋藻多糖的结构及生物学活性研究[J].中国生化药物杂志, 2005, 26(3): 185-187.
[29]徐宝顺,程爱斌,宋勇春,等.海洋真菌YS4108抗肿瘤多糖YCP发酵条件的优化[J].中国生化药物杂志, 2006, 27(5): 257-261.
[30]王海生,范廷英,任青华,等.壳聚糖对小鼠微循环及移植性肿瘤的影响[J].中国生化药物杂志, 2006, 26(5): 301-302.
[31]黄芳,蒙义文.活性多糖的研究进展[J].天然产物研究与开发, 1998, 11(5): 90-98.
[32]郑维发,陈才法,程启平.隐杆藻胞外多糖抗肿瘤活性研究[J].中草药, 2005, 6(7): 1026-1030.
[33]郑尧,何景华,高建华,等.甘草多糖对小鼠巨噬细胞吞噬功能的影响[J].中医药学刊, 2003, 21(2): 254.
[34]顾笑梅,孔健,王富生,等.一株乳酸菌所产胞外多糖对荷瘤小鼠机体免疫功能影响的研究[J].微生物学报, 2003, 42(3): 251.
[35]季宇彬,高世勇,张秀娟.羊栖菜多糖诱导肿瘤细胞凋亡的研究[J].中国中药杂志, 2004, 29(3): 166.
[36]魏小龙,茹祥斌.低分子质量地黄多糖体外对Lewis肺癌细胞p53基因表达的影响[J].中国药理学通报, 1998, 14(3): 245.
[37] Koyangi S, Tanigawa N, Nakagawa H, et al. Oversulfation of fucoidan enhances its anti-angiogenic and antitumor activities [J]. Biochem pharmaco, 2003, 65(2): 173-179.
[38]张惟杰.唾液酸[J].中国生物化学与分子生物学报, 1986, 2(5): 1.
[39]咚丽,黄添友,梁谋,等.植物多糖对5180细胞膜脂肪酸组成的影响[J].第一军医大学学报, 1995, 15(4): 305-307.
[40] Zhang LN, Chen L , Xu X J, et a1. Comparison on chain stiffncss of a water_insoluble (1-3) -α-D-glucan isolated from Poria cocosmycelia and its sulfated derivative[J]. Carbohydrate Polymers, 2005, 59: 257.
[41]史宝军,聂小华,许泓渝.灰树花多糖硫酸酯的制备及其抗肿瘤活性[J].中国医药工业杂志, 2003, 34(8): 383-385.
[42]高贵珍,陈雷,李绪亮.硫酸化茯苓多糖急性毒性实验研究[ J].生物学杂志, 2004, 21(1): 34-37.
[43]范曼芳,陈琼华.褐藻淀粉和褐藻淀粉硫酸酯的制取,分析及生物活性比较[ J].中国药科大学学报, 1998, 19(1): 30-34.
[44]赖萍,林跃鑫.天然多糖分子修饰研究进展[J].生命的化学, 2003, 23(3): 183-187.
[45] Yoshida O, Nakashim aH, Yosh idaT, et al. Sulfation of the immune om odulating polysa-ccharide lentinan: A noval strategy for antivirals to hum an immunode ficiency virus (HIV) [J]. Biochem Pharm, 1998, 37(7): 2887-2889.
[46]董浦江,姚榛祥,涂刚. LAMS对肝癌细胞株的Bcl-2、Bax基因蛋白影响[J].重庆医科大学学报, 2002, 27(1): 26-31.
[47]翟振国,蒋捍东,秦筱梅,等.海藻硫酸多糖对肺癌增殖的抑制作用及其机制[J].中华结核和呼吸杂志, 2004, 27(2): 97-100.
[48]盛玉青,尹鸿萍,李海涛,等.螺旋藻多糖硫酸酯化修饰前后抗肿瘤及免疫活性的研究[J].药物生物技术, 2006, 13(2): 107-111.
