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To date, the United States Food and Drug Administration (FDA) has approved four drugs to mitigate hematopoietic acute radiation syndrome and all four are repurposed radiomitigators. There are several additional drug candidates currently under evaluation that may also be helpful for use during a widespread emergency. One possible candidate is Ex-Rad, also known as ON01210, a chlorobenzyl sulfone derivative (organosulfur compound), which is a novel, small-molecule kinase inhibitor with demonstrated efficacy in the murine model. In this study, we have evaluated the metabolomic and lipidomic profiles in serum samples of nonhuman primates (NHPs) treated with Ex-Rad after exposure to ionizing radiation. Two different dose administration schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation), were used and evaluated using a global molecular profiling approach. We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems.

Tocols induce high levels of granulocyte-colony-stimulating factor (G-CSF). G-CSF mobilises progenitors that allow mice that have been severely immunocompromised by exposure to acute, high-dose ionising irradiation to recover and to survive. The neutralisation of G-CSF abrogates the radioprotective efficacy of tocols. This article reviews studies in which CD2F1 mice were irradiated with sufficiently high doses to cause acute radiation syndrome symptoms and then administered (iv) progenitor-enriched whole blood or peripheral blood mononuclear cells from tocol- and AMD3100-injected donor mice (AMD3100 is a chemokine receptor antagonist used to improve the yield of mobilised progenitors). In some experiments, G-CSF was neutralised completely. Irradiated recipient mice were observed for 30 d post-irradiation for survival, a primary endpoint used for determining therapeutic effectiveness. Additionally, potential tocol-induced biomarkers (cytokines, chemokines and growth factors) were quantified. The authors suggest that tocols are highly effective agents for mobilising progenitors with significant therapeutic potential., (Published by Oxford University Press 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

We showed previously that treatment of gamma-irradiated female B6D2F1 mice with 5-androstenediol (AED) enhanced survival, stimulated myelopoiesis, and ameliorated radiation-induced decreases in circulating neutrophils and platelets. We have now tested survival in male CD2F1 mice, and we have investigated molecular and functional effects on neutrophils and bone marrow stromal cells and screened for toxicity in female B6D2F1 mice. AED (160 mg/kg, subcutaneously, 24 hours before irradiation) enhanced survival in male CD2F1 mice with a dose-reduction factor of 1.23, similar to the dose-reduction factor of 1.26 found previously for female B6D2F1 mice. Expression of CD11b, a developmental marker, was reduced on circulating neutrophils after either in vivo AED administration or whole-body gamma-irradiation (3 Gy), but neutrophil peroxidase activity was unchanged. Stromal cell progenitors (fibroblastoid colony-forming units) were reduced in marrow 5 days after AED injection in nonirradiated mice. Clinical chemistry, histopathology, and behavioral assays showed no evidence of toxicity. We conclude that AED and related steroids are attractive candidates to explore as countermeasures to high- and low-level ionizing radiation.

In attempting to evaluate the possible health consequences of chronic ionizing radiation exposure during extended space travel (e.g., Mars Mission), ground-based experimental studies of the clinical and pathological responses of canines under low daily doses of 60Co gamma irradiation (0.3-26.3 cGy d-1) have been examined. Specific reference was given to responses of the blood forming system. Results suggest that the daily dose rate of 7.5 cGy d-1 represents a threshold below which the hematopoietic system can retain either partial or full trilineal cell-producing capacity (erythropoiesis, myelopoiesis, and megakaryopoiesis) for extended periods of exposure (>1 yr). Trilineal capacity was fully retained for several years of exposure at the lowest dose-rate tested (0.3 cGy d-1) but was completely lost within several hundred days at the highest dose-rate (26.3 cGy d-1). Retention of hematopoietic capacity under chronic exposure has been demonstrated to be mediated by hematopoietic progenitors with acquired radioresistance and repair functions, altered cytogenetics, and cell-cycle characteristics. Radiological, biological, and temporal parameters responsible for these vital acquisitions by hematopoietic progenitors have been partially characterized. These parameters, along with threshold responses, are described and discussed in relation to potential health risks of the space traveler under chronic stress of low-dose irradiation., (Published by Elsevier Science Ltd on behalf of COSPAR.)

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). In our laboratory we have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d-1). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific (three major responding subgroups identified) and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup 1), the failure to augment basic repair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments (particularly marked within erythroid compartments) that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 & 3) appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity. The kinetics of these repair-mediated, regenerative hematopoietic responses within the major subgroups are under study and should provide useful insights into the nature of hematopoietic accommodation (or its failure) under greatly extended periods of chronic, low-daily-dose ionizing radiation exposure.

Male beagles chronically exposed to low daily doses of 60Co gamma rays (7.5 cGy/22h/day) show one of three hematopoietic patterns, which reflect three different distinctly responding subgroups: (1) low radioresistance with progressing aplastic anemia and shortened survival (-S-AA subgroup); (2) high radioresistance with a complex of progressing myeloproliferative disorders (+R-MPD group); or (3) high radioresistance with other nonMPD syndromes (+R-nonMPD group). Blood cell levels (granulocytes, monocytes, erythrocytes, lymphocytes, and platelets) were assessed and fitted to a flexible polynomial spline model, thus defining the (a) initial suppressive and (b) subsequent recovery phases for the subgroups. Results showed that relative to the overall magnitude of blood cell loss as well as to the maximum rate of suppression during the initial phase, the subgroups were generally ranked -S-AA much greater than +R-MPD greater than +R-nonMPD. Relative to the overall strength of the recovery response, the subgroups were generally ranked +R-MPD greater than +R-nonMPD much much greater than -S-AA. In terms of overall maintenance levels of circulating blood cells during the recovery phase, however, the +R-nonMPD subgroup consistently exhibited stronger responses than the +R-MPD subgroup. These results tend to support our contention that selected subgroups of dogs have strong propensities to specific hematopathologies (i.e. aplastic anemia and myeloid leukemia) under chronic irradiation and that these pathology-prone animals exhibit a series of marked differential hematopoietic responses during early preclinical phases, which serve effectively to prognosticate subsequent pathological progression.