In vitro inhibition of endothelial cell growth by the antiangiogenic drug AGM-1470 (TNP-470) and the anti-endoglin antibody TEC-11.
Angiogenesis plays a key role in tumor growth, progression and metastasis. The modulation of angiogenesis represents a potentially useful target for novel forms of anticancer therapy. Two such modulators are AGM-1470 (TNP-470, angioinhibin), which is a synthetic analog of the antibiotic fumagallin, and the monoclonal antibody TEC-11 to endoglin. We investigated the mechanisms of action of these modulators on human microvascular and macrovascular endothelial cells and on the transformed endothelial cell line ECV-304 in vitro. The administration of AGM-1470 or TEC-11 resulted in a significant inhibition of cell proliferation in all cell types used; this effect was reversible upon removal of these compounds from the culture medium. Furthermore, biochemical and morphological analyses showed that neither AGM-1470 or TEC-11 induce apoptosis. Both AGM-1470 and TEC-11 inhibited the production of urokinase-type plasminogen activator (u-PA), an enzyme involved in the early steps of neovascularization. Finally, the incubation of endothelial cells with both AGM-1470 and TEC-11 did not produce an additive effect on growth cell inhibition, apoptosis or u-PA production. Since both AGM 1470 and TEC-11 inhibit crucial events such as endothelial cell growth and protease production, our results provide a basis for their therapeutic use as angiostatic molecules in cancer.
Maier
J A
JA
Department of Biological and Technological Research (DIBIT), San Raffaele Scientific Institute, Milan, Italy.
Delia
D
D
Thorpe
P E
PE
Gasparini
G
G
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003470:Culture Media; D003510:Cyclohexanes; D004591:Electrophoresis, Polyacrylamide Gel; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007202:Indicators and Reagents; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010960:Plasminogen Activators / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D003470:Culture Media; D003510:Cyclohexanes; D007202:Indicators and Reagents; D012717:Sesquiterpenes; D010960:Plasminogen Activators; D014568:Urokinase-Type Plasminogen Activator; D000077609:O-(Chloroacetylcarbamoyl)fumagillol