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- Title
Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model.
- Authors
Henneke I; Greschus S; Savai R; Korfei M; Markart P; Mahavadi P; Schermuly RT; Wygrecka M; Stürzebecher J; Seeger W; Günther A; Ruppert C; Henneke, Ingrid; Greschus, Susanne; Savai, Rajkumar; Korfei, Martina; Markart, Philipp; Mahavadi, Poornima; Schermuly, Ralph T; Wygrecka, Malgorzata
- Abstract
<bold>Rationale: </bold>Lung cancer is the most common malignancy in humans. Urokinase (uPA) plays a crucial role in carcinogenesis by facilitating tumor cell invasion and metastasis. <bold>Objectives: </bold>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. <bold>Methods: </bold>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. <bold>Measurements and Main Results: </bold>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. <bold>Conclusions: </bold>Our results suggest that synthetic low-molecular-weight uPA-inhibitors offer as novel agents for treatment of lung cancer.
- Publication
American Journal of Respiratory & Critical Care Medicine, 2010, Vol 181, Issue 6, p611
- ISSN
1073-449X
- Publication type
journal article
- DOI
10.1164/rccm.200903-0342OC