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 antiangiogenic 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.

Expression of a fibronectin in the dental pulp of lead intoxicated rats with experimentally induced diabetes mellitus

“…In vivo animal models used in this study, provide an acceptable alternative to human models, although differences between species should be taken into account while interpreting tissue response [30].…”

Digestive System

“…38 These changes can be reproduced in rodents. 39 It has been shown that vincristine which interferes with the assembly of microtubules and reduces secretory activity in a number of cells including osteoblasts and chondroblasts alters dentine formation in the rat incisor. Two weeks following a single intravenous dose of vincristine to young adult rats, a faint incremental line in the dentine was shown to occur, probably a reflection of a direct effect of the drug on the dentinogenic tissue at the time of injection.…”

“…50 Administration of inhibitors of the vascular endothelial growth factor receptor or fibroblast growth factor receptor also has been shown to alter tooth formation in the rat. 39,51 After several weeks' administration teeth become whitened and fractured. Histologically the teeth show reduced dentine formation with degeneration of ondotoblasts, presumably as a result of defective vascularization in a manner similar to that seen in the epiphyseal growth plate (see Chapter 5).…”

Evaluation of Cumulative Effects of Chemotherapy and Bevacizumab (Avastin�) in Oncological Patients with Periodontal Disease

“…When VEGF and other endothelial growth factors bind to endothelial cell receptors signals are transmitted into their interior where growth and the survival of a new blood vessel is initiated. Angiogenesis inhibitors interfere in many stages of this process [12]. Bevacizumab is a monoclonal antibody that recognizes in a specific manner and binds to VEGF preventing the ladder to activate the receptor [13,14].…”