Suramin. A potent inhibitor of melanoma heparanase and invasion.
Suramin. A potent inhibitor of melanoma heparanase and invasion.
复制标题
DOI：
10.1016/s0021-9258(18)92871-1
复制
发表时间：
1991-05
期刊：
影响因子：
--
通讯作者：
M. Nakajima;A. DeChavigny;C. Johnson;J. Hamada;C. Stein;G. Nicolson
中科院分区：
文献类型：
--
作者：
M. Nakajima;A. DeChavigny;C. Johnson;J. Hamada;C. Stein;G. Nicolson
苏拉明是一种聚磺化萘脲，具有抗逆转录酶和抗增殖活性，并抑制各种生长因子与其细胞表面受体的结合。这种药物用于治疗获得性免疫缺陷综合征和几种类型的癌症。在接受苏拉明治疗的癌症患者中观察到循环糖胺聚糖水平升高，表明它可能抑制糖胺聚糖分解代谢。黑色素瘤衍生的肝素酶是一种硫酸肝素特异性内切- β -d -葡萄糖醛酸酶，在转移性黑色素瘤细胞通过基底膜侵袭中起重要作用，苏拉明以剂量依赖的方式抑制该酶：在约100微米的浓度下观察到100%的抑制作用。结构相关的多磺酸化合物，如特泮蓝和埃文斯蓝，具有较低的肝素酶抑制活性：50%肝素酶抑制所需的浓度（ID50）为310-320 μ m，比苏拉明（ID50 = 46 μ m）高6倍。过硫酸化肝素四糖的平均分子大小与苏拉明相似，其肝素酶抑制活性也比苏拉明低得多。对苏拉明和过硫酸肝素四糖的抑制常数（Ki）分别为48和290微米。苏拉明通过重组基底膜对B16黑色素瘤细胞的侵袭具有显著的抑制作用（ID50小于10微米）。苏拉明对黑色素瘤肝素酶和细胞侵袭的抑制作用似乎完全独立于其抗增殖活性，因为在本研究中使用的苏拉明浓度下未观察到对黑色素瘤细胞生长的显著影响。结果提示苏拉明的抗转移作用可能是由于其抗侵袭性而非抗增殖活性。
Suramin, a polysulfonated naphthylurea, has anti-reverse transcriptase and anti-proliferative activities and inhibits the binding of various growth factors to their cell surface receptors. This drug is used in the treatment of acquired immunodeficiency syndrome and several types of cancers. Increased levels of circulating glycosaminoglycans have been observed in suramin-treated cancer patients, suggesting that it may inhibit glycosaminoglycan catabolism. Melanoma-derived heparanase, a heparan sulfate-specific endo-beta-D-glucuronidase that plays an important role in metastatic melanoma cell invasion through basement membranes, is inhibited by suramin in a dose-dependent manner: 100% inhibition was observed at a concentration of approximately 100 microM. Structurally related polysulfonated compounds, such as trypan blue and Evans blue, had lower heparanase inhibitory activities: the concentrations required for 50% heparanase inhibition (ID50) were 310-320 microM and six times higher than for suramin (ID50 = 46 microM). Oversulfated heparin tetrasaccharide, whose average molecular size is similar to suramin, had also much lower heparanase inhibitory activity than suramin. The inhibition constants (Ki) for suramin and oversulfated heparin tetrasaccharide were 48 and 290 microM, respectively. Suramin had a remarkable inhibitory activity against B16 melanoma cell invasion through reconstituted basement membranes (ID50 less than 10 microM). The inhibitory effects of suramin on melanoma heparanase and cell invasion appeared to be completely independent of its antiproliferative activity, because significant effects on melanoma cell growth were not observed at the concentrations of suramin used in this study. The results suggest that the antimetastatic effects of suramin may be due to its antiinvasive rather than antiproliferative activities.