Animal models for radiation injury, protection and therapy

Current events throughout the world underscore the growing threat of different forms of terrorism, including radiological or nuclear attack. Pharmaceutical products and other approaches are needed to protect the civilian population from radiation and to treat those with radiation-induced injuries. In the event of an attack, radiation exposures will be heterogeneous in terms of both dose and quality, depending on the type of device used and each victim's location relative to the radiation source. Therefore, methods are needed to protect against and treat a wide range of early and slowly developing radiation-induced injuries. Equally important is the development of rapid and accurate biodosimetry methods for estimating radiation doses to individuals and guiding clinical treatment decisions. Acute effects of high-dose radiation include hematopoietic cell loss, immune suppression, mucosal damage (gastrointestinal and oral), and potential injury to other sites such as the lung, kidney and central nervous system (CNS). Long-term effects, as a result of both high- and low-dose radiation, include dysfunction or fibrosis in a wide range of organs and tissues and cancer. The availability of appropriate types of animal models, as well as adequate numbers of animals, is likely to be a major bottleneck in the development of new or improved radioprotectors, mitigators and therapeutic agents to prevent or treat radiation injuries and of biodosimetry methods to measure radiation doses to individuals.     

Molecular and cellular biology of moderate-dose (1-10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda,Maryland, December 17-18, 2001

Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) Research: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.     

Medical countermeasures for radiation combined injury: radiation with burn, blast, trauma and/or sepsis. report of an NIAID Workshop, March 26-27, 2007

Non-clinical human radiation exposure events such as the Hiroshima and Nagasaki bombings or the Chernobyl accident are often coupled with other forms of injury, such as wounds, burns, blunt trauma, and infection. Radiation combined injury would also be expected after a radiological or nuclear attack. Few animal models of radiation combined injury exist, and mechanisms underlying the high mortality associated with complex radiation injuries are poorly understood. Medical countermeasures are currently available for management of the non-radiation components of radiation combined injury, but it is not known whether treatments for other insults will be effective when the injury is combined with radiation exposure. Further research is needed to elucidate mechanisms behind the synergistic lethality of radiation combined injury and to identify targets for medical countermeasures. To address these issues, the National Institute of Allergy and Infectious Diseases convened a workshop to make recommendations on the development of animal models of radiation combined injury, possible mechanisms of radiation combined injury, and future directions for countermeasure research, including target identification and end points to evaluate treatment efficacy.     

Canadians' Representation of Chemical,Biological, Radiological,Nuclear, and Explosive (CBRNE) Terrorism: A Content Analysis

The global threat of terrorism raises questions about preparedness and risk communication in the context of public health and security. Although experts discriminate between chemical, biological, radiological, nuclear, and explosive (CNRNE) terrorist events, little is known about how the Canadian public represents these forms of terrorism. A stratified random sample of 1502 Canadians participated in a telephone survey on CBRNE terrorism. A word association technique was used to assess first words or images that came to mind while thinking about different types of terrorist scenarios. Content analysis of this data revealed a number of potential uncertainties and misconceptions regarding different types of terrorism scenarios. Despite most frequently providing agents in response questions surrounding chemical or biological terrorism, respondents frequently confounded agents of biological and chemical nature. Similarly, different aspects of nuclear events were not consistently distinguished. Most notably, however, a sizable proportion of respondents had difficulty providing word associations to the different types of terrorist events or only provided vague responses that closely mirrored the scenario in question. Finally, images regarding the potential impacts of scenarios were infrequent. Implications for risk communication and preparedness are discussed; in particular, the need to provide the public with more detailed information regarding the nature of different forms of CBRNE terrorism and how to best prepare for a potential event.     

