Journal
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
Volume 181, Issue 6, Pages 611-619Publisher
AMER THORACIC SOC
DOI: 10.1164/rccm.200903-0342OC
Keywords
SCLC; NSCLC; plasminogen activator; angiogenesis; active site inhibitor
Categories
Funding
- Solvay
- Ergonex
- Actelion
- Pfizer
- Bayer-Schering
- Bayer Schering Pharma AG
- Lung Rx. Inc.
- Encysive
- United Therapeutics
- Gilead
- Colorado
- Nycomed
- Sanofi
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Rationale: Lung cancer is the most common malignancy in humans. Urokinase (uPA) plays a crucial role in carcinogenesis by facilitating tumor cell invasion and metastasis. Objectives: 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. Methods: A quantity of 3 x 10(6) LLC cells were subcutaneously injected into the right flank of C57BI6/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. Measurements and Main Results: 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 micro-metastasis 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. Conclusions: Our results suggest that synthetic low-molecular-weight uPA-inhibitors offer as novel agents for treatment of lung cancer.
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