Angiogenesis Inhibitor TNP-470 Inhibits Murine Cutaneous Wound Healing

• Published in: The Journal of surgical research 1999-04, Vol.82 (2), p.268-274
• Main Authors: Klein, Scott A., Bond, Sheldon J., Gupta, Subhas C., Yacoub, Oraib A., Anderson, Gary L.
• Format: Article
• Language: English
• Subjects: AGM-1470; angiogenesis inhibitor; Angiogenesis Inhibitors - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; basic fibroblast growth factor (bFGF); Biological and medical sciences; Cyclohexanes; Drug Combinations; Fibroblast Growth Factor 2 - pharmacology; Male; Medical sciences; Mice; Mice, Hairless; Minocycline - pharmacology; Pharmacology. Drug treatments; Sesquiterpenes - pharmacology; Skin - injuries; Skin - pathology; Skin, nail, hair, dermoskeleton; TNP-470; wound healing; Wound Healing - drug effects; Wounds, Penetrating - pathology; Wounds, Penetrating - physiopathology
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1006/jsre.1998.5551

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 μg/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.