RESUMO
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.
Assuntos
Inibidores da Angiogênese/toxicidade , Incisivo/efeitos dos fármacos , Inibidores de Proteínas Quinases/toxicidade , Pirróis/toxicidade , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Triazinas/toxicidade , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Animais , Dentina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Incisivo/patologia , Masculino , Necrose , Odontoblastos/efeitos dos fármacos , Odontoblastos/metabolismo , Ratos , Ratos Sprague-Dawley , Testes de ToxicidadeRESUMO
The Executive Committee of the Society of Toxicologic Pathology (STP) appointed an ad hoc task force to devise and recommend a standard list of tissues to be evaluated histopathologically in repeat-dose toxicity and carcinogenicity studies that are used to support the registration of new pharmaceutical products. The recommended tissue list is intended to be a minimum core list that can be used for all types of repeat-dose toxicity and carcinogenicity studies, regardless of route of administration, species or strain of mammalian laboratory animal, duration, or class of drug to be tested. The resulting recommendations of the task force, presented here, were subsequently reviewed by the STP membership and endorsed by the STP Executive Committee.