Universty of Giessen Lung Center, Dept. of Internal Medicine, Germany.
Am J Respir Crit Care Med. 2010 Mar 15;181(6):611-9. doi: 10.1164/rccm.200903-0342OC. Epub 2010 Jan 7.
Lung cancer is the most common malignancy in humans. Urokinase (uPA) plays a crucial role in carcinogenesis by facilitating tumor cell invasion and metastasis.
We investigated the effect of the highly specific urokinase inhibitor CJ-463 (benzylsulfonyl-D-Ser-Ser-4-amidinobenzylamide) on tumor growth, metastasis formation, and tumor vascularization in the murine Lewis lung carcinoma (LLC) and a human small lung cancer model.
A quantity of 3 x 10(6) LLC cells were subcutaneously injected into the right flank of C57Bl6/N mice, uPA knock out, and uPA receptor knockout mice. Seven days later mice were randomized to receive intraperitoneally either saline (control group), CJ-463 (10 and 100 mg/kg, twice a day), or its ineffective stereoisomer (10 mg/kg, twice a day). Tumor volume was measured every second day and metastasis formation was monitored by volumetric-computed tomography. Twelve days after onset of treatment mice were killed and tumors were prepared for histologic examination.
Treatment with CJ-463 resulted in a significant inhibition of primary tumor growth, with the highest efficacy seen in the 100 mg/kg group. In addition, histological analysis of the lung revealed a significant reduction in lung micrometastasis in the 100 mg/kg group. Similarly, a reduced seeding of tumor cells into the lung after intravenous injection of LLC cells was observed in inhibitor-treated mice. In these mice, treatment with CJ-463 appeared not to significantly alter the relative extent of tumor vascularization. In vitro, proliferation of LLC cells remained unchanged upon inhibitor treatment. CJ-463 was found to similarly reduce tumor growth in uPA receptor knockout mice, but was ineffective in uPA knockout mice.
Our results suggest that synthetic low-molecular-weight uPA-inhibitors offer as novel agents for treatment of lung cancer.
肺癌是人类最常见的恶性肿瘤。尿激酶（uPA）通过促进肿瘤细胞侵袭和转移，在肿瘤发生中起着至关重要的作用。
我们研究了高度特异性尿激酶抑制剂 CJ-463（苯磺酰-D-丝氨酰-丝氨酰-4-氨甲酰基苄基酰胺）对小鼠 Lewis 肺癌（LLC）和人类小肺癌模型中肿瘤生长、转移形成和肿瘤血管生成的影响。
将 3x10(6)个 LLC 细胞皮下注射到 C57Bl6/N 小鼠、uPA 敲除和 uPA 受体敲除小鼠的右侧肋部。7 天后，将小鼠随机分为腹腔内注射生理盐水（对照组）、CJ-463（10 和 100mg/kg，每天两次）或其无效立体异构体（10mg/kg，每天两次）。每隔一天测量肿瘤体积，并通过体积计算机断层扫描监测转移形成。治疗开始后 12 天，处死小鼠并准备肿瘤进行组织学检查。
用 CJ-463 治疗导致原发性肿瘤生长显著抑制，100mg/kg 组疗效最高。此外，对肺的组织学分析显示，100mg/kg 组肺微转移明显减少。同样，在静脉注射 LLC 细胞后，抑制剂治疗的小鼠中观察到肿瘤细胞在肺部的播种减少。在这些小鼠中，用 CJ-463 治疗似乎没有明显改变肿瘤血管化的相对程度。体外，用抑制剂处理后 LLC 细胞的增殖没有变化。发现 CJ-463 同样可以减少 uPA 受体敲除小鼠的肿瘤生长，但对 uPA 敲除小鼠无效。
我们的结果表明，合成的低分子量 uPA 抑制剂为治疗肺癌提供了新的药物。
