Angiogenesis inhibitor TNP-470 inhibits murine cutaneous wound healing.
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.


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.


CONCLUSIONS
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.
Klein
S A
SA
Department of Physiology and Biophysics, Division of Pediatric Surgery, Louisville, Kentucky, 40292, USA.
Bond
S J
SJ
Gupta
S C
SC
Yacoub
O A
OA
Anderson
G L
GL
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D003510:Cyclohexanes; D004338:Drug Combinations; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008812:Mice, Hairless; D008911:Minocycline / Q000494:pharmacology; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D012717:Sesquiterpenes / Q000494:pharmacology*; D012867:Skin / Q000293:injuries* / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects*; D014950:Wounds, Penetrating / Q000473:pathology / Q000503:physiopathology*
D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D003510:Cyclohexanes; D004338:Drug Combinations; D012717:Sesquiterpenes; D016222:Fibroblast Growth Factor 2; D008911:Minocycline; D000077609:O-(Chloroacetylcarbamoyl)fumagillol