Dietary selenium for the mitigation of radiation injury: effects of selenium dose escalation and timing of supplementation

We recently reported that daily dietary supplementation with 100?μg selenium (a dose exceeding a rat's nutritional requirement by about 33-fold) initiated immediately after total-body irradiation (TBI) and maintained for 21?weeks mitigates radiation nephropathy in a rat model as indicated by blood urea nitrogen (BUN) levels and histopathological criteria (Radiat Res. 2009; 17:368-73). In this follow-up study, we explored the risks and benefits of delaying the onset of supplementation, shortening periods of supplementation, and escalating selenium supplementation beyond 100?μg/day. Supplementation with 200?μg selenium/day (as selenite or seleno-l-methionine) substantially improved the mitigation of radiation nephropathy by lowering BUN levels at 4?months after TBI from 115 to as low as 34?mg/dl and by proportionally lowering the incidence of histopathological abnormalities. Shortening the period of supplementation to 3 or 2?months did not compromise efficacy. Delaying the onset of supplementation for 1?week reduced but did not abrogate the mitigation of radiation nephropathy. Supplementation with 300?μg/day mitigated radiation nephropathy less effectively than 200?μg and was poorly tolerated. Rats that had been given 10?Gy of TBI were less tolerant of high-dose selenium than nonirradiated rats. This reduced tolerance of high-dose selenium would need to be taken into consideration when selenium is used for the mitigation of radiation injury in victims of nuclear accidents or acts of radiological terrorism. The high dose requirements, the pronounced threshold effect, and the superior performance of selenite suggest that the mitigation of radiation nephropathy involves mechanisms that go beyond the induction of selenoproteins.     

Captopril and losartan for mitigation of renal injury caused by single-dose total-body irradiation

It is known that angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II type-1 receptor blockers (ARBs) can be used to mitigate radiation-induced renal injury. However, for a variety of reasons, these previous results are not directly applicable to the development of agents for the mitigation of injuries caused by terrorism-related radiation exposure. As part of an effort to develop an animal model that would fit the requirements of the U.S. Food and Drug Administration (FDA) "Animal Efficacy Rule", we designed new studies which used an FDA-approved ACEI (captopril) or an FDA-approved ARB (losartan, Cozaar?) started 10 days after a single total-body irradiation (TBI) at drug doses that are equivalent (on a g/m(2)/day basis) to the doses prescribed to humans. Captopril and losartan were equally effective as mitigators, with DMFs of 1.23 and 1.21, respectively, for delaying renal failure. These studies show that radiation nephropathy in a realistic rodent model can be mitigated with relevant doses of FDA-approved agents. This lays the necessary groundwork for pivotal rodent studies under the FDA Animal Efficacy Rule and provides an outline of how the FDA-required large-animal studies could be designed.     

Emergency communication and information issues in terrorist events involving radioactive materials

With the threat posed by terrorism involving radioactive materials now high on the nation's agenda, local, state, and federal agencies are moving to enhance preparedness and response capabilities. Crucial to these efforts is the development of effective risk communication strategies. This article reports findings from an ongoing study of risk communication issues in nuclear/radiological terrorism situations. It is part of a larger CDC-funded effort that aims to better understand communication challenges associated with weapons of mass destruction terrorism incidents. Presented here are formative research findings from 16 focus groups (n = 163) in which a multi-part, hypothetical radioactive materials terrorism situation was discussed. Twelve of the focus groups were carried out with members of the general public (drawn from a variety of ethnic backgrounds and geographic locations), and four groups were composed of first responders, hospital emergency department personnel, and public health professionals. One aim of the focus groups was to elicit detailed information on people's knowledge, views, perceptions, reactions, and concerns related to a nuclear/radiological terrorism event, and to better understand people's specific information needs and preferred information sources. A second aim was to pretest draft informational materials prepared by CDC and NIOSH. Key findings for the public and professional groups are presented, and the implications of the research for developing messages in radiological/nuclear terrorism situations are explored.     

