Control of pulmonary metastases of rat mammary cancer by inhibition of uPA and COX-2, singly and in combination.

Tumor cell metastasis can be suppressed by the attenuation of proteolytic and angiogenic events that are mediated by tumor and endothelial cells. Combinations of specific inhibitors directed to separate stages of the metastatic cascade may improve the potential for adjuvant therapies. Amiloride is an effective plasminogen activator inhibitor, while celecoxib is a cylcooxygenase-2 inhibitor. In vitro invasion assays were used to assess the effect of each inhibitor on the cellular invasion of MATB rat mammary carcinoma cells. Individually, both amiloride and celecoxib impeded cellular invasion in a dose-dependent manner. Combinations consistently exerted a significant inhibitory response (91 to 99%). These inhibitors were administered alone and in combination to evaluate their efficacy in the prevention of pulmonary metastases from a primary rat mammary carcinoma. Amiloride and celecoxib, alone and in combination, consistently showed no effect on the growth of primary tumors. The combined inhibitors were able to reduce significantly the growth of local recurrences following primary tumor excision and metastatic incidence rates. Numbers of pulmonary metastases were reproducibly and significantly decreased with the administration of amiloride and celecoxib, alone and in combination. Celecoxib alone was most effective with a reduction in 98% of the metastases, yet distinctions were observed in the results with respect to the local recurrences, blood levels for the inhibitors and tissue production of prostaglandin E2. These data demonstrate the potential use for celecoxib, alone and in combination with amiloride, in the suppression of metastases.