Small molecule derived from a natural product that mitigates radiation injury

Abstract

Exposure to ionizing radiation is unavoidable for the many cancer patients that require radiotherapy as a component of their treatment. Radiation exposure also occurs from rare events, such as nuclear power plant malfunctions, terrorist attacks with “dirty bombs,” or detonation of nuclear weapons. The Chernobyl and Fukushima Daiichi disasters have demonstrated that the first responders to such emergencies have particularly high risks of radiation exposure. The types of ailments that victims suffer following total body exposures are dose-dependent (1). With total body exposures of <2 Gy, lymphocyte counts fall by about 50% in the first 24 h, nadir at 10–15 d, and take 3–6 mo to recover. The hematopoietic syndrome is a more extreme version of this that occurs following exposure to 2.5–5 Gy, during which bone marrow depletion can be fatal without bone marrow transplantation. Following whole-body exposures of 5–12 Gy, the victims who survive hematopoietic crisis via bone marrow transplantation subsequently face fatal intestinal injury. All survivors of these different situations are at risk for developing radiation-induced mutations and associated carcinogenesis. Several academic and governmental groups have organized to develop medical countermeasures in preparation for nuclear disasters. Compounds, termed radioprotectors, are capable of ameliorating radiation effects if delivered before or during the radiation exposure. A more elusive class of agents, termed radiation mitigators, are effective when administered hours or days after the radiation exposure occurs. The distinction between radioprotectors and mitigators is important, because the mobilization of countermeasures is logistically difficult in the midst of an unexpected disaster, so treatment is likely to begin at a time well after the radiation exposure occurs. Both classes of drugs were recently reviewed (2). It is noteworthy that these drugs could be valuable in clinical oncology, if they can protect normal tissues from radiotherapy injury while not simultaneously protecting tumor cells. Currently, the only Food and Drug Administration-approved radioprotector is Amifostine, and its only approved radiation-related indication is resected head and neck carcinomas.