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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Publikationen des W. G. Kerckhoff-Instituts     Display Documents

ID: 474522.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Publikationen des W. G. Kerckhoff-Instituts
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, R. T.; Wygrecka, M.; Sturzebecher, J.; Seeger, W.; Gunther, A.; Ruppert, C.
Date of Publication (YYYY-MM-DD):2010
Title of Journal:Am J Respir Crit Care Med
Audience:Not Specified
Abstract / Description: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: 3x 10(6) LLC-cells were subcutaneously injected with into the right flank of C57Bl6/N mice, uPA knock out and uPAR knock out mice. Seven days later mice were randomized to receive i.p. either saline (control group), CJ-463 (10, 100mg/kg, twice a day), or its ineffective stereoisomer (10mg/kg, twice a day). Tumor volume was measured every second day and metastasis formation was monitored by volumetric-computed tomography. 12 days after onset of treatment mice were sacrificed and tumors were prepared for histological 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 100mg/kg group. In addition, histological analysis of the lung revealed a significant reduction in lung micrometastasis in the 100mg/kg group. Similarly, a reduced seeding of tumor cells into the lung after i.v. 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 uPAR 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.
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:University of Giessen Lung Center(UGLC), Department of Internal Medicine, Medical Clinic II, Giessen, Germany.
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking)
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