Antineoplastic Drugs Induce Morphological Changes During Dental Root Development in Young Mice

Abstract

In recent decades, improvements in therapeutic modalities for childhood cancer, including chemo­therapy, irradiation, surgery, stem cell transplantation, and their combinations, have increased survival rates, demonstrating their increasing effectiveness. However, along with improved survival, the late effects of antineoplastic therapy deserve more attention. Notably, late effects involving dental disturbances have been reported in patients treated with can­cer therapy. Furthermore, adverse effects of cancer and cancer therapy during childhood on dental health have been reported, such as mineralization disturbances, dental caries, microdontia, hypodontia, root stunting, and taurodontism, as well as dental disturbances caused by chemotherapy and radiation therapy. However, because multimodal therapy is used for nearly all types of childhood cancer, it is difficult to attribute these effects to any single agent or treatment modality. The effects of antineoplastic treatment, particularly those of alkylating drugs, on the oral health of childhood cancer survivors are well known and widely documented. Cyclophosphamide (CY), an N­-mustard derivative, is an alkylating drug widely utilized for treatment of cancer because of its capac­ity to interfere with cancer cell division. However, administration of CY results in certain undesirable secondary effects caused by nonspecific actions on cells with a high mitotic index, resulting in dam­ age to both neoplastic and normal cells. In this study, to evaluate the effects of CY on root development until occlusion completion, we ex­amined the molar teeth of young mice treated solely with CY. Using 3D structural imaging, morpho­logical changes in the molar roots of mice were analyzed to investigate the mechanism underlying the adverse effects of CY on dental root formation. Our results showed that CY administration in the early stages of root formation resulted in impaired root development and early closure of the apical foramen. Additionally, CY inhibited regular formation of Hertwig's epithelial root sheath and might have caused disturbances to the developing molar root. Additional studies are needed to elucidate anticancer treatment effects in relation to dose and age, as well as time­related effects on dental development. The number of long­term survivors following diagnosis of cancer childhood will no doubt show a steady increase in the future. Therefore, oral care programs designed to prevent periodontal disease are vital in consideration of the irreversible condi­tion of shortened tooth roots that often develops.