在小鼠模型中，NS - 398通过诱导凋亡和抑制纤溶酶原激活系统来抑制结肠癌的肿瘤生长和肝转移。

NS-398 inhibits tumor growth and liver metastasis of colon cancer through induction of apoptosis and suppression of the plasminogen activation system in a mouse model.

作者信息

Nishikawa Masayasu, Stapleton Philip P, Freeman Tracy A, Gaughan John P, Matsuda Takeaki, Daly John M

机构信息

Department of Surgery, Weill Medical College of Cornell University, New York, NY, USA.

出版信息

J Am Coll Surg. 2004 Sep;199(3):428-35. doi: 10.1016/j.jamcollsurg.2004.05.265.

DOI:10.1016/j.jamcollsurg.2004.05.265

PMID:15325613

Abstract

BACKGROUND

Cyclooxygenase-2 (COX-2) is overexpressed in colon cancers. The plasminogen activation (PA) system relates to cancer invasion and metastasis through the degradation of the extracellular matrix. COX-2 also relates to degradation of the extracellular matrix, but the relationship between COX-2 and the plasminogen activator system is unclear.

STUDY DESIGN

In vivo: Colon 38 (G0) primary and (G5) metastatic cell lines were implanted in C57BL/6 mice treated with or without COX-2 inhibitor (NS-398). Animal survival and tumor growth were measured. On day 19, tumors were excised and tumor cell apoptosis measured. For metastasis, G5 cells were injected into the spleen, and, after 23 days, liver metastasis was determined. In vitro: G0 or G5 cells were treated with NS-398. Supernatant prostaglandin E2 and mRNA expressions of COX-2, vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (u-PA), u-PA receptor, plasminogen activator inhibitor type-1 (PAI-1), and PAI-2 were measured. Tumor cell proliferation was also determined.

RESULTS

In vivo: Mean survival of NS-398-treated animals was higher than controls for both G5 and G0 (G5: p < 0.003, G0: p < 0.02). G5 tumors grew faster than G0 tumors (p < 0.001) and NS-398 significantly inhibited tumor growth (p < 0.001), induced tumor cell apoptosis (p < 0.001), and significantly reduced metastasis (p < 0.003) in G5 animals. In vitro: PGE(2) production was higher in G5 than G0 cells (p < 0.001); NS-398 significantly reduced prostaglandin E(2) levels in G5 cells (p < 0.001). mRNA expression of COX-2, vascular endothelial growth factor, and u-PA receptor was higher in G5 than G0 cells, and NS-398 significantly inhibited u-PA mRNA expression in G5 cells. NS-398 significantly reduced proliferation in G5 cells (p < 0.05).

CONCLUSIONS

COX-2 inhibition significantly decreases tumor growth in this model by inducing apoptosis and blocking u-PA production in G5 colon cancer cells, which is associated with significant inhibition of liver metastases.

摘要

背景

环氧化酶 - 2（COX - 2）在结肠癌中过度表达。纤溶酶原激活（PA）系统通过细胞外基质的降解与癌症侵袭和转移相关。COX - 2也与细胞外基质的降解有关，但COX - 2与纤溶酶原激活剂系统之间的关系尚不清楚。

研究设计

体内实验：将结肠38（G0）原发性和（G5）转移性细胞系植入接受或未接受COX - 2抑制剂（NS - 398）治疗的C57BL / 6小鼠体内。测量动物存活率和肿瘤生长情况。在第19天，切除肿瘤并测量肿瘤细胞凋亡情况。对于转移实验，将G5细胞注入脾脏，23天后确定肝转移情况。体外实验：用NS - 398处理G0或G5细胞。测量上清液中前列腺素E2以及COX - 2、血管内皮生长因子（VEGF）、尿激酶型纤溶酶原激活剂（u - PA）、u - PA受体、纤溶酶原激活剂抑制剂1型（PAI - 1）和PAI - 2的mRNA表达。同时也测定肿瘤细胞增殖情况。

结果

体内实验：对于G5和G0细胞系，接受NS - 398治疗的动物平均存活率高于对照组（G5：p < 0.003，G0：p < 0.02）。G5肿瘤比G0肿瘤生长更快（p < 0.001），且NS - 398显著抑制肿瘤生长（p < 0.001），诱导肿瘤细胞凋亡（p < 0.001），并显著减少G5动物的转移（p < 0.003）。体外实验：G5细胞中前列腺素E2的产生高于G0细胞（p < 0.001）；NS - 398显著降低G5细胞中前列腺素E2水平（p < 0.001）。G5细胞中COX - 2、血管内皮生长因子和u - PA受体的mRNA表达高于G0细胞，且NS - 398显著抑制G5细胞中u - PA的mRNA表达。NS - 398显著降低G5细胞的增殖（p < 0.05）。