肝素、低分子肝素的抗肿瘤作用研究进展

肝素、低分子肝素是临床常用的一种抗凝药物.近年来研究发现,其还具有多种生物活性和临床用途,包括抗血管生成及抗肿瘤作用等.肝素、低分子肝素可通过改变肿瘤细胞的细胞和分子学环境而干预肿瘤的发展,例如,肝素、低分子肝素具有抗肿瘤细胞增殖作用,抑制血管内皮细胞增殖和抑制血管形成,通过抑制乙酰肝素酶、基质金属蛋白酶等酶的活性及作...     

肝癌组织中乙酰肝素酶与碱性成纤维细胞生长因子的表达及其与微血管密度的关系

乙酰肝素酶（Hpa）可降解细胞外基质（ECM）和基底膜中的硫酸乙酰肝素,破坏其完整性,同时释放在细胞外基质中储存的碱性成纤维细胞生长因子（b-FGF）,促进肿瘤血管的生成,从而有利于肿瘤细胞的侵袭和转移.现探讨Hpa、b-FGF与肝癌的临床病理特征及肿瘤血管新生之间的关系.     

肝素酶:肿瘤治疗的新靶标

肝素酶是肿瘤发生、浸润和转移过程中的关键酶,主要通过降解硫酸肝素,破坏细胞外基质和基底膜完整性而发挥作用.肝素酶与肿瘤发生和转移的密切相关性,使得肝素酶成为肿瘤治疗的新靶标.本文主要阐述肝素酶的生物学特性、促肿瘤转移的作用机制和在肿瘤发生发展中的重要作用,并且对目前以肝素酶为靶标的肿瘤治疗方法和临床前景进行综述.     

乙酰肝素酶在胃癌组织中的表达及临床意义

癌细胞侵袭和转移的一个重要机制是降解基底膜和细胞外基质结构.硫酸乙酰肝素降解性糖苷内切酶的激活与肿瘤细胞转移有关,这在鼠B16-Fl0黑色素瘤细胞在血管内皮细胞细胞外基质上的培养试验中被证实[1].Takaoka等[2]采用逆转录聚合酶链反应(RT-PCR)和免疫组化方法在临床标本和细胞中证明乙酰肝素酶的表达与胃癌的侵袭性和预后不良有关.     

乙酰肝素酶在肿瘤侵袭转移和血管生成中的作用

侵袭和转移是肿瘤重要的生物学特征，而细胞外基质(extracenular matrix，ECM)的降解和新生血管的形成则是促进肿瘤侵袭转移的关键因素。乙酰肝素酶(heparanase，HJPSE)是新近克隆出来的一种基质降解酶，可降解ECM和基底膜(basement membrance，BM)中的硫酸乙酰肝素(heparan sulfate，HS)，在肿瘤细胞的侵袭转移和血管生成过程中发挥着重要作用。     

肝素酶基因在肺腺癌中的表达及临床病理学意义

肿瘤转移的两个必备条件为瘤细胞侵犯基底膜(BM)与细胞外基质(ECM)和肿瘤血管的生成。BM及ECM的重要成分之一为硫酸肝素蛋白多糖(HSPGs)，其作用酶为肝素酶。为从分子水平上了解肺癌侵袭转移的机制，进一步探讨控制侵袭转移的方法，从而改善患者预后，提高生存率，我们采用逆转录聚合酶链反应(RT—PCR)技术研究肺腺癌组织中肝素酶基因的表达及临床病理学意义。     

肝素酶:一种新的广谱的肿瘤转移相关抗原在中晚期肿瘤免疫治疗中的作用研究进展

肝素酶(Hpa)是裂解硫酸乙酰肝素蛋白多糖的唯一酶类,能破坏细胞外基质及基底膜,参与肿瘤血管生成,与肿瘤的侵袭转移密切相关.目前的研究表明,Hpa在大多数中晚期肿瘤中都有表达,尤其在转移性肿瘤中强表达,而Hpa表达的下调可以抑制肿瘤细胞的转移,提示Hpa可以作为一种广谱的肿瘤转移相关抗原用于中晚期肿瘤的免疫治疗.Hpa疫苗的开发可望为中晚期肿瘤的治疗开辟新的途径.本文详细综述了Hpa的结构与功能、对肿瘤转移的促进作用及其机制、以及其作为肿瘤转移相关抗原用于中晚期肿瘤免疫治疗的可能性.     

修饰性肝素抗消化道肿瘤作用机制的研究进展

普通肝素用化学方法处理后,可得到修饰性肝素.其抗肿瘤作用机制包括抑制类肝素酶活性及细胞黏附分子P、L选择素、抗凝、抗血管生成、对免疫系统的调控等.因此,该类药物在抗肿瘤方面的应用将有非常广泛的前景.此文对修饰性肝素抗肿瘤作用机制方面的研究作一综述.     

