肝素的抗肿瘤转移活性及其与选凝素的关系

肝素作为传统抗凝剂,常用来治疗癌症患者静脉血栓。临床和实验数据证实,肝素具有抗肿瘤活性。同时也有大量研究发现,肝素有抗肿瘤转移的作用。肝素可以通过各种机制抑制肿瘤转移,包括抑制细胞间的相互作用;抑制肝素酶的表达;调节各种生长因子以及调节机体凝血功能等。选凝素(seletin)是介导肿瘤转移初始阶段的重要因子,而肝素能够抑制选凝素介导的的肿瘤细胞与白细胞、血小板及内皮细胞的相互作用,从而达到抗转移的效果。本文综述了肝素抑制选凝素介导的肿瘤转移的作用机制,为肝素在抗肿瘤转移方面的临床应用提供参考。     

肝素在肿瘤治疗中的应用

肝素作为传统抗凝剂已众所周知。研究发现,肝素尚具有多种生物学活性,特别是抗肿瘤作用备受学者关注。尽管临床上并未将肝素疗法作为一种常规抗肿瘤手段,但是许多研究已经证明了肝素能够抑制肿瘤细胞的侵袭与转移。本文综述肝素治疗肿瘤的主要机制以及肝素结构修饰在抗癌方面的应用。     

肝素结构与功能的研究进展

肝素是一类结构异常复杂的糖胺聚糖,与此相对应的是其多种生物学功能。除了经典的抗凝血及其相关的抗血拴生成以外,肝素还具有抗平滑肌细胞增殖、抗炎症、抗肿瘤及抗病毒等,并且这些生物活性同抗凝活性无关,而同肝素的特异结构密切相关。本文综述了肝素的多种生物学功能、作用机制及结构与功能的关系。     

肝素结构与功能的研究进展

肝素是一类结构异常复杂的糖胺聚糖,与此相对应的是其多种生物学功能。除了经典的抗凝血及其相关的抗血栓生成以外,肝素还具有抗平滑肌细胞增殖,抗炎症,抗肿瘤及抗病毒等,并且这些生物活性同抗凝活性无关,而同肝素的特异结构密切相关。     

鞘胺醇杆菌肝素酶的产生

肝素类分子是一类结构异常复杂的高度硫酸化的糖胺聚糖,是临床上的一种主要的抗凝剂。除了抗凝血及其相关的抗栓活性以外,肝素还具有多种其他生物学功能,如抗平滑肌细胞及肾小球系膜细胞的增殖^[1]、抗炎症^[2]和阻止肿瘤生长及转移的作用^[3]等。因而肝素可用于防治球囊扩充血管成型术后的血管再狭窄、肾小球系膜细胞增生性肾炎、病理性炎症及肿瘤。但由于完整肝素的抗凝血活性,会引起出血及血小板减少综合症等负作用,限制了肝素在这些方面的临床应用。研究表明,肝素的抗凝血活性依赖于一种独特的肝素五糖序列,约占完整肝素链的1／3,除了五糖序列以外,还需要附近的至少13糖残基,因而不含五糖序列或含五糖序列小于18糖的肝素其抗凝活性大大降低^[4]。而六糖以上的肝素片段就具有抗平滑肌细胞增生、抗炎症及抗肿瘤的活性,并且这些活性与抗凝活性无关。因此,可利用特异性的肝素酶降解肝素长链,产生一系列不同结构及大小的肝素片段,并从中筛选出具有不同生物活性的片段。     

乙酰肝素酶的生物学特性的研究进展

乙酰肝素酶是切割哺乳动物细胞中硫酸肝素蛋白多糖侧链——硫酸乙酰肝素的内源性糖苷酶,是抗肿瘤转移的理想靶点。本就乙酰肝素酶的分子结构特点、亚细胞定位、活性调控机制、与肿瘤转移的关系、底物特异性和抑制剂开发等方面的研究进展进行了综述。     

具抗肿瘤活性的乙酰肝素酶抑制剂的研究与开发

乙酰肝素酶是一种内源β-D-葡萄糖醛酸酶,通过抑制肝素酶的活性可抑制肿瘤细胞的生成及转移等。肝素酶抑制剂的研究,已成为抗肿瘤药物的研究热点之一。本文对肝素酶抑制剂作用的机理、筛选方法和已分离或合成的抑制剂等进行了综述,并讨论了今后对潜在的乙酰肝素酶抑制剂海洋生物羊栖菜多糖的开发。本文就DLC-1基因的结构及生物学功能、在乳腺癌中失活的机制和在乳腺癌中的表达及其意义作一综述。     

