Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin.
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.
Satchi-Fainaro
Ronit
R
Children's Hospital Boston and Harvard Medical School, Vascular Biology Program, Department of Surgery, 1 Blackfan Circle, Karp Family Research Laboratories, Floor 12, Boston, Massachusetts 02115, USA.
Mamluk
Roni
R
Wang
Ling
L
Short
Sarah M
SM
Nagy
Janice A
JA
Feng
Dian
D
Dvorak
Ann M
AM
Dvorak
Harold F
HF
Puder
Mark
M
Mukhopadhyay
Debabrata
D
Folkman
Judah
J
D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D043168:Angiostatins / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects; D003510:Cyclohexanes; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006968:Hypersensitivity, Delayed; D007376:Interleukin-2 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011654:Pulmonary Edema / Q000139:chemically induced; D012717:Sesquiterpenes / Q000737:chemistry* / Q000494:pharmacology*; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D007376:Interleukin-2; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; D043168:Angiostatins; D040301:Vascular Endothelial Growth Factor Receptor-2; D020928:Mitogen-Activated Protein Kinases; D020742:rhoA GTP-Binding Protein; D002118:Calcium; D000077609:O-(Chloroacetylcarbamoyl)fumagillol