title: 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.affiliation: Drug Safety Evaluation, Bristol-Myers Squibb Company, Syracuse, New York, NY 13221-4755, USA. anthony.fletcher@bms.com
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Fletcher
authors.forename: Carla L
authors.initials: CL
authors.lastname: Bregman
authors.forename: Jochen
authors.initials: J
authors.lastname: Woicke
authors.forename: Theodora W
authors.initials: TW
authors.lastname: Salcedo
authors.forename: Robert H
authors.initials: RH
authors.lastname: Zidell
authors.forename: Helen E
authors.initials: HE
authors.lastname: Janke
authors.forename: Hengsheng
authors.initials: H
authors.lastname: Fang
authors.forename: William J
authors.initials: WJ
authors.lastname: Janusz
authors.forename: Gene E
authors.initials: GE
authors.lastname: Schulze
authors.forename: Mark G
authors.initials: MG
authors.lastname: Mense
mesh_terms: D020533:Angiogenesis Inhibitors / Q000633:toxicity*; D000818:Animals; D003804:Dentin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007180:Incisor / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009336:Necrosis; D009804:Odontoblasts / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011758:Pyrroles / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors*; D018675:Toxicity Tests; D014227:Triazines / Q000633:toxicity*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: C529910:5-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; D020533:Angiogenesis Inhibitors; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D014227:Triazines; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2