低分子肝素与普通肝素在介入手术中安全性与疗效的比较

肝素已经普遍用于冠状动脉介入术中,但是由于在应用过程中抗凝效果个体差异大、出血风险相对较高、并发症等问题的日益显现,已经引起了医生们的注意。相对而言,低分子肝素具有抗凝作用强、出血风险低、并发症发生率相对较低、无需实验室监测等优点,进而越来越广泛的在冠状动脉介入术中担当重要角色。普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性的比较是值得我们去探讨的,知道普通肝素与低分子肝素的优缺点后,可使我们在冠状动脉介入术中更好的选择抗凝药物,使手术的成功率大大提高,降低术后并发症的发生,减轻患者的痛苦。本文结合普通肝素与低分子肝素的药理作用及相关临床研究的结果,分析比较了普通肝素与低分子肝素在冠状动脉介入术中的有效性与安全性。     

乙酰肝素酶的结构、功能及调控

乙酰肝素酶是目前发现的哺乳动物细胞中唯一能切割细胞外基质中硫酸肝素蛋白多糖侧链--硫酸乙酰肝素--的内源性糖苷酶,是抗肿瘤,抗炎症的理想靶点。对其深入研究将有助于揭示组织修复,血管形成,自身免疫,肿瘤转移等生理及病理过程。本就乙酰肝素酶的发现,分子特性,基因定位,转录,表达调控,细胞内的亚定位及其功能活性调控机制方面的研究进展进行综述。     

乙酰肝素酶与胃癌发展的关系及其检测

乙酰肝素酶是目前发现的哺乳动物细胞中惟一能切割细胞外基质中硫酸乙酰肝素蛋白多糖侧链——硫酸乙酰肝素的一种葡萄糖醛酸内切酶,在胃癌侵袭转移中起重要作用。我们就乙酰肝素酶的分子结构特点、在胃癌侵袭转移中的作用机制及其检测等方面的研究进展进行综述。     

Highly active heparin species with multiple binding sites for antithrombin

Porcine heparin has been fractionated by Sephadex G-100 gel filtration and affinity chromatography into mucopolysaccharide species with approximate molecular sizes of 20,000 daltons, and 7000 daltons, respectively. The larger component has a specific anticoagulant activity of 738 USP units/mg and contains two binding regions for antithrombin. The smaller component has a specific anticoagulant activity of 363 USP units/mg and possesses only a single interaction site for the inhibitor. These results provide the first demonstration that heparin molecules may bear multiple binding sites for antithrombin.     

肝素6位羧基修饰对抑制P?鄄选择素介导的A375细胞粘附活性的影响

已有的研究表明,肝素可以作为P-选择素的配体,显著抑制肿瘤转移过程中P-选择素介导的肿瘤细胞与血小板间的粘附.但是,肝素被P-选择素识别所必需的确切寡糖结构信息仍很缺乏.通过选择性化学修饰方法制备了2种低抗凝血肝素衍生物,即羧基还原肝素(CR-肝素)和羧基还原后再硫酸化肝素(SCR-肝素),系统地研究了它们对P-选择素介导的A375细胞粘附的抑制.研究结果表明,显著失去抗凝血活性的CR-肝素仍能有效地抑制P-选择素介导的A375细胞粘附,说明肝素的C6羧基并不是被P-选择素识别所必需的.而SCR-肝素所发生的C6羧基向羟甲硫酸酯基的转化却显著降低了抗粘附活性,说明P-选择素对肝素的识别并不只依赖于肝素的电荷密度.研究结果为深入阐明拮抗P-选择素介导的肿瘤细胞粘附的分子机制提供了有价值的实验基础.     

肝素的抗炎作用与抗细胞粘附调节

肝素类药物具有抗凝以外的包括抗炎在内的多种生物学活性。炎症反应是多种因子、细胞参与的复杂的病生理过程,其物质基础是粘附分子介导的白细胞粘附及其粘附级联反应。近来研究证实肝素抗炎机制主要与抗细胞粘附调节有关,肝素通过竞争抑制L—、P—选择素与其配基sLe^X的结合,阻止白细胞粘附活化及调抑炎症级联反应,进而起到抗炎作用。对肝素抗炎机制的深入研究,将有助于进一步阐明抗粘附／抗炎的作用机制。     

