Narrow Amifostine Dose Windows Define Radioprotection Outcome, Following Fractionated Whole-body Irradiation of Mice

Background: Amifostine is an important broad spectrum cytoprotective agent approved for protection during fractionated radiotherapy. The daily dose of amifostine used, however, is arbitrarily chosen and low compared to the actual tolerable dose. Materials and Methods: Cohorts of mice (n=6) were treated with one up to 4 consecutive fractions of 6 Gy of whole-body γ-irradiation ( 60 Co), supported with increasing daily subcutaneous (s.c.) doses of amifostine (10 mg/g-300 mg/g). Survival and weight loss were monitored. Histopathological analysis was performed in mice receiving 3×6 Gy. Results: By increasing the amifostine dose from 13 to 50 mg and to 160 mg/g, the 50% lethal dose of radiotherapy increased from 2×6 Gy to 3×6 Gy and to 4×6 Gy, respectively. To keep the median weight loss to less than 25% of the initial weight, the dose of amifostine demanded was 23 mg/g, 68 mg/g and 121 mg/g, for 2×6 Gy, 3×6 Gy and 4×6 Gy, respectively. Histopathological analysis revealed a net protection of the liver and intestine of the mice receiving amifostine. Extensive and multiple vacuolar degeneration of the cytoplasm with focal necrosis of hepatocytes and loss of the intestinal villi was the most striking finding in the dying mice treated without amifostine. Conclusion: Taking into account the strong association of daily amifostine dose with cytoprotective efficacy and that a slight reduction of the daily amifostine dose can substantially reduce the clinical protective effect during fractionated radiotherapy, it is suggested that randomized trials should be re-appraised adopting amifostine schedules close to the maximum tolerable dose. Amifostine is an important broad-spectrum cytoprotective agent approved for the prevention of cisplatin-related toxicities