Endostatin: an endogenous inhibitor of angiogenesis and tumor growth.
We previously identified the angiogenesis inhibitor angiostatin. Using a similar strategy, we have identified endostatin, an angiogenesis inhibitor produced by hemangioendothelioma. Endostatin is a 20 kDa C-terminal fragment of collagen XVIII. Endostatin specifically inhibits endothelial proliferation and potently inhibits angiogenesis and tumor growth. By a novel method of sustained release, E. coli-derived endostatin was administered as a nonrefolded suspension. Primary tumors were regressed to dormant microscopic lesions. Immunohistochemistry revealed blocked angiogenesis accompanied by high proliferation balanced by apoptosis in tumor cells. There was no toxicity. Together with angiostatin data, these findings validate a strategy for identifying endogenous angiogenesis inhibitors, suggest a theme of fragments of proteins as angiogenesis inhibitors, and demonstrate dormancy therapy.
O'Reilly
M S
MS
Department of Surgery, Children's Hospital, Boston, Massachusetts 02115, USA.
Boehm
T
T
Shing
Y
Y
Fukai
N
N
Vasios
G
G
Lane
W S
WS
Flynn
E
E
Birkhead
J R
JR
Olsen
B R
BR
Folkman
J
J
D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D002196:Capillaries / Q000166:cytology; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D043170:Collagen Type XVIII; D017077:Culture Media, Conditioned; D043169:Endostatins; D004730:Endothelium, Vascular / Q000166:cytology; D006390:Hemangioendothelioma / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010446:Peptide Fragments / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology* / Q000633:toxicity; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D043170:Collagen Type XVIII; D017077:Culture Media, Conditioned; D043169:Endostatins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D003094:Collagen