腹水脱落细胞中肝素酶的表达对良恶性腹水鉴别诊断的价值

肝素酶是近年来发现的能够降解基底膜及细胞外基质的关键酶．具有促进肿瘤细胞向周围组织间隙侵袭的作用。我们前期研究表明，肝素酶在胃癌组织中高表达，能够促进胃癌的血管生成，浸润与转移，是胃癌患者预后不良的一个指标。在腹水脱落细胞中肝素酶是否表达，能否用于鉴别腹水的性质鲜见报道。我们采用逆转录聚合酶链反应（RT-PCR）法检测肝素酶在腹水脱落细胞中的表达，探讨肝素酶在良恶性腹水鉴别诊断中的意义。     

乙酰肝素酶在肺癌侵袭转移及治疗中作用的研究进展

乙酰肝素酶是一种β-D-葡萄糖醛酸内切酶,为体内惟一能够降解硫酸乙酰肝素蛋白多糖的酶,可以在特定部位裂解硫酸乙酰肝素蛋白多糖,破坏细胞外基质及基底膜,并参与恶性肿瘤新生血管的形成,与恶性肿瘤的侵袭转移密切相关,乙酰肝素酶由此成为抗肿瘤作用的新靶点,其抑制剂有望成为临床抗肿瘤治疗的新途径.本文就乙酰肝素酶在肺癌侵袭转移及治疗中作用的研究作一综述.     

Treatment of concanavalin A-induced hepatitis in mice with low molecular weight heparin

BACKGROUND/AIMS: Heparin has been noted to inhibit inflammation independent of its known anti-coagulant activity. In the present study, we examined the ability of heparin and low molecular weight heparin to prevent immune-mediated, concanavalin A-induced liver damage. METHODS: Mice were pretreated with either heparin or low molecular weight heparin (Fragmin) prior to their inoculation with concanavalin A (10 mg/kg). Liver enzymes, liver histology, and the serum levels of tumor necrosis factor-a, interleukin-6, and interleukin-10 were examined in the control and treated mice. RESULTS: The histopathologic damage in the liver, and the concanavalin A-induced release of aminotransferases, tumor necrosis factor-a, and interleukin-6 were significantly inhibited in mice pretreated with low molecular weight heparin, whereas the serum levels of the anti-inflammatory cytokine interleukin-10 were increased (p<0.01). Interestingly, maximal inhibition was obtained with low low molecular weight heparin doses (5 and 1 microg/mouse, p<0.001), while higher doses were less effective. Concanavalin A-induced liver injury was not prevented by pretreatment of the mice with heparan sulphate (p<0.001), which although it is structurally similar to heparin possesses neither anti-inflammatory nor anti-coagulant properties. CONCLUSIONS: This study demonstrates the efficacy of low molecular weight heparin in preventing immune-mediated liver damage in mice.     

The role of heparin in alleviating complement-mediated acute intravascular haemolysis

Heparin is commonly used as an anticoagulant but its many other pharmacologic properties are less well known. It has an important effect on complement regulation and has been shown in vitro to inhibit complement-mediated lysis of red cells. Although the beneficial effects of heparin for treatment of haemolytic anaemia were described many decades ago, its use in this scenario is not standard practice. Here we report a case where the use of heparin had a beneficial effect on a life-threatening episode of intravascular haemolysis. We also show unfractionated heparin to be more beneficial than low molecular weight heparin. We suggest that heparin has an important role to play in the management of complement-mediated haemolytic episodes.     

Enzymatic synthesis of glycosaminoglycan heparin

Heparin and its low molecular weight heparin derivatives, widely used as clinical anticoagulants, are acidic polysaccharide members of a family of biomacromolecules called glycosaminoglycans (GAGs). Heparin and the related heparan sulfate are biosynthesized in the Golgi apparatus of eukaryotic cells. Heparin is a polycomponent drug that currently is prepared for clinical use by extraction from animal tissues. A heparin pentasaccharide, fondaparinux, has also been prepared through chemical synthesis for use as a homogenous anticoagulant drug. Recent enabling technologies suggest that it may now be possible to synthesize heparin and its derivatives enzymatically. Moreover, new technologies including advances in synthetic carbohydrate synthesis, enzyme-based GAG synthesis, micro- and nano-display of GAGs, rapid on-line structural analysis, and microarray/microfluidic technologies might be applied to the enzymatic synthesis of heparins with defined structures and exhibiting selected activities. The advent of these new technologies also makes it possible to consider the construction of an artificial Golgi to increase our understanding of the cellular control of GAG biosyntheses in this organelle.     

