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



ID: 559810.0, 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.
Title of Journal:Am J Respir Crit Care Med
Volume:181
Issue / Number:6
Start Page:611
End Page:9
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: 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. 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 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. CONCLUSIONS: Our results suggest that synthetic low-molecular-weight uPA-inhibitors offer as novel agents for treatment of lung cancer.
Free Keywords:Animals; Benzamidines; Blotting, Western/methods; Carcinoma, Lewis Lung/*enzymology/pathology/secondary; Cell Culture Techniques/methods; Cell Proliferation/drug effects; Cone-Beam Computed Tomography/methods; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Lung/enzymology/radiography; Male; Mice; Mice, Inbred C57BL; Mice, SCID; Small Cell Lung Carcinoma/*enzymology/pathology/secondary; Sodium Chloride/administration & dosage; Treatment Outcome; Tumor Burden/drug effects; Urokinase-Type Plasminogen Activator/*drug effects
External Publication Status:published
Document Type:Article
Communicated by:N. N.
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Universty of Giessen Lung Center, Dept. of Internal Medicine, Germany.
Identifiers:ISSN:1535-4970 (Electronic) 1073-449X (Linking)
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=..
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