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

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 maintenance of small-diameter vessels that support the formation of dentin and enamel in growing teeth and/or to perturbances of function of odontoblasts and ameloblasts or their precursors.

• Authors: Anthony M Fletcher, Carla L Bregman, Jochen Woicke, Theodora W Salcedo, Robert H Zidell, Helen E Janke, Hengsheng Fang, William J Janusz, Gene E Schulze, Mark G Mense
• Journal: Toxicologic pathology (Toxicol Pathol) Vol. 38 Issue 2 Pg. 267-79 (Feb 2010) ISSN: 1533-1601 [Electronic] United States
• PMID: 20100840 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5-isopropyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2-methyl-1H-pyrrolo(2,3-b)pyridin-5-yl)pyrrolo(2,1-f)(1,2,4)triazin-4-amine
• Angiogenesis Inhibitors
• Protein Kinase Inhibitors
• Pyrroles
• Triazines
• Receptor, Fibroblast Growth Factor, Type 1
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (toxicity)
• Animals
• Dentin (metabolism)
• Dose-Response Relationship, Drug
• Female
• Incisor (drug effects, pathology)
• Male
• Necrosis
• Odontoblasts (drug effects, metabolism)
• Protein Kinase Inhibitors (toxicity)
• Pyrroles (toxicity)
• Rats
• Rats, Sprague-Dawley
• Receptor, Fibroblast Growth Factor, Type 1 (antagonists & inhibitors)
• Toxicity Tests
• Triazines (toxicity)
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors)