title: Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model.
abstract: BACKGROUND
  Lung cancer is the most common malignancy in humans. Urokinase (uPA) plays a crucial role in carcinogenesis by facilitating tumor cell invasion and metastasis.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Universty of Giessen Lung Center, Dept. of Internal Medicine, Germany.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Henneke
authors.forename: Susanne
authors.initials: S
authors.lastname: Greschus
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Savai
authors.forename: Martina
authors.initials: M
authors.lastname: Korfei
authors.forename: Philipp
authors.initials: P
authors.lastname: Markart
authors.forename: Poornima
authors.initials: P
authors.lastname: Mahavadi
authors.forename: Ralph T
authors.initials: RT
authors.lastname: Schermuly
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Wygrecka
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Andreas
authors.initials: A
authors.lastname: Günther
authors.forename: Clemens
authors.initials: C
authors.lastname: Ruppert
mesh_terms: D000818:Animals; D001550:Benzamidines; D015153:Blotting, Western / Q000379:methods; D018827:Carcinoma, Lewis Lung / Q000201:enzymology* / Q000473:pathology / Q000556:secondary; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D054893:Cone-Beam Computed Tomography / Q000379:methods; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D006801:Humans; D008168:Lung / Q000000981:diagnostic imaging / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D055752:Small Cell Lung Carcinoma / Q000201:enzymology* / Q000473:pathology / Q000556:secondary; D012965:Sodium Chloride / Q000008:administration & dosage; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D014568:Urokinase-Type Plasminogen Activator / Q000187:drug effects*
chemical_list: D001550:Benzamidines; D004791:Enzyme Inhibitors; D012965:Sodium Chloride; D014568:Urokinase-Type Plasminogen Activator