[49] Soeda S, Kozako T, Iwata K, et al. Oversulfated fucoidan inhibits the basic fibroblast growth factor-2 induced tube formation by human umbilical vein endothelial cells: its possible mechanism of action[J]. Biochim BiophysActa, 2000, 1497(1) :127-134.
[50]徐中平,李福川,王海仁,等.昆布多糖硫酸酯的抑制血管生成和抗肿瘤作用[J].中草药, 1999, 30(1): 551-553.
[51]廖玉麟,我国的海参[J].生物学通报, 2001, 36(009): 1-3.
[52] Cui F, Xue C, Li Z, Zhang Y, et al. Characterization and subunit composition of collagen from the body wall of sea cucumber Stichopus japonicus[J]. Food Chemistry, 2007, 100(3):1120-1125.
[53] Zou Z, Yi Y, Wu H, et al. Intercedensides AC, three new cytotoxic triterpene glycosides from the sea cucumber Mensamaria intercedens Lampert[J]. J Nat Prod, 2003, 66(8): 1055-1060.
[54] Vieira R, Mourao P. Occurrence of a unique fucose-branched chondroitin sulfate in the body wall of a sea cucumber[J]. Journal of Biological Chemistry, 1988, 263(34): 18176-18183.
[55] Mulloy B, Ribeiro A, Alves A, et al. Sulfated fucans from echinoderms have a regular tetrasaccharide repeating unit defined by specific patterns of sulfating at the 0-2 and 0-4 positions. Journal of Biological Chemistry, 1994, 269(35): 22113-22123.
[56]樊绘曾,陈菊娣.一种刺参酸性粘多糖分离提纯的新方法[J].中国中药杂志, 1982, (04).
[57]樊绘曾,陈菊娣,吕培宏,等.玉足海参酸性多糖的研究[J].药学导报, 1983, (03).
[58] Vieira R, Mulloy B, Mourao P. Structure of a fucose-branched chondroitin sulfate from sea cucumber. Evidence for the presence of 3-O-sulfo-beta-D-glucuronosyl residues[J]. Journal of Biological Chemistry, 1991, 266(21): 13530-13536.
[59] Kariya Y, Sakai T, Kaneko T, et al. Enhancement of t-PA-mediated plasminogen activation by partially defucosylated glycosaminoglycans from the sea cucumber Stichopus japonicus[J]. J Biochem, 2002, 132(2): 335-343.
[60]尹力昂,陈士国,薛长湖,等. 4种海参中含岩藻糖支链的硫酸软骨素化学组成差异的分析[J].中国海洋大学学报, 2009, 39: 63-68.
[61] Suzuki N, Kitazato K, Takamatsu J, Saito H. Antithrombotic and anticoagulant activity of depolymerized fragment of the glycosaminoglycan extracted from Stichopus japonicus Selenka[J]. Thromb Haemost, 1991, 65(4):369-73.
[62] li G. Basic and clinical study on the antithrombotic mechanism of glycosaminoglycan extracted from sea cucumber[J]. Chinese medical journal, 2000, 113(8): 706-711.
[63]杨晓光,陈关珍. Sjamp对纤溶系统影响的初步观察[J].中国医学科学院学报1990, 12(03): 187-192.
[64] Mourao P A, Boisson-Vidal C, Tapon-Bretaudiere J, et al. Inactivation of thrombin by a fucosylated chondroitin sulfate from echinoderm[J]. Thromb Res, 2001, 102(2): 167-176.
[65] Glauser B, Pereira M, Monteiro R, Mourao P. Serpin-independent anticoagulant activity of a fucosylated chondroitin sulfate[J]. Thromb Haemost, 2008, 100(3):420-428.
[66] Borsig L, Wang L, Cavalcante M C, et al. Selectin blocking activity of a fucosylated chondroitin sulfate glycosaminoglycan from sea cucumber. effect on tumor metastasis and neutrophil recruitment[J]. J Biol Chem, 2007, 282(20): 14984-14991.
[67]王颖.刺参黏多糖对人宫颈癌Hela细胞caspase表达影响[J].齐鲁医学杂志, 2008,23(3).