Severe thrombopenia from heparin: value of the use of low molecular weight heparin. Apropos of 6 cases

Severe heparin-induced thrombocytopaenia associated with thromboembolism is a well known complication, although the exact pathogenic mechanism remains unclear. It sets the problem of whether to continue heparin therapy because standard heparin must be withdrawn. Heparin is a mucopolysaccharide composed of fractions of different molecular weights. The fractions with high molecular weights have been held responsible for these severe thrombocytopenias and so, the use of low molecular weight heparin has been suggested. The authors used subcutaneous low molecular weight heparin (CY 216 Choay Institute) at empirical doses of 350 to 1 500 units/kg/24 hour in six cases of severe heparin-induced thrombocytopaenia. Platelet counts rapidly returned to normal (4 days on average) in 5 cases. Thrombocytopaenia persisted with low molecular weight heparin in 1 case. The study of platelet aggregation was positive with low molecular weight heparin in this case and the platelet count returned to normal when the treatment was withdrawn. The authors conclude that, although low molecular weight heparin is useful in severe heparin-induced thrombocytopaenia, its efficacy remains modest. Not only may platelet aggregation persist with low molecular weight heparin which rekindles the debate as to its pathogenic mechanism, but also low molecular weight heparin may have a slight antithrombin effect which limits its use in patients at high risk of thromboembolism, imposing treatment with fast acting vitamin K antagonists.     

Dual effect of heparin and low molecular weight heparin on cultured smooth muscle cells.

The effects of heparin and low molecular weight heparin (LMWH) on the growth of cultured human aortic smooth muscle cells (hASMCs) were studied. The fourth-passage hASMCs were planted onto a 24-well plate (5 wells for each concentration of heparin or LMWH) and cultured by DMEM containing 5% either old or fresh human serum (HS), 10% fetal calf serum (FCS), and differing concentrations of heparin or LMWH (heparin and LMWH were presented as hexuronic acid) together with corresponding control groups (without heparin or LMWH) for 24h. hASMCs growth was estimated both morphologically and by 3H-TdR incorporation. The results revealed that both heparin and LMWH inhibited the proliferation of healthy growth hASMCs, but promoted the proliferation of weak growth hASMCs. These results suggest for the first time that heparin and LMWH have a dual regulative role (inhibition and promotion) in hASMCs growth and indicate that they may play an important role in controlling the proliferation of vascular smooth muscle cells and maintaining the integrity of vascular structure.     

Cardiovascular hypertrophy in one-kidney, one-clip renal hypertension is resistant to heparin

OBJECTIVE: Heparin inhibits vascular hypertrophy in angiotensin-induced hypertension, in addition to its well-known role in inhibiting injury-induced vascular smooth muscle proliferation. We tested whether hypertension and vascular hypertrophy could be reduced by heparin independently from the renin-angiotensin system. METHODS: Rats were made hypertensive with a one-kidney, one-clip (1K1C) procedure and received heparin from osmotic minipumps (0.3 mg/h per kg i.v.) or saline vehicle for 2 weeks. Blood pressure was measured by the tail-cuff method and vessel cross-sectional area was measured by morphometry in the aorta and mesenteric arteries. Proliferation was assessed with bromodeoxyuridine labelling. RESULTS: Blood pressure elevation and cardiovascular hypertrophy were evident in 1K1C rats. The media of mesenteric arteries was increased by 25%, and the media : lumen ratio by 35%, in hypertensive rats. DNA synthesis by smooth muscle cells in the mesenteric arteries was increased sevenfold in renal hypertension. Heparin treatment did not influence either the increase in blood pressure, the cardiovascular hypertrophy response or hypertension-mediated proliferation of arterial smooth muscle cells. CONCLUSIONS: These data suggest that the vascular hypertrophy mechanisms operating in 1K1C renal hypertension are not inhibited by heparin and thus are different from those in angiotensin-mediated hypertension. Identifying such mechanisms in the future will be important for devising appropriate intervention strategies in angiotensin-independent forms of vascular hypertrophy.     

肝素对大鼠肝星状细胞生长、细胞外基质和基质金属蛋白酶基因表达的影响

目的 探讨肝素对ＨＳＣ生长、细胞外基质和基质金属蛋白酶基因表达的影响。方法 用肝素和不用肝素对活化的ＨＳＣ进行处理,以直接细胞计数和ＢｒｄＵ标记免疫细胞化学染色检测细胞的生长情况。用免疫细胞化学染色和细胞闰核酸分子杂交分别检测Ｉ、Ⅳ型前胶原蛋白、纤连蛋白和Ⅰ、Ⅳ型胶原、纤连蛋白、基质金属蛋白酶－２及膜型基质金属蛋白酶基因的表达,并用酶图法检测基质金属蛋白酶－２的活性。结果 肝素使血清所致的ＨＳＣ生     

A case of heparin induced thrombocytopenia treated with lepirudin infusion: case report

Heparin induced thrombocytopenia (HIT) is a life-threatening complication that can be seen in the course of heparin treatment. The syndrome is much likely to be seen during treatment with standard heparin but it can also be seen due to low molecular weight heparins. In this article, we presented a case of HIT who was given low molecular weight heparin for prophylaxis that developed massive pulmonary thromboembolism. The patient was successfully treated with lepirudin infusion and no complications due to treatment was seen.