Angiostatin induces and sustains dormancy of human primary tumors in mice.
There is now considerable direct evidence that tumor growth is angiogenesis-dependent. The most compelling evidence is based on the discovery of angiostatin, an angiogenesis inhibitor that selectively instructs endothelium to become refractory to angiogenic stimuli. Angiostatin, which specifically inhibits endothelial proliferation, induced dormancy of metastases defined by a balance of apoptosis and proliferation. We now show that systemic administration of human angiostatin potently inhibits the growth of three human and three murine primary carcinomas in mice. An almost complete inhibition of tumor growth was observed without detectable toxicity or resistance. The human carcinomas regressed to microscopic dormant foci in which tumor cell proliferation was balanced by apoptosis in the presence of blocked angiogenesis. This regression of primary tumors without toxicity has not been previously described. This is also the first demonstration of dormancy therapy, a novel anticancer strategy in which malignant tumors are regressed by prolonged blockade of angiogenesis.
O'Reilly
M S
MS
Department of Surgery, Children's Hospital, Boston, Massachusetts, USA.
Holmgren
L
L
Chen
C
C
Folkman
J
J
D043168:Angiostatins; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D009389:Neovascularization, Pathologic; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D010958:Plasminogen / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
D000970:Antineoplastic Agents; D010446:Peptide Fragments; D043168:Angiostatins; D010958:Plasminogen