metastasis formation in a murine lung carcinoma model

Abstract 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-4amidinobenzylamide) 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, a reduction in lung metastases was observed in the treatment groups, however, without reaching statistical significance. 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. Word count (abstract): 249 Keywords: lung cancer, SCLC, NSCLC, plasminogen activator, uPAR, angiogenesis, active site inhibitor