Incisor degeneration in rats induced by vascular endothelial growth factor/fibroblast growth factor receptor tyrosine kinase inhibition

Toxicologic Pathology
Anthony M FletcherMark G Mense

Abstract

BMS-645737, an inhibitor of vascular endothelial growth factor (VEGF) receptor-2 and fibroblast growth factor (FGF) receptor-1, has anti-angiogenic activity and was evaluated in nonclinical studies as a treatment for cancer. This article characterizes the BMS-645737-induced clinical, gross, and histologic lesions of incisor teeth in Sprague-Dawley (SD) rats. Rats received 0 800 mg/kg BMS-645737 in a single-dose study or consecutive daily doses of 0 20 mg/kg/day in a 1-month study. The reversibility of these effects was assessed in the 1-month study. White discoloration and fracture of incisors were observed clinically and grossly in the 1-month study. In both studies, dose-dependent histopathologic lesions of incisors were degeneration and/or necrosis of odontoblasts and ameloblasts; decreased mineralization of dentin; inflammation and necrosis of the dental pulp; and edema, congestion, and hemorrhage in the pulp and periodontal tissue adjacent to the enamel organ. Partial recovery was observed at lower doses after a two-week dose-free period in the one-month study. Drug-induced incisor lesions were considered to be related to the pharmacologic inhibitory effects on VEGF and FGF signaling, that is, inhibition of growth and main...Continue Reading

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Citations

Jul 23, 2013·Toxicological Sciences : an Official Journal of the Society of Toxicology·Gina M YanochkoEileen Blasi
Oct 6, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alberto BroniscerAmar Gajjar
Dec 2, 2014·Archives of Oral Biology·V A CentenoR V Gallará
Oct 19, 2014·Toxicologic Pathology·A P HallK C Hickling
Apr 8, 2015·World Journal of Hepatology·Gülsüm Özlem Elpek

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Methods Mentioned

BETA
xenograft
light microscopy

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