Incisor degeneration in rats induced by vascular endothelial growth factor/fibroblast growth factor receptor tyrosine kinase inhibition.
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.
Fletcher
Anthony M
AM
Drug Safety Evaluation, Bristol-Myers Squibb Company, Syracuse, New York, NY 13221-4755, USA. anthony.fletcher@bms.com
Bregman
Carla L
CL
Woicke
Jochen
J
Salcedo
Theodora W
TW
Zidell
Robert H
RH
Janke
Helen E
HE
Fang
Hengsheng
H
Janusz
William J
WJ
Schulze
Gene E
GE
Mense
Mark G
MG
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*
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