Urokinase plasminogen activator metastasis

Lung metastases were more responsive than those in lymph nodes, and bone metastases are highly refractory to sorafenib treatment 2 , 3. Additionally, there were several adverse side effects resulting from sorafenib treatment.

More dangerous side effects reported included pericardial effusion and reversible neutropenia 2 , 3. Perhaps most distressing, however, was the subsequent development of new primary cancers in a subset of patients receiving sorafenib therapy. Cabanillas et al.

Treatment of the cells with sorafenib and the MEK inhibitor U was unable to induce responsiveness to apoptotic stimuli, despite inhibiting ERK signaling; this phenomenon may further explain the ineffectiveness of sorafenib on some metastatic thyroid tumors 6.

Given the apparent shortcomings of both conventional RAI and experimental TKI like sorafenib, we propose that inhibitors of other molecular targets be explored in clinical trials.

Plasmin can then degrade extracellular matrix components, a prerequisite for tumor invasion and metastasis 7. Previous work by our group has shown that uPAR and uPA are consistently up-regulated in PTC tissue, and the degree of up-regulation positively correlates with metastasis. Our data corroborate studies showing similar importance of this system in other malignancies 7. Potent, orally bioavailable inhibitors of uPA have recently been developed and may hold great potential for the treatment of any metastatic tumor expressing this marker, including PTC 10 , One such agent, designed by Wilex Mesupron, WX , is currently being studied in clinical trials for other cancers.

In cellular and animal models, Mesupron has been shown to effectively inhibit tumor growth and metastatic spread. Early clinical studies in head and neck carcinoma revealed that Mesupron achieved therapeutic concentrations in tumor tissue while causing no significant side effects, beyond minor gastrointestinal effects A phase II clinical trial in nonmetastatic pancreatic cancer has yielded further promising results.

In this trial, addition of Mesupron to conventional chemotherapy gemcitabine was well tolerated, causing no specific toxicities beyond those attributed to gemcitabine and improving response rates partial or complete remissions , progression-free survival, and overall survival rates Furthermore, it would avoid therapy-limiting side effects and the potential risk of skin cancer development seen in sorafenib and other TKI. National Center for Biotechnology Information , U. J Clin Endocrinol Metab.

The plasminogen activator urokinase u-PA mediates proteolysis by a variety of human tumor cells. Competitive displacement of u-PA from cellular binding sites results in decreased proteolysis in vitro, suggesting that the cell surface is the preferred site for u-PA-mediated protein degradation.

We studied the effect of u-PA receptor blockade on the metastatic capacity of human PC3 prostate carcinoma cells, using transfectants which expressed chloramphenicol acetyl-transferase CAT. Abstract The urokinase plasminogen activator uPA system is central to a spectrum of biologic processes including fibrinoloysis, inflammation, atherosclerotic plaque formation, matrix remodeling during wound healing, tumor invasion, angiogenesis, and metastasis.

Publication types Research Support, Non-U. Gov't Review.