[68] Chen S G, Xue C H, Ying L A, et al. Comparison of structures and anticoagulant activities of fucosylated chondroitin sulfates from different sea cucumbers[J]. Carbohydrate Polymers, 2011, 83: 688-696.
[69] Tapon Bretaudiere J, Chabut D, Zierer M, et al. A fucosylated chondroitin sulfate from echinoderm modulates in vitro fibroblast growth factor 2-dependent angiogenesis. Mol Cancer Res, 2002, 1 (2): 96-102.
[70] Mourao P A, Pereira M S, Pavao M S, et al. Structure and anticoagulant activity of a fucosylated chondroitin sulfate from echinoderm Sulfated fucose branches on the polysaccharide account for its high anticoagulant action[J]. J Biol Chem, 1996, 271(39): 73-84.
[71]樊绘曾,陈菊娣,林克忠.刺参酸性粘多糖的分离及其理化性质[J].药学学报, 1980, 15(5): 263-269.
[72] Millau J F, Bastien N, Drouin R. p53 transcriptional activities: a general overview and some thoughts[J]. Mutat Res, 2009, 681(23): 118-133.
[73] Kang MH, Reynolds CP. Bcl-2 inhibitors: targeting mitochondrial apoptotic pathways in cancer therapy[J]. Clin Cancer Res, 2009, 15(4): 1126-1132.
[74]陈乃耀,汪静,王雪明,等. STI571联合三氧化二砷对K562细胞增殖、凋亡及Caspase-3、Bcl-xL表达的影响[J].中国实验血液学杂志, 2010, 18(4): 882-886.
[75]邹明畅,崔飞伦,盛玉,等.昆布多糖硫酸酯对PC-3细胞PTEN和p27kip1基因表达的影响[J].中华男科学杂志, 2010, 16(6): 498-503.
[76] Liotta L A, Steeg P S, Stetler-Stevenson W G. Cancer metastasis and angiogensis: imbalance of positive and negative regulation[J]. Cell,1991, 64(2): 327-336.
[77] Stetler-Stevenson W G. Type N collagenases in tumor invasion and metastasis[J]. Cancer Metastasis Rev, 1990, 9(4): 289-303.
[78] Eccles S A. Heparanase: breaking down barriers in tumors[J]. Nat Med, 1999, 5:735-736.
[79] Hulett M D, Freeman C, Hamdorf B J, et al. Cloning of mammlian heparanase, an important enzyme in tumor invasion and metestasis[J]. Nat Med, 1999, 5(7): 803.
[80] Voldavsky I, Friedman Y, Elkin M, et al. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis[J]. Nat Med, 1999, 5(7):793-802.
[81] Parish C R, Freeman C, Brown K J, et al. Identification of sulfatde oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity[J]. Cancer Res, 1999, 59: 3433-3441.
[82] Baraz B, Haupt Y, Elkin M, et al. Tumor suppressor p53 regulates heparanase gene expression. Oncogene, 2006, 25: 3939-3947.
[83] Folkman J. Tumor angiogenesis: therapeutic implicatiotions[J]. N Engl J Med, 1971, 285(21): 1182-1186.
[84] Vlahakis NE, Young BA, Atakilit A, et al. Integrin alpha9beta1 directly binds to vascular endothelial growth factor (VEGF)-A and contributes to VEGFA- induced angiogenesis[J]. J Biol Chem, 2007, 282: 15187-15196.
[85] Fang J, Zhou Q, Liu L Z, et al. Apigenin inhibits tumor angiogenesis through decreasing HIF-1alpha and VEGF expression[J]. Carcinogenesis, 2007, 28: 858-864.
[86] A Wellstein, G Zugmaier, J A. Califano III, et al. Tumor growth dependent on kaposi's sarcoma-derived fibroblast growth factor inhibited by pentosan polysulfate[J]. J Natl Cancer Inst,1991, 83(10): 716-720.
