Compound and method for regulating plasminogen activation and cell migration

Abstract

The invention relates to novel regulators of plasminogen activation and their use for regulating cell migration, plasminolysis, angiogenesis, fibrinolysis, for treating cancer and thrombo-embolic diseases such as heart stroke. Furthermore, the present invention relates to novel pharmaceutical compositions form regulating cell migration, plasminolysis, angiogenesis and for treating cancer. In particular, the present invention relates to a method of regulating the activation of plasminogen comprising contacting a solution of pro-urokinase (uPA) or tissue plasminogen activator (tPA) and plasminogen with melanotransferrin (p97) for a time sufficient to effect regulation thereof.

1 . A pharmaceutical composition comprising a therapeutically effective amount of melanotransferrin (p97) or an enzymatically active fragment thereof, unconjugated to any moiety, in association with a pharmaceutically acceptable carrier. 
     
     
         2 . A method of regulating angiogenesis, comprising administering to an individual a pharmaceutically effective amount of a pharmaceutical composition according to  claim 1 . 
     
     
         3 . The method according to  claim 2 , wherein said administering is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intraarterially, transdermally or via a mucus membrane. 
     
     
         4 . A method for inhibiting angiogenesis caused by cells expressing melanotransferrin (p97) at their surface, said method comprising the step of administering to a patient in need thereof exogenous soluble p97 or an active fragment thereof, said soluble p97 or active fragment thereof being unconjugated to any moiety and competing with the p97 expressed on the cell surface, activating plasminogen in solution instead of membrane-bound plasminogen, thus preventing cell migration and preventing angiogenesis. 
     
     
         5 . The method of  claim 4 , wherein said cell is an endothelial cell. 
     
     
         6 . The method of  claim 4 , wherein said cell is selected from the group consisting of human vascular or microvascular endothelial cells. 
     
     
         7 . A method of inhibiting angiogenesis, comprising administering to an individual a therapeutically effective amount of a pharmaceutical composition comprising one of melanotransferrin (P97) or an active fragment thereof, said melanotransferrin or fragment thereof being unconjugated to any moiety, in association with a pharmaceutically acceptable carrier. 
     
     
         8 . The method according to  claim 7 , wherein said administering is carried out orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intraarterially, transdermally or via a mucus membrane.