Amifostine Treatment Mitigates the Damaging Effects of Radiation on Distraction Osteogenesis in the Murine Mandible

Abstract

According to the American Society of Clinical Oncology, in 2012, more than 53,000 new cases of head and neck cancers (HNCs) were reported in the United States alone and nearly 12,000 deaths occurred relating to HNC. Although radiotherapy (XRT) has increased survival, the adverse effects can be unrelenting and their management is rarely remedial. Current treatment dictates surgical mandibular reconstruction using free tissue transfer. These complex operations entail extended hospitalizations and attendant complications often lead to delays in initiation of adjuvant therapy, jeopardizing prognosis as well as quality of life. The creation of new bone by distraction osteogenesis (DO) generates a replacement of deficient tissue from local substrate and could have immense potential therapeutic ramifications. Radiotherapy drastically impairs bone healing, precluding its use as a reconstructive method for HNC. We posit that the deleterious effects of XRT on bone formation could be pharmacologically mitigated. To test this hypothesis, we used a rodent model of DO and treated with amifostine, a radioprotectant, to assuage the XRT-induced injury on new bone formation. Amifostine had a profound salutary effect on bone regeneration, allowing the successful implementation of DO as a reconstructive technique. The optimization of bone regeneration in the irradiated mandible has immense potential for translation from the bench to the bedside, providing improved therapeutic options for patients subjected to XRT.

Amifostine Suppresses the Side Effects of Radiation on BMSCs by Promoting Cell Proliferation and Reducing ROS Production

“…The most significant role of AMI in the clinical scenario is its differential effects on cancer cells and normal cells, which attribute to the higher pH and therefore higher activity of ALP in normal cells than in cancer cells, leading to an increased vascular permeation in normal tissues, which activates AMI [17–19]. In the distraction osteogenesis model of murine mandible, it was observed that although the regenerate bone mineral density (BMD) was significantly diminished by radiation, pretreatment with AMI did not only preserve the regenerate BMD but could also greatly promote bone value fraction beyond the normal regenerate density [20].…”

Amifostine inhibited the differentiation of RAW264.7 cells into osteoclasts by reducing the production of ROS under 2 Gy radiation

“…1,13,14 Prolonged exposure to spaceflight radiation harms astronauts' health by increasing the number and activity of osteoclasts, 1,14,15 which decreases the bone mineral density (BMD). [21][22][23][24] In an in vitro study, Wong et al 25 demonstrated that AMI showed a protective effect on normal osteoblastic differentiation in irradiated bone, and AMI could increase the activity of ALP in cells compared to that of radiation-only cells. 14,16 Recently, Buchman and Margulies demonstrated that amifostine (AMI) could elevate BMD, short fracture healing time, and increase the formation of bone mass in irradiated bones.…”

“…It also may cause a high risk of fracture and osteoporosis. 22,25 In an in vivo study, the regenerated BMD was significantly diminished by radiation therapy in a distraction osteogenesis model of the murine jaw. 17,18 In vivo, AMI could transform into a clinically active metabolite (WR-1065) by rapidly dephosphorylating by alkaline phosphatase (ALP).…”

“…14,16 Recently, Buchman and Margulies demonstrated that amifostine (AMI) could elevate BMD, short fracture healing time, and increase the formation of bone mass in irradiated bones. 22,25 In vivo studies [22][23][24][25] have proved that bone quality and bone quantity could be increased by AMI in irradiated models. After activation, cells could be protected from radiationinduced DNA damage, for AMI cloud prevent DNA double-strand damage and eliminate ROS induced by radiotherapy.…”

“…17,18 In vivo, AMI could transform into a clinically active metabolite (WR-1065) by rapidly dephosphorylating by alkaline phosphatase (ALP). [22][23][24][25] However, whether AMI could affect the differentiation of RAW264.7 cells into osteoclasts and how it affects RAW264.7 under radiotherapy are still unclear. At the same time, a large number of hydrogen ions are produced during the activation of AMI, which helps to repair DNA damage caused by radiation.…”