[87]陈伟,乔田奎,袁素娟,等.分次剂量卡铂联合X线对Lewis肺癌小鼠免疫功能的影响[J].中国癌症杂志, 2008, 18(7): 492-495.
[88] Dong J, Kukula A K, Toyoshima M, et al. Genomic organizationand chromosome localization of the newly identified human heparanase gene[J]. Gene, 2000, 253(2): 171-178.
[89] Miao H Q, Kelly T, Freeman C, et al. Expression of heparanase by primary breast tumors promotes bone resorption in the absence of detectable bonemetastases[J]. Cancer Res, 2005, 65(13): 5778-5784.
[90]李墨林,李传刚,舒晓宏.美法仑治愈荷瘤小鼠的过程与TNF-α的关系[J].细胞与分子免疫学杂志, 2007, 23(4): 320-323.
[91]方瑜.山仙颗粒对lewis肺癌小鼠模型抑制作用的影响[J].陕西中医学院学报, 2007, 30(2): 44-45.
[92]孙伟,张逊,韩兴鹏.肺癌患者γ-IFN和TNF-α免疫因子检测及其临床意义[J].细胞与分子免疫学杂志, 2010, 26(9): 891-892.
[93] Elson, L.A, Morgan W.T. A lorimetric method for determination of glucosamine[J]. Journal of Biochemistry, 1933, 27:1824-1828.
[94] Bitter T, Muir H.M. A modified uronic acid carbazole reaction[J]. Analytical Biochemistry, 1962, (4): 330-334.
[95]王俏梅,林永前.血清唾液酸在恶性肿瘤中的诊断价值[J].中国热带医学, 2006, 6(9): 1616-1617.
[96]张天泽,徐光炜.肿瘤学[M].天津:天津科学技术出版社, 2006, 780-816.
[97]袁效涵,黄霞,徐立然,等.不同方剂对肺纤维化模型小鼠的比较研究[J].中成药, 2009, 31(12): 1827-1829.
[98] Richard D. Price M.G, Berry, Harshad A, Navsaria. Hyaluronic acid: the scientific and clinical evidence[J]. Journal of Plastic, Reconstructive & Aesthetic Surgery, 2007, 60: 1110-1119.
[99]曾益新.肿瘤学[M].人民卫生出版社, 2003, 1(2): 267-293.
[100]周春辉,张宝憬,孙立娟,等.血清唾液酸的测定及其对恶性肿瘤的诊断价值[J].大连医科大学学报, 1999, 20(1): 22-26.
[101] Prezioso J A, Wang N, Duty L, et al. Enhancement of pulmonary metastasis formation and gamma- glutamyltranspeptidase activity in B16 melanoma induced by differentiation in vitro[J]. Clinical and Experimental Metastasis. 1993, 11(3): 263-274.
[102]韦仕高,韦霞,韦忠理.血清肿瘤标志物联合检测对原发性肝癌的诊断价值[J].现代预防医学, 2010, 37(13): 2598-2599.
[103]魏路清,刘斌,李振华,等.阿托伐他汀减轻博莱霉素诱导大鼠实验性肺纤维化[J].基础医学与临床, 2009, 29(11): 1198-1202.
[104]王胜霞,李俊,刘勇.玉屏风多糖对大鼠肺纤维化的干预作用及部分机制研究[J].安徽医科大学学报, 2009, 44(5): 586-589.
[105] Kikuchi S, Griffin C T, Wang S S, et al. Role of CD44 in epithelial wound repair: migration of rat hepatic stellate cells utilizes hyaluronic acid and CD44v6[J]. J Biol Chem, 2005, 280(15): 15398-15404.
[106] Mark E. Mummert, Mansour Mohamadzadeh, et al. Development of a peptide inhibitor of hyaluronan- mediated leukocyte trafficking[J]. J. Exp. Med. 2000, 192(6): 769-779.
[107] Mark E, Mummert, Diana I. Mummert, et al. Functional roles of hyaluronan in B16-F10 melanoma growth and Experimental Metastasis in Mice[J]. Molecular Cancer Therapeutics, 2003, 3(2):295-300.