Prophylactic administration of Amifostine protects vessel thickness in the setting of irradiated bone

Abstract

Although often beneficial in the treatment of head and neck cancer (HNC), radiation therapy (XRT) leads to the depletion of vascular supply and eventually decreased perfusion of the tissue. Specifically, previous studies have demonstrated the depletion of vessel volume fraction (VVF) and vessel thickness (VT) associated with XRT. Amifostine (AMF) provides protection from the detrimental effects of radiation damage, allowing for reliable post-irradiation fracture healing in the murine mandible. The purpose of this study is to investigate the prophylactic ability of AMF to protect the vascular network in an irradiated field. Sprague-Dawley rats (n=17) were divided into 3 groups: control (C, n=5), radiated (XRT, n=7), and radiated mandibles treated with Amifostine (AMF XRT, n=5). Both groups receiving radiation underwent a previously established, human equivalent dose of XRT totaling 35 Gray, equally fractionated over 5 days. The AMF XRT group received a weight dependent (0.5mg AMF/5g body weight) subcutaneous injection of AMF 45 minutes prior to XRT. Following a 56-day recovery period, mandibles were perfused, dissected, and imaged with µCT. ANOVA was used for comparisons between groups and p < 0.05 was considered statistically significant. Stereologic analysis demonstrated a significant and quantifiable restoration of VT in AMF treated mandibles as compared to those treated with radiation alone (0.061±.011mm versus 0.042±0.004mm, p=0.027). Interestingly, further analysis demonstrated no significant difference in VT between control mandibles and those treated with AMF (0.067±0.016mm versus 0.061±0.011mm, p=0.633). AMF treatment also showed an increase in VVF, however those results were not statistically significant from VVF values demonstrated by the XRT group. Our data support the contention that AMF therapy acts prophylactically to protect vessel thickness, as AMF-treated mandibles demonstrate VT levels that are not statistically different from controls in the setting of irradiation. Based on these findings, we support the continued investigation of this treatment paradigm in its potential translation for the prevention of vascular depletion after radiotherapy.

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

“…Besides, when administered prior to radiotherapy, AMI can protect the vascular network by maintaining the caliber of the blood vessels, such that they are comparable to those of normal, nonirradiated bones. AMI can significantly increase the thickness and vascular volume fraction of blood vessels in irradiated bones [12, 49].…”

Overcoming Nuclear Winter: The Cutting-edge Science of Bone Healing and Regeneration in Irradiated Fields

“…These results were supported in a nonfractured irradiated model, where amifostine prophylaxis also demonstrated statistically significant angioprotection based on micro-CT vascular analysis compared with the irradiated controls. 29 …”

“…These results were supported in a nonfractured irradiated model, where amifostine prophylaxis also demonstrated statistically significant angioprotection based on micro-CT vascular analysis compared with the irradiated controls. 29 Despite these benefits, clinical utilization of prophylactic amifostine has not been widely adopted in HNC radiation treatment. This may be due in part to its intravenous (IV) infusion administration approximately 30 minutes before each fractionated radiation session.…”

Clinical Use of Deferoxamine in Distraction Osteogenesis of Irradiated Bone

“…However, adequate perfusion is considered a prerequisite for successful bone regeneration (6-8), thus clinical reports of DO of the irradiated craniofacial skeleton are rare (9-12). Outcomes have been variable, stimulating clinicians and researchers to explore adjunctive measures to augment bone formation (10, 12-15). A particularly promising approach has been the administration of deferoxamine during the activation/distraction period.…”