Inhibition of inflammatory corneal angiogenesis by TNP-470

Invest Ophthalmol Vis Sci. 2001 Oct;42(11):2510-6.


Purpose: To determine the efficacy of the angiogenic inhibitor TNP-470 on inflammatory corneal neovascularization. Topical and systemic delivery of the drug were investigated in a murine model as well as inhibition of endothelial cell proliferation in vitro and in vivo.

Methods: The effect of TNP-470 on VEGF- and bFGF-stimulated bovine capillary endothelial (BCE) cell proliferation was evaluated in vitro. Corneal neovascularization was induced in vivo by mechanical debridement of the corneal and limbal epithelium with 0.15 M NaOH on C57BL6 mice. TNP-470 was administered systemically at 30 mg/kg body weight (BW) every other day or topically three times daily in a concentration of 5 ng/ml dissolved in methylcellulose. Vessel length was investigated on day 7. VEGF protein content in murine corneas was analyzed by ELISA on days 2, 4, and 7 of treatment. A modified bromouridine (BrdU) ELISA was used to quantify endothelial cell proliferation.

Results: TNP-470 exerted a dose-dependent inhibition of bFGF- and VEGF-induced endothelial cell proliferation in vitro. Both systemic and topical application of TNP-470 led to a significant reduction of inflammatory corneal neovascularization (P < 1 x 10(-5)). BrdU labeling showed that TNP-470 inhibited endothelial cell proliferation. VEGF protein levels were reduced by systemic TNP-470 treatment.

Conclusions: These results suggest that TNP-470 reduces inflammatory corneal angiogenesis by directly inhibiting endothelial cell proliferation. Topical and systemic treatment with TNP-470 reduces VEGF levels that are responsible for vessel growth during the neovascularization process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Topical
  • Angiogenesis Inhibitors / pharmacology
  • Angiogenesis Inhibitors / therapeutic use*
  • Animals
  • Bromodeoxyuridine
  • Cell Division / drug effects
  • Corneal Neovascularization / pathology
  • Corneal Neovascularization / prevention & control*
  • Cyclohexanes
  • DNA Replication / drug effects
  • Dose-Response Relationship, Drug
  • Endothelial Growth Factors / pharmacology
  • Endothelium, Corneal / drug effects
  • Endothelium, Corneal / pathology
  • Endothelium, Vascular / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Fibroblast Growth Factor 2 / pharmacology
  • Injections, Subcutaneous
  • Lymphokines / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Sesquiterpenes / pharmacology
  • Sesquiterpenes / therapeutic use*
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors


  • Angiogenesis Inhibitors
  • Cyclohexanes
  • Endothelial Growth Factors
  • Lymphokines
  • Sesquiterpenes
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Fibroblast Growth Factor 2
  • Bromodeoxyuridine
  • O-(Chloroacetylcarbamoyl)fumagillol