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)
|