Amifostine

The metabolic basis of amifostine‑mediated radioprotection was explored in this study. In cancer patients, amifostine lowered oxygen consumption and carbon dioxide emission while raising blood lactate, consistent with a Warburg‑type shift. In mouse liver and normal hepatocytes, the active metabolite WR‑1065 induced HIF1α, increased lactate dehydrogenase and glucose transporter levels, and reduced mitochondrial pyruvate use, leading to lower acetyl‑CoA and ATP. Notably, neoplastic cells did not share this protective effect. The findings indicate that amifostine transiently redirects normal cell metabolism toward glycolysis, thereby reducing mitochondrial oxidative stress during radiation.

Fig. 1 Western blot images and band densitometry analysis of levels of proteins involved in anaerobic metabolism, as assessed in mouse liver before and after administration of amifostine. (Koukourakis MI, et al., 2016)

Retroductal delivery of amifostine or its active metabolite WR‑1065 directly to murine submandibular glands was tested for radioprotection while avoiding systemic toxicity. A single 15 Gy radiation dose severely reduced salivary gland function and acinar cell survival. In contrast, retrograde delivery before irradiation maintained stimulated saliva secretion and acinar cell survival at levels significantly higher than irradiated‑only controls and systemically treated animals. Localized delivery also attenuated the hypotension typical of intravenous amifostine. The authors conclude that direct salivary gland delivery markedly improves cellular radioprotection and mitigates adverse effects, supporting development of localized delivery systems for fractionated radiotherapy.

Fig. 2 Gland histology and Mist1 immunofluorescence at 12 weeks postirradiation. (Varghese JJ, et al., 2018)