New approaches to radiation protection

Abstract

Radioprotectors are compounds that protect against radiation injury when given prior to radiation exposure. Mitigators can protect against radiation injury when given after exposure but before symptoms appear. Radioprotectors and mitigators can potentially improve the outcomes of radiotherapy for cancer treatment by allowing higher doses of radiation and/or reduced damage to normal tissues. Such compounds can also potentially counteract the effects of accidental exposure to radiation or deliberate exposure (e.g., nuclear reactor meltdown, dirty bomb, or nuclear bomb explosion); hence they are called radiation countermeasures. Here, we will review the general principles of radiation injury and protection and describe selected examples of radioprotectors/mitigators ranging from small-molecules to proteins to cell-based treatments. We will emphasize agents that are in more advanced stages of development.

Keywords: cancer treatment; irradiation; mitigators; radiation protection; radioprotectors.

Figure 1

DNA damage response (DDR) to double-strand DNA breaks (DSBs) in relation to acute radiation syndrome and late effects. DSBs caused by oxidative radicals are sensed by the MRN complex (MRE11–RAD50–NBS1), resulting in an ATM (ataxia-telangiectasia, mutated)-driven DDR. Gamma-H2AX (phosphorylated histone H2AX protein) is both a participant in the DDR and a marker of DSBs. Depending upon the dose of radiation, the type of radiation, the volume of tissue irradiated, and other factors, the DDR may lead to some combination of DNA repair, permanent cell cycle arrest (senescence), cell death, or survival with DNA damage. As a result of these processes, acute and late radiation effects may ensue, resulting in survival, death, or survival with late tissue damage. Note that “acute radiation syndrome” refers to the consequences of whole body radiation exposure. Acute effects of radiation may be limited to specific tissues or organs in the case of partial body radiation exposures or radiotherapy treatment to tumor-bearing tissue.