Amifostine and the endogenous cellular antioxidant enzyme manganese superoxide dismutase in radioprotection

Abstract

Amifostine is currently the only drug approved by the US Food and Drug Administration for use as a radiation protector in the clinical treatment of cancer. While its approved use is limited to reducing the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where a substantial portion of the parotid glands are in the radiation field, the drug has been used in a number of off-label applications. Amifostine's effectiveness as a radioprotector is due to a number of factors that include the following: a polyamine-like structure that facilitates its concentration within mitochondria and the microenvironment of chromatin; a free thiol group in its active form that participates directly in free radical scavenging processes; and through its reductive properties, the ability to activate a nuclear transcription factor κB signaling pathway that culminates in an inductive, antioxidant-mediated protective process resulting from the enhanced transcription and subsequent elevation in activity of the potent mitochondrial antioxidant enzyme manganese superoxide dismutase. This latter effect is a thiol-mediated adaptive response that is the basis for a newly identified phenomenon described as a delayed radioprotective effect. If limited to only normal tissues, this phenomenon could be exploited to enhance amifostine's overall usefulness as a radiation protector. Concomitant effects on malignant tissues would, however, severely compromise therapeutic gain and limit its usefulness as a radiation protector in cancer treatment.