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Increase in cell-associated proteolytic activity triggered by the upregulated expression of the urokinase-type plasminogen activator (uPA) system is associated with the malignant phenotype of many cancer types and with their ability to spread. In line with this the expression level of the uPA system in breast and other cancers is inversely correlated with survival of cancer patients. Hence, inhibition of the uPA system is a promising approach in anti-cancer therapy aiming at the prevention of tumor spread. We investigated the anti-cancer and anti-metastatic activity of a new uPA inhibitor WX-671 by oral gavage in a rat breast adenocarcinoma model. Six groups (n=18) of female Brown Norwegian rats were orthotopically inoculated with small cubes of the syngeneic, transplantable and spontaneously metastasizing breast tumor, BN472. From day 3 after inoculation onwards the animals received WX-671 once daily at dose levels ranging from 0.01 to 10.0 mg/kg or vehicle by oral gavage for 6 weeks. Tumor growth was followed by caliper measurements twice weekly. Tumor-related endpoints determined six weeks after tumor inoculation were the weight of the primary tumor, the degree of axillary lymph node invasion as reflected by its organ weight and the number of macroscopic metastases on the lung surface. The significance of effects (P<0.05) were calculated with the Mann-Whitney-rank sum test. Relative to control tumor endpoints were uniformly reduced in the treatment groups as assessed by comparing median values. Final median primary tumor sizes were reduced by 36% to 66% in the dose groups with the least effect observed at 0.01 mg/kg. At dose levels of 0.1 mg/kg and higher a significant reduction by 33% to 42% of the median weight of the axillary lymph node was noted with the highest dose being most efficacious. Likewise, the median number of lung foci was reduced across all dose groups. The effects were nonsignificant at 0.01 mg/kg (reduction by 18%) and significant at dose levels of 0.1 mg/kg or higher (reduction range 33% to 44%) with no clearcut dose/effect relationship above 0.01 mg/kg. In conclusion, WX-671 given orally as a single agent is effective in reducing primary tumor growth and preventing metastasis formation.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]