Journal article

Publication year: 2010

Pages: 611-619

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 181

Issue number: 6

ISSN: 1073-449X

eISSN: 1535-4970

DOI Link: https://doi.org/10.1164/rccm.200903-0342OC

Publisher: American Thoracic Society

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-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 C57BI6/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 micro-metastasis 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.

Harvard Citation style: Henneke, I., Greschus, S., Savai, R., Korfei, M., Markart, P., Mahavadi, P., et al. (2010) Inhibition of Urokinase Activity Reduces Primary Tumor Growth and Metastasis Formation in a Murine Lung Carcinoma Model, American Journal of Respiratory and Critical Care Medicine, 181(6), pp. 611-619. https://doi.org/10.1164/rccm.200903-0342OC

APA Citation style: Henneke, I., Greschus, S., Savai, R., Korfei, M., Markart, P., Mahavadi, P., Schermuly, R., Wygrecka, M., Stuerzebecher, J., Seeger, W., Guenther, A., & Ruppert, C. (2010). Inhibition of Urokinase Activity Reduces Primary Tumor Growth and Metastasis Formation in a Murine Lung Carcinoma Model. American Journal of Respiratory and Critical Care Medicine. 181(6), 611-619. https://doi.org/10.1164/rccm.200903-0342OC