A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination
A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination
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DOI：
10.1158/1078-0432.ccr-05-2745
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发表时间：
2006-05-01
影响因子：
11.5
通讯作者：
Esko, JD
中科院分区：
文献类型：
--
作者：
Brown, JR;Fuster, MM;Esko, JD
目的：表达碳水化合物唾液酸路易斯 X (sLe(x)) 的血源性恶性细胞与白细胞、血小板和内皮细胞上的选择素粘附受体结合，促进转移。糖基化抑制剂全-O-乙酰化 GlcNAc β 1,3Gal β-O-萘甲醇 (AcGnG-NM) 可抑制肿瘤细胞中 sLex 的生物合成。为了评估 AcGnG-NM 作为抗转移剂的功效，我们检查了其对小鼠 Lewis 肺癌和 B16BL6 黑色素瘤细胞的实验性转移和自发血行播散的影响。实验设计：用 AcGnG-NM 体外处理肿瘤细胞，并分析选择素配体抑制和实验性转移的程度。 野生型和 P-选择素缺陷型小鼠。开发了 AcGnG-NM 全身给药的条件，并使用体内溴脱氧尿苷标记评估了肺部肿瘤细胞的存在。使用急性腹膜炎模型检查AcGnG-NM对炎症的影响。结果：用AcGnG-NM体外处理Lewis肺癌细胞，降低了sLe(x)-和P-选择素依赖性细胞粘附到涂有P-选择素的平板上的表达。当细胞被注射到同基因小鼠体内时，治疗还减少了肺病灶的形成。全身给予二糖显着抑制细胞从原发性皮下自发扩散到肺部。肿瘤，而结构上与 sLe(x) 无关的乙酰化二糖则没有作用。 AcGnG-NM 不会改变循环白细胞或血小板的水平、中性粒细胞上 P-选择素配体的表达或 s Le(x) 依赖性炎症。结论：综上所述，这些数据表明 AcGnG-NM 为治疗肿瘤细胞的血行播散提供了一种基于糖苷的靶向疗法。
Purpose: The binding of hematogenously borne malignant cells that express the carbohydrate sialyl Lewis X (sLe(x)) to selectin adhesion receptors on leukocytes, platelets, and endothelial cells facilitates metastasis. The glycosylation inhibitor, per-O-acetylated GlcNAc beta 1,3Gal beta-O-naphthalenemethanol (AcGnG-NM), inhibits the biosynthesis of sLex in tumor cells. To evaluate the efficacy of AcGnG-NM as an antimetastatic agent, we examined its effect on experimental metastasis and on spontaneous hematogenous dissemination of murine Lewis lung carcinoma and B16BL6 melanoma cells.Experimental Design: Tumor cells were treated in vitro with AcGnG-NM, and the degree of selectin ligand inhibition and experimental metastasis was analyzed in wild-type and P-selectin-deficient mice. Conditions were developed for systemic administration of AcGnG-NM, and the presence of tumor cells in the lungs was assessed using bromodeoxyuridine labeling in vivo. The effect of AcGnG-NM on inflammation was examined using an acute peritonitis model.Results: In vitro treatment of Lewis lung carcinoma cells with AcGnG-NM reduced expression of sLe(x)- and P-selectin-dependent cell adhesion to plates coated with P-selectin. Treatment also reduced formation of lung foci when cells were injected into syngeneic mice. Systemic administration of the disaccharide significantly inhibited spontaneous dissemination of the cells to the lungs from a primary s.c. tumor, whereas an acetylated disaccharide not related to sLe(x) in structure had no effect. AcGnG-NM did not alter the level of circulating leukocytes or platelets, the expression of P-selectin ligands on neutrophils, or s Le(x)-dependent inflammation.Conclusion: Taken together, these data show that AcGnG-NM provides a targeted glycoside-based therapy for the treatment of hematogenous dissemination of tumor cells.