Abstract
Angiogenesis inhibitors, such as TNP-470 and the nontoxic HPMA copolymer-TNP-470 (caplostatin), are emerging as a class of anticancer drugs. We report that TNP-470 and caplostatin inhibit vascular hyperpermeability of tumor blood vessels as well as that induced in mouse skin by different mediators. Treatment with TNP-470 or angiostatin for 3 days was sufficient to reduce permeability of tumor blood vessels, delayed-type hypersensitivity, and pulmonary edema induced by IL-2. TNP-470 also inhibited VPF/VEGF-induced phosphorylation of VEGFR-2, calcium influx, and RhoA activation in endothelial cells. These results identify an activity of TNP-470, that of inhibiting vessel hyperpermeability. This activity likely contributes to TNP-470's antiangiogenic effect and suggests that caplostatin can be used in the treatment of cancer and inflammation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Angiogenesis Inhibitors / chemistry*
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Angiogenesis Inhibitors / pharmacology*
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Angiostatins / pharmacology
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Animals
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Calcium / metabolism
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Capillaries / drug effects*
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Capillaries / metabolism
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Capillaries / ultrastructure
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Capillary Permeability / drug effects*
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Capillary Permeability / physiology
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Cell Movement / drug effects
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Cyclohexanes
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelial Cells / ultrastructure
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Female
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Hypersensitivity, Delayed
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Interleukin-2 / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, SCID
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Mitogen-Activated Protein Kinases / metabolism
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Neoplasms / blood supply
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Neoplasms / metabolism
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Neoplasms / pathology
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O-(Chloroacetylcarbamoyl)fumagillol
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Pulmonary Edema / chemically induced
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Sesquiterpenes / chemistry*
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Sesquiterpenes / pharmacology*
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Skin / blood supply
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Skin / drug effects
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Skin / pathology
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Vascular Endothelial Growth Factor A / metabolism
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Vascular Endothelial Growth Factor Receptor-2 / metabolism
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rhoA GTP-Binding Protein / metabolism
Substances
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Angiogenesis Inhibitors
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Cyclohexanes
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Interleukin-2
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Sesquiterpenes
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Vascular Endothelial Growth Factor A
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Angiostatins
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Vascular Endothelial Growth Factor Receptor-2
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Mitogen-Activated Protein Kinases
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rhoA GTP-Binding Protein
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Calcium
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O-(Chloroacetylcarbamoyl)fumagillol