Mechanisms of action for an anti-radiation vaccine in reducing the biological impact of high dose and dose-rate, low-linear energy transfer radiation exposure

The development of an anti-radiation vaccine could be very useful in reducing acute radiation syndromes. Existing principles for the treatment of acute radiation syndromes are based on the amelioration of progressive pathophysiological changes, using the concept of replacement therapy. Active immunization by small quantities of the essential radiation-induced systemic toxins of what we call the Specific Radiation Determinant (SRD) before irradiation increased duration of life among animals that were irradiated by lethal or sub-lethal doses of gamma-radiation. The SRD toxins possess antigenic properties that are specific to different forms of acute radiation sickness. Intramuscular injection of larger quantities of the SRD toxins induce signs and symptoms in irradiated naive animals similar to those observed in acute radiation syndromes, including death. Providing passive immunization, at variable periods of time following radiation, with preparations of immune-globulins directed at the SRD molecules, can confer some protection in the development of clinical sequelae in irradiated animals. Improved survival rates and times were observed in animals that received lower, sublethal doses of the same SRDs prior to irradiation. Therefore, active immunization can be induced by SRD molecules as a prophylaxis. The protective effects of the immunization begin to manifest 15-35 days after an injection of a biologically active SDR preparation. The SRD molecules are a group of radiation toxins with antigenic properties that correlate specifically with different forms of radiation disease. The SRD molecules are composed of glycoproteins and lipoproteins that accumulate in the lymphatic system of mammals in the first hours after irradiation, and preliminary analysis suggests that they may originate from cellular membrane components. The molecular weight of the SRD group ranges from 200-250 kDa. The SRD molecules were isolated from the lymphatic systems of laboratory animals that were irradiated with doses known to induce the development of cerebral (SRD-1), non-specific toxic effects (SRD-2), gastrointestinal (SRD-3) and hematological (bone marrow) (SRD-4) syndromes. Our results suggest that an anti-radiation vaccine can be developed for prophylactic use against radiation damage induced by acute exposure to significant doses of low Linear Energy Transfer (LET) radiation for humans, including nuclear power workers, commercial and military pilots, cosmonauts/astronauts, nuclear-powered engine vessel operators and possibly even the civilian population in the case of a nuclear terrorism event.     

Plerixafor, a CXCR4 antagonist, mitigates skin radiation-induced injury in mice

Even with modern 3D conformal treatments skin radiation injury can be an inadvertent complication associated with clinical radiotherapy particularly at tissue folds. It is also of concern in the context of a radiological terrorism incident or accident, since skin irradiation lowers the lethal dose of whole body radiation. We hypothesize that radiation-induced skin injury originates from a loss of stem and progenitor cells, accompanied by excessive ROS production and proinflammatory cytokines. Plerixafor, a CXCR-4 antagonist, is one of the most efficient bone marrow stem cell mobilizers and these studies were designed to experimentally assess the potential of Plerixafor to reduce skin radiation injury. The right hind legs of groups of C57BL/6 mice were exposed to radiation alone or in combination with Plerixafor. Plerixafor was administered intraperitoneally at a dose of 5 mg/kg given in two doses separated by two days and started either on day 0, 4, 7, 15 or 24 after irradiation. The primary end point was skin injury, which was assessed three times a week for at least 2 months using a semi-quantitative scale. Secondary end points measured at selected time points included histology (primarily H&E) and cytokine levels (TGF-β and TNF-α). The acute and late skin injury in mice receiving Plerixafor was highly dependent on the timing of administration of the drug. The maximum benefit was observed when the drug was started 1 week after radiation exposure, and earlier or later administration of the drug decreased its efficacy. Secondary damage end points (cytokine levels and histologically assessed tissue thickness) provided confirmatory observations. In an attempt to gain insight into the effect of timing of administration of the agent on the mitigation effect, the ligand to CXCR4, stromal derived factor, SDF-1, was measured as a function of time after radiation exposure. Expression of SDF-1 monitored in skin as a function of time after a 30 Gy radiation exposure suggested a strong correlation between timing of administration of Plerixafor and expression of SDF-1 in irradiated skin: optimum drug administration timing coincided with maximal SDF-1 expression in the skin of irradiated mice. This report presents the first observation that CXCR4 antagonist improves both acute and late skin response to radiation exposure. ? 2012 by Radiation Research Society.     

