Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin
Anti-metastatic effect of a non-anticoagulant low-molecular-weight heparin versus the standard low-molecular-weight heparin, enoxaparin
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DOI：
10.1160/th06-05-0289
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发表时间：
2006-12-01
影响因子：
6.7
通讯作者：
Amirkhosravi, Ali
中科院分区：
文献类型：
--
作者：
Mousa, Shaker A.;Linhardt, Robert;Amirkhosravi, Ali
低分子量肝素（LMWH）通过其对凝血酶和Xa因子的血浆效应表现出强效抗凝效力。这些药物还可有效释放内皮组织因子途径抑制剂（TFPI）（组织因子的天然抑制剂），并在实验动物模型中表现出显著的抗转移作用。然而，出血并发症的可能性减缓了LMWH治疗在癌症患者中的更广泛采用。在这项研究中，一种非抗凝形式的低分子肝素（NA-LMWH）对实验性肺转移和肿瘤细胞诱导的血小板聚集在体内的影响进行了比较，LMWH依诺肝素。使用转移的B 16黑素瘤小鼠模型，皮下（s.c.）注射NA-LMWH或依诺肝素（10 mg/kg），在静脉内（i. v.）注射转移性黑色素瘤细胞，然后每天给药14天，使肺肿瘤形成减少70%（P < 0.001）。静脉注射肿瘤细胞导致血小板计数显著下降（50- 62%，P < 0.01）。注射前（i. v.）依诺肝素完全消除了肿瘤细胞诱导的血小板减少症，而NA-LMWH没有效果。一次皮下注射后四小时。剂量，依诺肝素而不是NA-LMWH延长凝血时间3倍，延迟时间凝块开始超过10倍，分别通过Sono-clot分析仪和血栓弹力图测量。依诺肝素而非NA-LMWH在小鼠中显示出显著的抗凝作用。NA-LMWH和依诺肝素在体外引起内皮细胞释放TFPI相似。这些数据提供了证据，支持NA-LMWH作为抗转移药物的潜力，对凝血无任何显著影响。
Low-molecular-weight heparins (LMWH) exhibit potent anticoagulant efficacy via their plasmatic effects on thrombin and factor Xa. These agents are also effective in releasing endothelial tissue factor pathway inhibitor (TFPI),the natural inhibitor of tissue factor, and exhibit significant anti-metastatic effects in experimental animal models. However, the potential for bleeding complications has slowed down the more widespread adoption of LMWH therapy in cancer patients. In this study, the effect of a non-anticoagulant form of LMWH (NA-LMWH) on experimental lung metastasis and tumor cell-induced platelet aggregation in vivo was compared to the LMWH enoxaparin. Using the B 16 melanoma mouse model of metastasis, subcutaneous (s.c.) injection of NA-LMWH or enoxaparin (10 mg/kg), three hours before intravenous (i.v.) injection of metastatic melanoma cells, followed by daily doses for 14 days, reduced lung tumor formation by 70% (P < 0.001).I.v. injection of tumor cells resulted in a significant (50-62%, P < 0.01) fall in platelet counts. Pre-injection (i.v.) of enoxaparin completely abolished the tumor cell-induced thrombocytopenia, whereas NA-LMWH had no effect. Four hours after a single s.c. dose, enoxaparin but not NA-LMWH prolonged the clotting time three-fold and delayed the time to clot initiation more than 10-fold as measured by a Sono-clot analyzer and by thromboelastography, respectively. Enoxaparin but not NA-LMWH demonstrated a significant anticoagulant effect in mice. Both NA-LMWH and enoxaparin caused similar TFPI release from endothelial cells in vitro. These data provide evidence to support the potential of NA-LMWH as an anti-metastatic agent without any significant impact on coagulation.