ENDOTHELIAL CELL PROLIFERATION INHIBITORS DERIVED FROM HUMAN PROTHROMBIN

摘要

The present invention provides a human prothrombin kringle-1 and 2 which have anti-endothelial cell proliferation and anti-tumor activities, cDNAs encoding the human prothrombin kringle-1 and 2 derived from human prothrombin, recombinant expression vectors comprising the cDNAs, recombinant microorganisms transformed with the recombinant expression vectors comprising the cDNA encoding the human prothrombin kringle-1 or 2, processes for preparing the human prothrombin kringle-1 and 2 from human plasma and recombinant human prothrombin kringle-2 from the recombinant microorganisms and pharmaceutical application of the said proteins. In contrast to human prothrombin, human prothrombin kringle-1 and 2 obtained as proteolytic fragments of human prothrombin display potent inhibitory effects on bovine capillary endothelial cells with a half-maximal concentration (ED50) of approximately 100nM and 120nM, respectively, and angiogenesis in the chorioallantoic membrane. The human prothrombin kringle-2 significantly suppresses tumor growth in vivo. In addition, peptides having sequences of human prothrombin kringle-2 can inhibit the endothelial cell proliferation. Since the anti-angiogenic therapy directed against tumor's endothelial cells induces little or no drug resistance, human prothrombin kringle-1 and 2 have been proposed as the most reliable candidates for cancer therapy.