Education and training for radiation scientists: radiation research program and American Society of Therapeutic Radiology and Oncology Workshop, Bethesda, Maryland, May 12-14, 2003

Current and potential shortfalls in the number of radiation scientists stand in sharp contrast to the emerging scientific opportunities and the need for new knowledge to address issues of cancer survivorship and radiological and nuclear terrorism. In response to these challenges, workshops organized by the Radiation Research Program (RRP), National Cancer Institute (NCI) (Radiat. Res. 157, 204-223, 2002; Radiat. Res. 159, 812-834, 2003), and National Institute of Allergy and Infectious Diseases (NIAID) (Nature, 421, 787, 2003) have engaged experts from a range of federal agencies, academia and industry. This workshop, Education and Training for Radiation Scientists, addressed the need to establish a sustainable pool of expertise and talent for a wide range of activities and careers related to radiation biology, oncology and epidemiology. Although fundamental radiation chemistry and physics are also critical to radiation sciences, this workshop did not address workforce needs in these areas. The recommendations include: (1) Establish a National Council of Radiation Sciences to develop a strategy for increasing the number of radiation scientists. The strategy includes NIH training grants, interagency cooperation, interinstitutional collaboration among universities, and active involvement of all stakeholders. (2) Create new and expanded training programs with sustained funding. These may take the form of regional Centers of Excellence for Radiation Sciences. (3) Continue and broaden educational efforts of the American Society for Therapeutic Radiology and Oncology (ASTRO), the American Association for Cancer Research (AACR), the Radiological Society of North America (RSNA), and the Radiation Research Society (RRS). (4) Foster education and training in the radiation sciences for the range of career opportunities including radiation oncology, radiation biology, radiation epidemiology, radiation safety, health/government policy, and industrial research. (5) Educate other scientists and the general public on the quantitative, basic, molecular, translational and applied aspects of radiation sciences.     

Which place for stem cell therapy in the treatment of acute radiation syndrome?

Radiation-induced (RI) tissue injuries can be caused by radiation therapy, nuclear accidents or radiological terrorism. Notwithstanding the complexity of RI pathophysiology, there are some effective approaches to treatment of both acute and chronic radiation damages. Cytokine therapy is the main strategy capable of preventing or reducing the acute radiation syndrome (ARS), and hematopoietic growth factors (GF) are particularly effective in mitigating bone marrow (BM) aplasia and stimulating hematopoietic recovery. However, first, as a consequence of RI stem and progenitor cell death, use of cytokines should be restricted to a range of intermediate radiation doses (3 to 7 Gy total body irradiation). Second, ARS is a global illness that requires treatment of damages to other tissues (epithelial, endothelial, glial, etc.), which could be achieved using pleiotropic or tissue-specific cytokines. Stem cell therapy (SCT) is a promising approach developed in the laboratory that could expand the ability to treat severe radiation injuries. Allogeneic hematopoietic stem cell transplantation (BM, mobilized peripheral blood and cord blood) transplantation has been used in radiation casualties with variable success due to limiting toxicity related to the degree of graft histocompatibility and combined injuries. Ex vivo expansion should be used to augment cord blood graft size and/or promote very immature stem cells. Autologous SCT might also be applied to radiation casualties from residual hematopoietic stem and progenitor cells (HSPC). Stem cell plasticity of different tissues such as liver or skeletal muscle, may also be used as a source of hematopoietic stem cells. Finally, other types of stem cells such as mesenchymal, endothelial stem cells or other tissue committed stem cells (TCSC), could be used for treating damages to nonhematopoietic organs.     