Microbial heparin/heparan sulphate lyases: potential and applications

Heparin/heparan sulphate glycosaminoglycans (HSGAGs) are composed of linear chains of 20–100 disaccharide units of N-acetylated d-glucosamine α (1–4) linked to glucuronic acid. HSGAGs are widely distributed on the cell surface and extracellular cell matrix of virtually every mammalian cell type and play critical role in regulating numerous functions of blood vessel wall, blood coagulation, inflammation response and cell differentiation. These glycosaminoglycans present in this extracellular environment very significantly influence the blood coagulation system and cardiovascular functions. Recent studies have investigated the mechanism by which cancer causes thrombosis and emphasizes the importance of the coagulation system in angiogenesis and tumour metastasis. Heparan sulphate/heparin lyases or heparinases are a class of enzymes that are capable of specifically cleaving the (1–4) glycosidic linkages in heparin and heparan sulphate to generate biologically active oligosaccharides with substantially significant and distinct clinical, pharmaceutical and prophylactic/therapeutic applications. Bioavailability and pharmacokinetic behaviour and characteristics of these oligosaccharides vary significantly depending on the origin/nature of the substrate (heparin or heparan sulphate-like glycosaminoglycans), the source of enzyme and method of preparation. Various microorganisms are reported/patented to produce these enzymes with different properties. Heparinases are commercially used for the depolymerization of unfractionated heparin to produce low molecular weight heparins (LMWHs), an effective anticoagulant. Individual LMWHs are chemically different and unique and thus cannot be interchanged therapeutically. Heparinases and LMWHs are reported to control angiogenesis and metastasis also. This review catalogues the degradation of HSGAGs by microbial heparin/heparan sulphate lyases and their potential either specific to the enzymes or with the dual role for generation of oligosaccharides for a new generation of compounds, as shown by various laboratory or clinical studies.     

Vascular galectins: Regulators of tumor progression and targets for cancer therapy

Galectins are a family of carbohydrate binding proteins with a broad range of cytokine and growth factor-like functions in multiple steps of cancer progression. They contribute to tumor cell transformation, promote tumor angiogenesis, hamper the anti-tumor immune response, and facilitate tumor metastasis. Consequently, galectins are considered as multifunctional targets for cancer therapy. Interestingly, many of the functions related to tumor progression can be linked to galectins expressed by endothelial cells in the tumor vascular bed. Since the tumor vasculature is an easily accessible target for cancer therapy, understanding how galectins in the tumor endothelium influence cancer progression is important for the translational development of galectin-targeting therapies.     

Anticoagulant properties of a sulfated galactan preparation from a marine green alga, Codium cylindricum

An anticoagulant was isolated from a marine green alga, Codium cylindricum. The anticoagulant was composed mainly of galactose with a small amount of glucose, and was highly sulfated (13.1% as SO3Na). The anticoagulant properties of the purified anticoagulant were compared with that of heparin by assays of activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) using normal human plasma. The anticoagulant showed similar activities with heparin, however, weaker than heparin. On the other hand, the anticoagulant did not affect PT even at the concentration at which APTT and TT were strongly prolonged. The anticoagulant did not potentiate antithrombin III (AT III) and heparin cofactor II (HC II), thus the anticoagulant mechanism would be different from that of other anticoagulants isolated so far from the genus Codium.     

Modified heparin inhibits P-selectin-mediated cell adhesion of human colon carcinoma cells to immobilized platelets under dynamic flow conditions

Accumulating evidence indicates that the formation of tumor cell platelet emboli complexes in the blood stream is a very important step during metastases and that the anti-metastasis effects of heparin are partially due to a blockade of P-selectin on platelets. In this study, heparin and chemically modified heparins were tested as inhibitors of three human colon carcinoma cell lines (COLO320, LS174T, and CW-2) binding to P-selectin, adhering to CHO cells expressing a transfected human P-selectin cDNA, and adhering to surface-anchored platelets expressing P-selectin under static and flow conditions. The aim was to screen for heparin derivatives with high anti-adhesion activity but negligible anticoagulant activity. In this study, four modified heparins with high anti-adhesion activity were identified including RO-heparin, CR-heparin, 2/3ODS-heparin, and N/2/3DS-heparin. NMR analysis proved the reliability of structure of the four modified heparins. Our findings suggested that the 6-O-sulfate group of glucosamine units in heparin is critical for the inhibition of P-selectin-mediated tumor cell adhesion. Heparan sulfate-like proteoglycans on these tumor cell surfaces are implicated in adhesion of the tumor cells to P-selectin. Some chemically modified heparins with low anticoagulant activities, such as 2/3ODS-heparin, may have potential value as therapeutic agents that block P-selectin-mediated cell adhesion and prevent tumor metastasis.