Non-anticoagulant heparins and inhibition of cancer.
Non-anticoagulant heparins and inhibition of cancer.
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非抗癌肝素和抑制癌症。
DOI：
10.1159/000175157
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发表时间：
2008
影响因子：
--
通讯作者：
Sanderson RD
中科院分区：
文献类型：
--
作者：
Casu B;Vlodavsky I;Sanderson RD
低分子量肝素（LMWH）似乎可以延长癌症患者的生存期。这种有益作用被认为与涉及细胞表面和细胞外基质蛋白聚糖（HSPG）、生长因子及其受体、肝素酶和选择素的硫酸肝素（HS）链的分子机制的中断有关。肝素种类的有益作用也可能与它们从内皮细胞释放TFPA的能力有关。由于肝素和低分子肝素的抗凝特性，其作为抗癌药物的应用受到限制。非抗凝肝素可以通过去除含有抗凝血酶结合序列的链，或通过灭活该序列的关键官能团或单元来获得。研究最广泛的非抗凝肝素是区域选择性去硫肝素和“乙二醇分裂”肝素。两种类型的一些改良肝素都是肝素酶的有效抑制剂。在实验模型中，它们中的一些也能减弱转移。由于癌细胞过度表达选择素，肝素介导的抑制肿瘤细胞-血小板聚集和肿瘤细胞与血管内皮的相互作用似乎是早期转移衰减的普遍机制。肝素衍生物抑制生长因子、肝素酶和选择素的结构要求因活性的不同而有所不同。n -乙酰化，乙二醇分裂肝素提供了一个非抗凝肝素应用的例子，在动物模型中抑制癌症而没有不良副作用。将这种化合物传递给患有已建立的骨髓瘤肿瘤的小鼠，可显著阻止肿瘤的生长和进展。
Low-molecular weight heparins (LMWH) appear to prolong survival of patients with cancer. Such a beneficial effect is thought to be associated with interruption of molecular mechanisms involving the heparan sulfate (HS) chains of cell surface and extracellular matrix proteoglycans (HSPG), growth factors and their receptors, heparanase, and selectins. The benefiial effects of heparin species could be associated also with their ability to release TFPA from endothelium. The utility of heparin and LMWH as anticancer drugs is limited due to their anticoagulant properties. Non anticoagulant heparins can be obtained either by removing chains containing the antithrombin-binding sequence, or by inactivating critical functional groups or units of this sequence.The non anticoagulant heparins most extensively studied are regioselectively desulfated heparins and “glycol-split” heparins. Some modified heparins of both types are potent inhibitors of heparanase. A number of them also attenuate metastasis in experimental models. With cancer cells overexpressing selectins, heparin-mediated inhibition of tumor cells-platelets aggregation and tumor cell interaction with the vascular endothelium appears to be the prevalent mechanism of attenuation of early stages of metastasis. The structural requirements for inhibition of growth factors, heparanase, and selectins by heparin derivatives are somewhat different for the different activities. An N-acetylated, glycol-split heparin provides an example of application of a non anticoagulant heparin that inhibits cancer in animal models without unwanted side effects. Delivery of this compound to mice bearing established myeloma tumors dramatically blocked tumor growth and progression.