A TPO receptor agonist, ALXN4100TPO, mitigates radiation-induced lethality and stimulates hematopoiesis in CD2F1 mice

Thrombopoietin (TPO) receptor agonists lacking sequence homology to TPO were designed by grafting a known peptide sequence into the hinge and/or kappa constant regions of a human anti-anthrax antibody. Some of these proteins were equipotent to TPO in stimulating cMpl-r activity in vitro and in increasing platelet levels in vivo. ALXN4100TPO (4100TPO), the best agonist in this series with a K(d) of 30 nM for cMpl-r, exhibited potent activity as a radiation countermeasure in CD2F1 mice exposed to lethal total-body radiation from a cobalt-60 γ-ray source. 4100TPO (2 mg/kg, s.c.) administered once either 24 h before or 6 h after TBI showed superior protection to five daily doses given before or after TBI. Prophylactic administration (69 to 94% survival) was superior to therapeutic schedules (60% survival). 4100TPO conferred a significant survival benefit (P < 0.01) when administered 4 days before or even 12 h after exposure and across a dose range of 0.1 to 8 mg/kg. The dose reduction factors (DRFs) with a single dose of 1 mg/kg 4100TPO 24 h before or 12 h after TBI were 1.32 and 1.11, respectively (P < 0.0001). Furthermore, 4100TPO increased bone marrow cellularity and megakaryocytic development and accelerated multi-lineage hematopoietic recovery in irradiated mice, demonstrating the potential of 4100TPO as both a protector and a mitigator in the event of a radiological incident.     

Strategies for improving antitumor activity utilizing IL-2: Preclinical models and analysis of antitumor activity of lymphocytes from patients receiving IL-2

Conclusions Considerable enthusiasm remains for the successful utilization of the immune system for the immunotherapy of human cancers. Immunotherapeutic maneuvers have been able to mediate impressive antitumor responses for some patients with advanced and refractory malignancies. Unfortunately, the number of patients who benefit from current immunotherapies is low, while the toxicity for many of the patients receiving these treatments is high. It is becoming quite clear that the development of successful immunotherapeutic strategies will involve a carefully chosen combination of immunotherapeutic modalities or of immunotherapy combined with either surgery, radiation therapy, or chemotherapy. The use of an IL-2 based regimen which is clinically tolerable and can provide significant immune activation continues to remain central to many of these treatment approaches. Preclinicalin vitro and animal model systems can evaluate promising treatment strategies, including combination approaches. As an effective immunotherapeutic approach will likely require use of a combination of biologically active agents, the scheduling of these therapies may have profound importance both for optimal antitumor responses as well as clinical tolerance.     

Terrorism, trauma, and mass casualty triage: how might we solve the latest mind-body problem?

The global war on terrorism has led to increased concern about the ability of the U.S. healthcare system to respond to casualties from a chemical, biological, or radiological agent attack. Relatively little attention, however, has focused on the potential, in the immediate aftermath of such an attack, for large numbers of casualties presenting to triage points with acute health anxiety and idiopathic physical symptoms. This sort of "mass idiopathic illness" is not a certain outcome of chemical, biological, or radiological attack. However, in the event that this phenomenon occurs, it could result in surges in demand for medical evaluations that may disrupt triage systems and endanger lives. Conversely, if continuous primary care is not available for such patients after initial triage, many may suffer with unrecognized physical and emotional injuries and illness. This report is the result of an expert planning initiative seeking to facilitate triage protocols that will address the possibility of mass idiopathic illness and bolster healthcare system surge capacity. The report reviews key triage assumptions and gaps in knowledge and offers a four-stage triage model for further discussion and research. Optimal triage approaches offer flexibility and should be based on empirical studies, critical incident modeling, lessons from simulation exercises, and case studies. In addition to staging, the proposed triage and longitudinal care model relies on early recognition of symptoms, development of a registry, and use of non-physician care management to facilitate later longitudinal followup and collaboration between primary care and psychiatry for the significant minority of patients who develop persistent idiopathic symptoms associated with reduced functional status.     

