Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model

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.

  • Henneke, I.
  • Greschus, S.
  • Savai, R.
  • Korfei, M.
  • Markart, P.
  • Mahavadi, P.
  • Schermuly, R. T.
  • Wygrecka, M.
  • Stürzebecher, J.
  • Seeger, W.
  • Günther, A.
  • Ruppert, C.


  • 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/diagnostic imaging/enzymology
  • 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
Publication details
DOI: 10.1164/rccm.200903-0342OC
Journal: Am J Respir Crit Care Med
Pages: 611-9
Number: 6
Work Type: Original
Access number: 20056905