Assuntos
Testes de Carcinogenicidade/métodos , Neoplasias Experimentais/induzido quimicamente , Hormônio Paratireóideo/toxicidade , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Incidência , Masculino , Neoplasias Experimentais/epidemiologia , Hormônio Paratireóideo/farmacocinética , Ratos , Ratos Endogâmicos F344 , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/toxicidade , Medição de Risco , Teriparatida/toxicidadeRESUMO
The carcinogenic potential of human parathyroid hormone 1-84 (PTH) was assessed by daily subcutaneous injection (0, 10, 50, 150 microg/kg/day) for 2 years in Fischer 344 rats. Histopathological analyses were conducted on the standard set of soft tissues, tissues with macroscopic abnormalities, selected bones, and bones with abnormalities identified radiographically. All PTH doses caused widespread osteosclerosis and significant, dose-dependent increases in femoral and vertebral bone mineral content and density. In the mid-and high-dose groups, proliferative changes in bone increased with dose. Osteosarcoma was the most common change, followed by focal osteoblast hyperplasia, osteoblastoma, osteoma and skeletal fibrosarcoma. The incidence of bone neoplasms was comparable in control and low-dose groups providing a noncarcinogenic dose for PTH of 10 microg/kg/day at a systemic exposure to PTH that is 4.6-fold higher than for a 100 microg dose in humans. The ability of PTH to interact with and balance the effects of both the PTH-1 receptor and the putative C-terminal PTH receptor, may lead to the lower carcinogenic potential observed with PTH than reported previously for teriparatide.
