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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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    • "While the availability of a radiation medical countermeasure (R-MCM) in the event of a large scale radiation emergency is critical for saving lives, currently no treatments are approved as R-MCMs by the US Food and Drug Administration (FDA). Since early 1990s, preclinical studies have demonstrated radioprotective and/or radiomitigating properties of various cytokines and cytokine cocktails, but their further clinical development was hindered by adverse reactions [3-5]. A cocktail containing stem cell factor, FMS-like tyrosine kinase 3 ligand, thrombopoietin, and interleukin-3 with or without a long-acting pegylated form of granulocyte-colony stimulating factor (G-CSF) has been shown to improve survival in murine and primate models of acute radiation [6]. "
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    ABSTRACT: The hematopoietic syndrome of the acute radiation syndrome (HSARS) is a life-threatening condition in humans exposed to total body irradiation (TBI); no drugs are approved for treating this condition. Recombinant human interleukin-12 (rHuIL-12) is being developed for HSARS mitigation under the FDA Animal Rule, where efficacy is proven in an appropriate animal model and safety is demonstrated in humans. In this blinded study, rhesus monkeys (9 animals/sex/dose group) were randomized to receive a single subcutaneous injection of placebo (group 1) or rHuIL-12 at doses of 50, 100, 250, or 500 ng/kg (groups 2-5, respectively), without antibiotics, fluids or blood transfusions, 24-25 hours after TBI (700 cGy). Survival rates at Day 60 were 11% , 33% , 39% , 39% , and 50% for groups 1-5, respectively (log rank p < 0.05 for each dose vs. control). rHuIL-12 also significantly reduced the incidences of severe neutropenia, severe thrombocytopenia, and sepsis (positive hemoculture). Additionally, bone marrow regeneration following TBI was significantly greater in monkeys treated with rHuIL-12 than in controls. Data from this study demonstrate that a single injection of rHuIL-12 delivered one day after TBI can significantly increase survival and reduce radiation-induced hematopoietic toxicity and infections. These data significantly advance development of rHuIL-12 toward approval under the Animal Rule as an effective stand-alone medical countermeasure against the lethal effects of radiation exposure.
    Journal of Hematology & Oncology 04/2014; 7(1):31. DOI:10.1186/1756-8722-7-31 · 4.93 Impact Factor
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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; 98(2). 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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