title: A recombinant human angiostatin protein inhibits experimental primary and metastatic cancer.
abstract: Endogenous murine angiostatin, identified as an internal fragment of plasminogen, blocks neovascularization and growth of experimental primary and metastatic tumors in vivo. A recombinant protein comprising kringles 1-4 of human plasminogen (amino acids 93-470) expressed in Pichia pastoris had physical properties (molecular size, binding to lysine, reactivity with antibody to kringles 1-3) that mimicked native angiostatin. This recombinant Angiostatin protein inhibited the proliferation of bovine capillary endothelial cells in vitro. Systemic administration of recombinant Angiostatin protein at doses of 1.5 mg/kg suppressed the growth of Lewis lung carcinoma-low metastatic phenotype metastases in C57BL/6 mice by greater than 90%; administration of the recombinant protein at doses of 100 mg/kg also suppressed the growth of primary Lewis lung carcinoma-low metastatic phenotype tumors. These findings demonstrate unambiguously that the antiangiogenic and antitumor activity of endogenous angiostatin resides within kringles 1-4 of plasminogen.
authors.affiliation: EntreMed, Inc., Rockville, Maryland 20850, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Sim
authors.forename: M S
authors.initials: MS
authors.lastname: O'Reilly
authors.forename: H
authors.initials: H
authors.lastname: Liang
authors.forename: A H
authors.initials: AH
authors.lastname: Fortier
authors.forename: W
authors.initials: W
authors.lastname: He
authors.forename: J W
authors.initials: JW
authors.lastname: Madsen
authors.forename: R
authors.initials: R
authors.lastname: Lapcevich
authors.forename: C A
authors.initials: CA
authors.lastname: Nacy
mesh_terms: D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects; D007150:Immunohistochemistry; D018082:Kringles / Q000235:genetics / Q000502:physiology; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D010958:Plasminogen / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014841:von Willebrand Factor / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D014841:von Willebrand Factor; D043168:Angiostatins; D010958:Plasminogen