publications by Mark W. Dewhirst.
- ZA Haroon, K Amin, W Saito, W Wilson, CS Greenberg, MW Dewhirst, SU5416 delays wound healing through inhibition of TGF-beta 1 activation.,
Cancer biology & therapy, vol. 1 no. 2
pp. 121-6 .
(last updated on 2013/05/16)
Angiogenesis, development of new blood vessels, is essential for wound healing and tumor growth. A potentially important side effect of anti-angiogenic therapy can be delayed wound healing. In this study we address this issue by using a novel in vivo method utilizing fibrin containing dual porous plexiglass chambers (Fibrin Z-Chambers; F-ZC) to investigate wound healing in rats administered with SU5416 (inhibitor of Flk-1 and Flt-1, at 20 mg/kg i.p.). SU5416 treated F-ZCs developed 45% less granulation tissue (p = 0.0076) and showed a 10% reduction in microvessel density (p = 0.0009) than controls treated with drug carrier alone. The granulation tissue showed distinctly decreased collagen deposition (p = 0.0006) in SU5416 treated animals that was associated with 90% reduction in active TGF-beta 1 level. We found that tissue transglutaminase (TG), a cross-linking enzyme involved in TGF-beta 1 activation and matrix stabilization, was inhibited by SU5416. These results suggest that SU5416 delays wound healing by reducing matrix synthesis and stabilization through inhibition of TGF-beta 1 activation. This study was made feasible via the development of a unique method to study anti-angiogenic compounds that provides highly reproducible and quantitative results. Further studies are needed to evaluate in vivo whether anti-angiogenic agents alter wound healing.
Adenosine Triphosphate • Angiogenesis Inhibitors • Animals • Collagen • Enzyme Inhibitors • Guanosine Triphosphate • Indoles • Protein-Tyrosine Kinases • Pyrroles • Rats • Rats, Inbred F344 • Transforming Growth Factor beta • Transforming Growth Factor beta1 • Transglutaminases • Wound Healing • antagonists & inhibitors* • biosynthesis • drug effects* • metabolism • pharmacology* • physiology