Angiogenesis inhibitor TNP-470 inhibits murine cutaneous wound healing

J Surg Res. 1999 Apr;82(2):268-74. doi: 10.1006/jsre.1998.5551.

Abstract

Background: TNP-470 (AGM-1470) is a potent inhibitor of angiogenesis with potential therapeutic applications in neoplastic and angio-proliferative diseases. This study evaluated its effect on cutaneous wound healing in a murine dorsal excisional wound model.

Materials and methods: Full-thickness wounds (1.60 cm2) were created on the dorsum of homozygous/hairless mice (7 to 9 weeks). Wound areas were measured on alternate days for 16 days. Experimental groups consisted of (1) TNP-470 administered in doses of 0.05, 0.5, and 5.0 mg/kg on Days 0, 2, and 4 or Days 0 through 6; (2) TNP-470 (5.0 mg/kg) coadministered with minocycline (4.0 and 10 mg/kg) on Days 0, 2, and 4; and (3) TNP-470 (5.0 mg/kg on Days 0, 2, and 4) coadministered with topical basic fibroblast growth factor (bFGF) 1. 0 microg/wound on Days 0, 1, and 2. Hematoxylin and eosin staining was used to compare experimental and control wounds.

Results: TNP-470 administration significantly decreased wound healing in a dose-dependent manner versus controls (P <.05). The 5.0 mg/kg concentration yielded the greatest effect by maintaining an average wound area 20.4% greater than controls and a marked delay in wound healing on H&E staining. Alternate-day dosing was as effective as consecutive day administration. Minocycline did not augment the wound healing inhibition of TNP-470. Coadministration of TNP-470 and bFGF eliminated any rate-altering effect of TNP-470 upon wound healing and resulted in wound areas similar to controls.

Conclusion: Therapy with TNP-470 induces a significant delay in murine cutaneous wound healing. This effect may be exploited for use in situations where wound healing is excessive and debilitating. Topical application of bFGF can overcome TNP-470-induced wound healing inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Cyclohexanes
  • Drug Combinations
  • Fibroblast Growth Factor 2 / pharmacology
  • Male
  • Mice
  • Mice, Hairless
  • Minocycline / pharmacology
  • O-(Chloroacetylcarbamoyl)fumagillol
  • Sesquiterpenes / pharmacology*
  • Skin / injuries*
  • Skin / pathology
  • Wound Healing / drug effects*
  • Wounds, Penetrating / pathology
  • Wounds, Penetrating / physiopathology*

Substances

  • Angiogenesis Inhibitors
  • Anti-Bacterial Agents
  • Cyclohexanes
  • Drug Combinations
  • Sesquiterpenes
  • Fibroblast Growth Factor 2
  • Minocycline
  • O-(Chloroacetylcarbamoyl)fumagillol