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In Vitro Model of Coronary Angiogenesis
Published on: March 10, 2020
Incisor degeneration in rats induced by vascular endothelial growth factor/fibroblast growth factor receptor tyrosine
Anthony M Fletcher1, Carla L Bregman, Jochen Woicke
1Drug Safety Evaluation, Bristol-Myers Squibb Company, Syracuse, New York, NY 13221-4755, USA. anthony.fletcher@bms.com
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.
Insights
BMS-645737, a vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) receptor inhibitor, caused dose-dependent incisor lesions in rats, including discoloration and fractures. Some recovery was noted after dose cessation.
Area of Science:
- Pharmacology
- Toxicology
- Dental Science
Background:
- BMS-645737 is an anti-angiogenic agent targeting VEGF and FGF receptors, investigated for cancer treatment.
- Nonclinical studies are crucial for understanding potential side effects of novel therapeutics.
Purpose of the Study:
- To characterize the clinical, gross, and histologic effects of BMS-645737 on incisor teeth in Sprague-Dawley rats.
- To assess the dose-dependency and reversibility of these induced dental lesions.
Main Methods:
- Rats received single or daily doses of BMS-645737.
- Clinical, gross, and histopathologic examinations of incisors were performed.
- Reversibility was assessed after a dose-free period.
Main Results:
- Clinical and gross findings included white discoloration and incisor fractures.
- Histopathologic lesions included odontoblast and ameloblast degeneration/necrosis, decreased dentin mineralization, pulp inflammation/necrosis, and vascular changes in supporting tissues.
- Lesions were dose-dependent.
Conclusions:
- BMS-645737 induces significant incisor lesions in rats, likely due to inhibition of VEGF and FGF signaling pathways.
- These effects may stem from impaired vascular support for tooth formation or direct toxicity to dental precursor cells.
- Partial reversibility suggests a dynamic process influenced by drug exposure duration and dose.
