Radiation countermeasure agents: an update (2011-2014)

Abstract

Introduction: Despite significant scientific advances over the past 60 years towards the development of a safe, nontoxic and effective radiation countermeasure for the acute radiation syndrome (ARS), no drug has been approved by the US FDA. A radiation countermeasure to protect the population at large from the effects of lethal radiation exposure remains a significant unmet medical need of the US citizenry and, thus, has been recognized as a high priority area by the government.

Area covered: This article reviews relevant publications and patents for recent developments and progress for potential ARS treatments in the area of radiation countermeasures. Emphasis is placed on the advanced development of existing agents since 2011 and new agents identified as radiation countermeasure for ARS during this period.

Expert opinion: A number of promising radiation countermeasures are currently under development, seven of which have received US FDA investigational new drug status for clinical investigation. Four of these agents, CBLB502, Ex-RAD, HemaMax and OrbeShield, are progressing with large animal studies and clinical trials. G-CSF has high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the US FDA in the future.

Keywords: countermeasures; gastrointestinal syndrome; hematopoietic syndrome; mice; nonhuman primates; radiation.

Figure 1.

Radiation countermeasures under development. Currently, there are seven radiation countermeasures that have US FDA IND status: Androstenediol (5-AED), BIO 300, CBLB502, Ex-RAD, HemaMax, Neupogen and OrbeShield. Neupogen and Leukine are expected to obtain US FDA Emergency Use Authorization and both are available in the SNS. Promising molecules at different stages of development are presented under different groups.

Figure 2.

Brief diagrammatic representation of radiation injury and the mode of action of radiation countermeasures at advanced stages of development. This simplified response pathway of a subject's irradiation shows that radiation exposure induces free radicals, DNA breaks and apoptosis. The various radiation countermeasures reduce the injurious effects of irradiation through different pathways as indicated by colored arrows. Only the drugs with well-understood mechanism of action are included and may have been indicated at multiple points, as several drugs work through several pathways. Red arrows indicate inhibition of deleterious effects of radiation injury and green arrows indicate enhancement of recovery.

Figure 3.

Schematic representation of TLR-ligand-mediated NF-κB activation. TLR ligands (multiple, not all radioprotective) interact with TLR receptor inducing two divergent signaling pathways controlled by two pairs of adaptor proteins: TRAM/TRIF and TIRAP/MyD88. The MyD88-dependent pathway quickly upregulates inflammatory cytokines via NF-κB activation by its dissociation from inhibitory component (IκB). This permits NF-κB to enter the nucleus where it can ‘turn on’ the expression of specific genes such as inflammatory or immune response, a cell survival response, cellular proliferation and oxygen-scavenging MnSOD. The MyD88-independent pathway does this as well, in addition to inducing type-1 IFN expression through IRFs and triggering IFN-β, which results in cell maturation. MyD88-independent pathways are activated with slower kinetics. Radiation produces ROS, which also activate NF-γB.