Effects of synthetic urokinase inhibitors on local invasion and metastasis in a murine mammary tumor model

Abstract

Urokinase-type plasminogen activator (uPA) initiates an extracellular proteolytic cascade with which invasive cells eliminate barriers to movement. We have evaluated the antiinvasive and antimetastatic properties of two recently developed synthetic uPA inhibitors, B428 and B623, in a BALB/c mouse mammary carcinoma model. We used the F3II and M3 tumor cell lines, previously described by our laboratory. In vitro, noncytotoxic concentrations of B428 or B623 inhibited secreted and cell-associated uPA activity produced by tumor cells and blocked uPA-mediated whole tumor cell degradation of fibronectin, allowing deposition of extracellular fibronectin fibrils. In vivo, administration of compounds was not associated with overt toxic effects. Daily i.p. treatment with B428 (20 mg/kg/day) or B623 (7.5 mg/kg/day) for 2 weeks, beginning after tumor take, markedly blocked the invasion of the muscle and adipose layers of the subcutis and dermis in mice bearing highly invasive F3II tumors. However, these compounds neither inhibited tumor-induced angiogenesis nor reduced the incidence of spontaneous lung metastasis. Moreover, B623 enhanced the formation of experimental lung metastasis. Our results suggest that synthetic uPA inhibitors act as potent antiinvasiveness agents in vivo but may be unable to control progression of the metastatic disease in the present mammary tumor model.