Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

Abstract

3 Daily local administration of 250 ng VEGF165 accelerated the rate of "33Xe clearance from the sponges and induced an intense neovascularisation. This VEGF165-induced angiogenesis was inhibited by daily co-administration of the selective PTK inhibitor, lavendustin A (10 jig), but not its negative control, lavendustin B (10 jig). Blood flow measurements and morphometric analysis of 8-day-old sponges showed that lavendustin A reduced the "33Xe clearance of VEGF165-treated sponges from 32.9 ± 1.5% to 20.9 ± 1.6% and the total fibrovascular growth area from 62.4 ± 6.1% to 21.6 ± 6.8% (n = 1 2, P < 0.05). 4 Co-injection of suramin (3 mg), an inhibitor of heparin-binding growth factors, also suppressed the VEGF165-elicited neovascular response. In contrast, neither lavendustin A nor suramin produced any effect on the basal sponge-induced angiogenesis. 5 When given alone, low doses of VEGF 165 (25 ng) or basic fibroblast growth factor (bFGF; 10 ng) did not modify the basal sponge-induced neovascularisation. However, co-administration of these two peptides to a single sponge together caused a significant increase in the rate of '33Xe clearance and angiogenesis similar to that seen with the high dose of VEGF165 (250 ng) acting alone. This VEGF/ bFGF neovascular response was also blocked by daily co-administration of lavendustin A (10 jig), suramin (3 mg) or a monoclonal anti-bFGF antibody (DG2, I jig), but not lavendustin B (10 g). 6 These results suggest that selective inhibition of PTK could have therapeutic potential in angiogenic diseases where VEGF plays a dominant role. Furthermore, blockade of the angiogenic activity of VEGF and VEGF,/bFGF by suramin reveals an alternative strategy in angiosuppression.

Influence of Muscarinic Agonists and Tyrosine Kinase Inhibitors on L-type Ca2+Channels in Human and Bovine Trabecular Meshwork Cells

“…In our experiments, the effect of acetylcholine on Ltype currents could be reduced by the tyrosine kinase inhibitor genistein (Akiyama et al, 1987) and by lavendustin A (Hu and Fan, 1995 ;Onoda et al, 1989). Genistein and lavendustin A are structurally different substances and both lead to an inhibition of L-type current.…”

Effects of the protein tyrosine kinase inhibitor genistein and taurine on retinal function in isolated superfused retina

“…VEGF stimulates endothelial cells via tyrosine kinase receptors. VEGF-induced angiogenesis can be inhibited by reducing the protein tyrosine kinase activity [12].…”

Role of the Matrix Metalloproteinase and Plasminogen Activator–Plasmin Systems in Angiogenesis

“…[11][12][13][14] Interestingly, it has been observed that VEGF and basic FGF (bFGF, or FGF-2) induce a synergistic angiogenic response, both in vitro 15,16 and in vivo. 17,18 A number of endogenous negative regulators have been described, including inhibitors of extracellular proteinases, thrombospondins 1 and 2, and bioactive fragments of the ECM and other molecules (see below). 1,19 -21 The notion of the "balance" applied to positive and negative regulators of angiogenesis can also be applied to extracellular proteolysis.…”