Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin
Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin
Speaker: 李秀儀 Date: PM 1:00~2:00; 06/08/2005
Commentator: 吳梨華 老師 Room: 601
Abstract
Angiogenesis, the growth of new capillary blood vessels, is important not only in physiological process, but also in pathological process such as tumor progression and metastasis. It is regulated by a number of growth factor, such as vascular endothelial growth factor A (VEGF-A)/vascular permeability factor (VPF). VEGF-A is a multifunctional cytokine that exerts a variety of effects on vascular endothelial cells. In addition to rendering microvessels hyperpermeability, VEGF-A stimulates endothelial cells (EC) to migrate, proliferation, and protects the cells from apoptosis and senescence. In this study, the authors investigated whether the angiogenesis inhibitors, TNP-470 and caplostain, had effects on vascular permeability (1). TNP-470 a synthetic analog of fumagillin, and its nontoxic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugate, caplostatin, are angiogenesis inhibitors (2). In this study the authors show that TNP-470, caplostain, and angiostain reduced vascular permeability which was induced by VPF/VEGF, PAF (platelet-activating factor) and histamine. TNP-470 not only inhibits the vascular hypermeability in different tumor cells and delayed-type hypersensitivity (DTH) reaction, but also protects the cells from the pulmonary edema induced by IL-2. Furthermore, TNP-470 inhibits VPF/VEGF-induced VEGFR-2 phosphorylation, endothelial cells (EC) proliferation, Ca2+ influx, MAPK phosphorylation, and Rho A activation in the cultured endothelium. Thus, TNP-470 and its nontoxic conjugate, caplostain, have therapeutic value not only in tumors but also in pathogenesis of vascular permeability (3).
References
1. Dvorak, H. F. et al. (2002). Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J. Clin. Oncol. 20, 4368-4380.
2. Satchi-Fainaro R. et al. (2004). Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nat. med., 10, 255-261.
3. Satchi-Fainaro R. et al. (2005). Inhibition of vessel permeability by TNP-470 and its polymer conjugate, caplostatin. Cancer cell 7, 251-261.