A review of radiation countermeasure work ongoing at the Armed Forces Radiobiology Research Institute.

Department of Radiation Biology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD 20889, USA.
International Journal of Radiation Biology (Impact Factor: 1.84). 12/2011; 88(4):296-310. DOI: 10.3109/09553002.2012.652726
Source: PubMed

ABSTRACT PURPOSE: The hazard of exposure to ionizing radiation is a serious public and military health concern that has justified substantial efforts to develop medically effective radiation countermeasure approaches, including radiation protectors, mitigators, and therapeutics. Although such efforts were initiated more than half a century ago, no safe and effective radiation countermeasure has been approved by the United States Food and Drug Administration (FDA) for the acute radiation syndrome. This situation has prompted intensified research among government laboratories, academic institutions, and pharmaceutical companies to identify a new generation of countermeasures. In this communication we discuss selected promising radiation countermeasures at advanced stages of development. CONCLUSION: Other than granulocyte colony-stimulating factor, which has an Emergency Use Investigational New Drug (IND) status, four countermeasures have FDA IND status and other promising countermeasures are in development. Here we review primarily the in vivo efficacy of selected countermeasures in animal models and clinical studies.

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Available from: Vijay K Singh, Mar 17, 2015
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    • "We have tested several promising radiation countermeasures (5- androstenediol, CBLB502, CBLB612, and CBLB613, tocopherol succinate, and gamma-tocotrienol) and reported stimulation of G-CSF and other cytokines by these drugs in mice and also in nonhuman primates (CBLB502 (Singh et al., 2012a) and gamma-tocotrienol (unpublished observation)). DT3 induces high levels of cytokines comparable to other tocols, which are being developed as radiation countermeasures (GT3 and TS) (Singh et al., 2010, 2011; Kulkarni et al., 2012). "
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    ABSTRACT: The objective of this study was to determine the cytokine induction by delta tocotrienol (DT3, a promising radiation countermeasure) and to investigate the role of granulocyte colony-stimulating factor (G-CSF) in its radioprotective efficacy against ionizing radiation in mice. Multiplex Luminex was used to analyze DT3- and other tocols (gamma-tocotrienol and tocopherol succinate)-induced cytokines in CD2F1 mice. Mice were injected with an optimal dose of DT3 and a G-CSF antibody, and their 30-day survival against cobalt-60 gamma-irradiation was monitored. Neutralization of G-CSF by administration of a G-CSF-specific antibody in DT3-injected mice was investigated by multiplex Luminex. Our data demonstrate that DT3 induced high levels of various cytokines comparable to other tocols being developed as radiation countermeasures. DT3 significantly protected mice against ionizing radiation, and administration of a G-CSF neutralizing antibody to DT3-treated animals resulted in complete abrogation of DT3's radioprotective efficacy and neutralization of G-CSF in peripheral blood. Our study findings suggest that G-CSF induced by DT3 mediates its radioprotective efficacy against ionizing radiation in mice.
    Life sciences 01/2014; DOI:10.1016/j.lfs.2014.01.065 · 2.30 Impact Factor
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    • "Several promising radiation countermea sures under development such as truncated flagellin (CBLB502) [6], mycoplasm a lipopolypept ides (CBLB612 and CBLB613) [25,36], 5-androsten ediol (5-AED) [6], soya isoflavone (genistein) [6], and tocopherol succinate [24] have been shown to induce high levels of G-CSF. Our ongoing studies with various radiation countermeasures have shown a strong correlation between radioprotecti ve efficacy and an increase in certain cytokine s in the circulating blood [6] [37]. "
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    ABSTRACT: This study aimed to determine the role of granulocyte colony-stimulating factor (G-CSF), induced by a promising radiation countermeasure, gamma tocotrienol (GT3), in protecting mice from lethal doses of ionizing radiation. CD2F1 mice were injected with an optimal dose of GT3 and a G-CSF antibody, and their 30-d survival was monitored. An appropriate antibody isotype was used as a control. Multiplex Luminex was used to analyze GT3-induced cytokines. G-CSF neutralization by exogenous administration of a G-CSF antibody was confirmed by analyzing serum cytokine levels. Our results demonstrate that GT3 significantly protected mice against ionizing radiation, and induced high levels of G-CSF in peripheral blood 24h after administration. Injection of a G-CSF neutralizing antibody to the GT3-treated mice resulted in complete neutralization of G-CSF and abrogation of its protective efficacy. Administration of a G-CSF antibody did not affect levels of other cytokines induced by GT3. Histopathology of bone marrow from GT3-treated and -irradiated mice demonstrated protection of the hematopoietic tissue, and also that such protection was abrogated by administering a G-CSF antibody. Our results suggest that induction of high levels of G-CSF by GT3 administration is responsible for its protective efficacy against radiation injury.
    Cytokine 04/2013; 62(2). DOI:10.1016/j.cyto.2013.03.009 · 2.87 Impact Factor
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    ABSTRACT: The bone marrow syndrome represents the most probable manifestation of the acute radiation disease following medical application of ionizing radiation, as well as contingent nuclear accidents. Protection and treatment of marrow damage induced by radiation exposures in the range of sublethal and near lethal doses is, at present, a serious medical problem. Moreover, radiation-induced haematopoietic suppression may serve as a model for studying the effects of other bone marrow damaging factors and medical procedures, including cytostatic chemotherapy. Among the compounds tested as potential stimulators of mammalian haematopoiesis damaged by ionizing radiation in the Institute of Biophysics, Brno, Czech Republic, also clinically available medicaments belonging to non-steroidal anti-inflammatory drugs (NSAIDs) or drugs used in cardiovascular medicine were used. NSAIDs act on the principle of inhibition of prostaglandin production. Prostaglandins operate in negative feedback control of haematopoiesis, especially granulopoiesis. Removal of this feedback enables to enhance production of functional blood cells. Indomethacin, diclofenac, flurbiprofen, and nitroxybutylester of flurbiprofen have been successfully tested as haematopoietic stimulators in irradiated mice. Administration of flurbiprofen nitroxybutylester, a newly synthesized flurbiprofen derivative, appears to be especially promising from the point of view of decreased gastrointestinal toxicity of this compound. Dipyridamole (DP) and adenosine monophosphate (AMP) used clinically for decreasing platelet aggregation (DP) and as vasodilators and cardioprotectors (DP, AMP) operate as enhancers of extracellular concentration of adenosine. Receptor-based extra-cellular action of adenosine has been found to stimulate haematopoiesis on the levels of stem and progenitor cell populations. Interesting results on synergistic action of DP + AMP and granulocyte colony-stimulating factor (G-CSF) on mouse granulopoiesis have been obtained as well. Haematopoiesis-enhancing effects of drugs elevating extracellular adenosine may be of clinical importance both from the point of view of medical benefit as well as from the standpoint of contingent financial savings obtained when using these unexpensive drugs.
    07/2011: pages 421-426;
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