Chemical safety in animal care,use, and research

Chemical safety is an essential element of an effective occupational health and safety program. Controlling exposures to chemical agents requires a careful process of hazard recognition, risk assessment, development of control measures, communication of the risks and control measures, and training to ensure that the indicated controls will be utilized. Managing chemical safety in animal care and use presents a unique challenge, in part because research is frequently conducted in two very different environments--the research laboratory and the animal care facility. The chemical agents specific to each of these environments are typically well understood by the employees working there; however, the extent of understanding may not be adequate when these individuals, or chemicals, cross over into the other environment. In addition, many chemicals utilized in animal research are not typically used in the research laboratory, and therefore the level of employee knowledge and proficiency may be less compared with more routinely used materials. Finally, the research protocol may involve the exposure of laboratory animals to either toxic chemicals or chemicals with unknown hazards. Such animal protocols require careful review to minimize the potential for unanticipated exposures of the research staff or animal care personnel. Numerous guidelines and regulations are cited, which define the standard of practice for the safe use of chemicals. Key chemical safety issues relevant to personnel involved in the care and use of research animals are discussed.     

Development and licensure of medical countermeasures to treat lung damage resulting from a radiological or nuclear incident

Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.     

Genetic aberrations in Chernobyl-related thyroid cancers: implications for possible future nuclear accidents or nuclear attacks

Cases of thyroid cancer among children in Belarus represent a unique model system in which the cause of the cancer is known--radiation. Although other sources of radiation-induced cancers are diminishing (survivors of Hiroshima and Nagasaki, and individuals exposed to diagnostic or therapeutic radiation) fears of radiation exposure from accidents and terrorism are increasing. Our analysis of current data reveals that Chernobyl-related cancer cases might have a specific pattern of genetic aberrations. These data strongly confirm the hypothesis that radiation-induced cancers might arise as a result of specific gene aberrations that are distinct from those in sporadic cancers, suggesting that methods of prevention and treatment of radiation-induced cancers might require a different approach. Understanding of the molecular mechanisms of Chernobyl-related papillary thyroid carcinomas will help to identify mechanisms by which radiation causes aberrations and oncogenic cell transformation. Thus, in turn, it will be important in the development of new treatments or technologies to minimize the effects of radiation damage from nuclear accidents or nuclear attacks.     

WR-1065, the active metabolite of amifostine,mitigates radiation-induced delayed genomic instability

Compounds that can protect cells from the effects of radiation are important for clinical use, in the event of an accidental or terrorist-generated radiation event, and for astronauts traveling in space. One of the major concerns regarding the use of radio-protective agents is that they may protect cells initially, but predispose surviving cells to increased genomic instability later. In this study we used WR-1065, the active metabolite of amifostine, to determine how protection from direct effects of high- and low-LET radiation exposure influences genomic stability. When added 30 min before irradiation and in high concentrations, WR-1065 protected cells from immediate radiation-induced effects as well as from delayed genomic instability. Lower, nontoxic concentrations of WR-1065 did not protect cells from death; however, it was effective in significantly decreasing delayed genomic instability in the progeny of irradiated cells. The observed increase in manganese superoxide dismutase protein levels and activity may provide an explanation for this effect. These results confirm that WR-1065 is protective against both low- and high-LET radiation-induced genomic instability in surviving cells.     

WR-1065, the active metabolite of amifostine, mitigates radiation-induced delayed genomic instability

Compounds that can protect cells from the effects of radiation are important for clinical use, in the event of an accidental or terrorist-generated radiation event, and for astronauts traveling in space. One of the major concerns regarding the use of radio-protective agents is that they may protect cells initially, but predispose surviving cells to increased genomic instability later. In this study we used WR-1065, the active metabolite of amifostine, to determine how protection from direct effects of high- and low-LET radiation exposure influences genomic stability. When added 30 min before irradiation and in high concentrations, WR-1065 protected cells from immediate radiation-induced effects as well as from delayed genomic instability. Lower, nontoxic concentrations of WR-1065 did not protect cells from death; however, it was effective in significantly decreasing delayed genomic instability in the progeny of irradiated cells. The observed increase in manganese superoxide dismutase protein levels and activity may provide an explanation for this effect. These results confirm that WR-1065 is protective against both low- and high-LET radiation-induced genomic instability in surviving cells.