Amifostine Remediates the Degenerative Effects of Radiation on the Mineralization Capacity of the Murine Mandible

Abstract

Background Although radiotherapy is a cornerstone in head and neck cancer treatment it causes substantial morbidity to the normal adjoining bone. Our specific aim is to assess the radioprotective effect of Amifostine (AMF) therapy on the mineralization of the mandible using micro-computed tomography (μCT). We hypothesize that AMF will safeguard the mandible from radiation-induced disruption of the mineralization process and the associated failure of new bone creation. Methods Male Sprague Dawley rats were randomized into 3 groups: Control (n=8), XRT (n=5) and AMF (n=8). XRT and AMF underwent human bioequivalent radiation of 70Gy in 5 fractions to the left hemimandible. 56 days post-radiation, the hemimandibles were harvested for radiomorphometric analyses. Results AMF exhibited less alopecia, mucositis and weight loss as well as increased cortical density in comparison to XRT. Bone and Tissue Mineral Densities showed statistically significant improvement in AMF versus XRT and no difference was observed between AMF versus Control. Detailed μCT analysis further demonstrated significant differences in the mineralization profile when comparing XRT and AMF. AMF maintained regions of lower mineralization consistent with the preservation of normal remodeling. Conclusion We have successfully demonstrated the ability of AMF pre-treatment to protect the natural mineralization profile of bone. This reflects the capacity of AMF prophylaxis to safeguard the normal surrounding mandible from the impediments of collateral damage imposed by radiation. Further study can now be directed at correlating these findings with the potential use of AMF to prevent the devastating associated morbidities of radiotherapy such as pathologic fractures and osteoradionecrosis.

Vascular analysis as a proxy for mechanostransduction response in an isogenic, irradiated murine model of mandibular distraction osteogenesis

“…Increased vessel separation translates into a decrease in vascular density. [20] Taken together, these two stereologic metrics may suggest inadequate blood supply to surrounding tissues. Insufficient blood supply hampers the growth of viable bony regenerate in the distraction gap.…”

“…It is known that radiotherapy can play a significant role in impairing the healing mechanisms in regenerate bone. [18, 12, 19, 20] Therefore, the purpose of this study was to specifically develop a novel isogenic rat model of impaired vasculogenesis of the regenerate mandible in order to determine quantifiable metrics of vascular injury and associated damage. Once the specific level and extent of injury is ascertained, cell based therapies can be utilized to remediate and assuage the damage, restore the ability to heal bone, and permit the utilization of Distraction Osteogenesis in this challenging patient population.…”

Amifostine Reduces Radiation-Induced Complications in a Murine Model of Expander-Based Breast Reconstruction

“…Rats receiving Amifostine were administered a 100mg/kg dorsal subcutaneous injection 45 minutes prior to radiation, a dose previously derived and utilized by our laboratory in published studies. 11,12 Just prior to radiation administration, animals underwent closed chamber induction with inhalational isoflurane. The animal was then placed in the radiation chamber and covered with a protective lead shield that exposed only a 4cm diameter circular region directly overlying the expander.…”

Prophylactic Amifostine Preserves the Biomechanical Properties of Irradiated Bone in the Murine Mandible

“…Specimens receiving amifostine were administered a 100-mg/kg dorsal subcutaneous injection 45 minutes before irradiation, a dose previously developed by our laboratory and used in published studies. 11,12 Animals underwent closed-chamber induction with inhalational isoflurane before being placed in the radiation chamber and covered with a protective lead shield that exposed only the left hemimandible. Low-flow isoflurane and oxygen were administered continuously duration irradiation, which lasted approximately 5 minutes for each fractionated dose.…”

“…8–10 In our laboratory, we have demonstrated that the cytoprotective properties exhibited by amifostine in soft tissues are also translatable to bone, as prophylactic amifostine administration was shown to preserve new bone formation in irradiated murine mandibles after distraction osteogenesis and fracture repair. 11,12 …”