Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model.
Am J Respir Crit Care Med
; 181(6): 611-9, 2010 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-20056905
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 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 MAINRESULTS:
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.
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Base de dados:
MEDLINE
Assunto principal:
Ativador de Plasminogênio Tipo Uroquinase
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Carcinoma Pulmonar de Lewis
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Carcinoma de Pequenas Células do Pulmão
Tipo de estudo:
Clinical_trials
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article