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  Countermeasure Development

2014 AFRRI Seminars

USU Dept. of Radiation Biology
You are here:  HOME  >  Research Programs  >  Countermeasure Development

Countermeasure Development

Jump to:  Strategic plan | Summary | Background | Previous work at AFRRI | Recent accomplishments: 5-androstene steroids | Animal models | Antibiotics | Cellular therapies | Cytokines and growth factors | Delayed effects | Enzyme mimetics and inhibitors | EX-RAD® | Guidance and reviews | Mechanisms of injury and recovery | Nutraceuticals | Radiation quality | Thiols | Toll-like receptor agonists
Overview  

Mission: To develop pharmacological countermeasures to radiation injury that can be used by military personnel and emergency responders.

Principal Investigators: Sanchita P. Ghosh, PhD; Michael R. Landauer, PhD; R. Joel Lowy, PhD; Alexandra C. Miller, PhD; Maria Moroni, PhD; Natalia I. Ossetrova, PhD; Vijay K. Singh, PhD; Venkataraman Srinivasan, PhD; Mark H. Whitnall, PhD; Mang Xiao, MD

Staff: Shukla Biswass; Georgetta Cannon, PhD; Lynnette H. Cary, PhD; Stuart Cohen, MAJ, USA, PhD; Donald Condliffe; Opeyimi (Opi) Fadiyimu, HM2, USN; Oluseyi O. Fatanmi; Carolyn J. Fisher, PhD; Dadin Fu, PhD; Esmeralda Gutierrez; Cam T. Ha, PhD; Kevin Hieber; Erin Horton; John E. Karaian; Katya Krasnopolsky; Janeen Lewis; Xianghong Li, MS; Robert McMahon, MAJ, USA; Virginia Menendez-Morales; Michelle Metrinko; Karvelisse Miller, Sgt, USAF; Patrick Ney; Victoria L. Newman; Hayley Nordstrom; Dilbert Nurmemet; Saule Nurmukhambetova; Arifur Rahman, PhD; Phyllis Reese, MS; Rafael Rivas; Patricia L.P. Romaine; Merriline Satyamitra, PhD; Jessica R.D. Scott; Sibyl Swift, PhD; Treniece Terry, PhD; Melissa Tompkins; Stephen Y. Wise

Radiation Countermeasures Symposium
 
Strategic plan
  1. Develop a better understanding of the biology of radiation injury and radiation countermeasure drugs.
  2. Use knowledge of processes involved in radiation injury and countermeasures to identify and assess novel drug candidates.
  3. Collaborate proactively with other research institutions, pharmaceutical firms, and government agencies to develop and obtain approval for radiation countermeasures for use in the field and the clinic.
Summary
  1. Seven radiation countermeasures for the Acute Radiation Syndrome (ARS) have US Food and Drug Administration (FDA) Investigational New Drug (IND) status, meaning they can be tested in the U.S. for safety in humans.
  2. These are 5-androstenediol (5-AED, Neumune), genistein (BIO300), Ex-Rad®, toll-like receptor 5 agonist CBLB502 (Entolimod), a corticosteroid (OrbeShield™), IL-12 (Hemamax™) and G-CSF (filgrastim, Neupogen®).
  3. Neupogen®, would be used in a nuclear/radiological emergency under an Emergency Use Authorization (EUA) approved by the FDA.
  4. AFRRI has been involved in the development of five of these seven agents.
  5. 5-AED and genistein were conceived and initially developed as countermeasures at AFRRI.
  6. Ex-Rad® and CBLB502 were initiated at private companies; AFRRI collaborated at early stages.
  7. AFRRI performed the earliest work on cytokines and growth factors as radiation countermeasures. This led to inclusion of Neupogen® in the Strategic National Stockpile.
  8. AFRRI is involved in evaluating hematopoietic progenitor cells as a radiation countermeasure. This therapy could be given days after an incident, when there is a chance significant numbers of casualties could be evacuated to medical facilities.
  9. Other promising AFRRI agents are tocols (Vitamin E), and dual-use drugs that address both the ARS and late effects such as cancer.
  10. Policy questions revolve around planning for particular disaster scenarios, timing and routes of drug administration, priorities of various classes of agents, addressing specific ARS subsyndromes, and funding allocations.
  11. Radiation countermeasure candidates tested for efficacy at AFRRI are chosen based on extensive basic research, which increases chances of success.
  12. AFRRI has an ongoing in vivo efficacy screening program and is frequently approached by organizations for research collaboration and/or consultation regarding their promising countermeasure candidates.
  13. The screening program is supplemented by a robust mechanistic research program that provides supporting data for approval of existing drugs and identifies potential drug targets.
  14. Nuclear detonations produce a mixture of neutrons and gamma rays. However, radiation countermeasures generally have been tested against only gamma rays or X-rays. AFRRI possesses a research nuclear reactor that produces mixed neutron/gamma fields that mimic those produced by nuclear detonations. Using this reactor, AFRRI has shown that some radiation countermeasures effective against gamma rays are not effective against mixed neutron/gamma fields.
  15. In addition to the standard animal models for studying radiation injury and countermeasures, AFRRI is developing an alternative large animal model: the minipig. This will facilitate advanced development of radiation countermeasures.
  16. AFRRI has a history of collaborating with private companies, providing supporting data for FDA applications, and attending meetings with the FDA and other government agencies as appropriate.
  17. AFRRI's mission covers research up to the IND stage. Advanced development of AFRRI products after IND approval is carried out by private companies or other government agencies.
  18. AFRRI participates in national and international panels that guide policy and funding for radiation countermeasures.
Background
  1. Ionizing radiation at certain doses damages the blood-forming system.
  2. This results in fewer blood cells and platelets in the circulatory system.
  3. White blood cells form part of the immune system: they attack infectious microorganisms. Platelets form clots and prevent uncontrolled bleeding.
  4. Therefore, susceptibility to infection and hemorrhage increase after exposure to radiation.
  5. These can cause death at a certain range of radiation doses (hematopoietic syndrome). Higher radiation doses cause death by damaging the gastrointestinal (GI) system or the central nervous system. There is some overlap: mortality due to the hematopoietic syndrome can be exacerbated by compromise of the GI barrier to bacteria.
  6. The concepts of sub-syndromes such as hematopoietic syndrome and GI syndrome now are being influenced by an appreciation of inter-tissue communication and synergies during ARS. Although the sub-syndrome terminology can be useful in some contexts, it is recognized that mortality is due to multi-organ dysfunction leading to multi-organ failure.
  7. Lower doses of radiation can increase the probability of cancer. (The probability of late effects such as cancer would also increase after higher radiation doses, in people who survived the acute effects.)
  8. Possible countermeasures to ionizing radiation can be broadly categorized into three groups.
    1. Drugs that prevent the initial radiation injury
      1. Free radical scavengers and antioxidants
      2. Hypoxia
      3. Enzymatic detoxification
      4. Oncogene targeting agents
    2. Drugs that repair the molecular damage caused by radiation
      1. Hydrogen transfer
      2. Enzymatic repair
    3. Drugs that stimulate proliferation of surviving stem and progenitor cells
      1. Immunomodulators
      2. Growth factors and cytokines
  9. Military personnel and emergency responders urgently need nontoxic countermeasures to ionizing radiation.
  10. The only approved countermeasures that can be used in the field are drugs that block the effects of several specific internalized radioisotopes. There are no approved drugs that can be used outside the clinic to ameliorate the effects of external ionizing radiation on the blood-forming or GI systems.
  11. The availability of medical facilities for radiation casualties after a nuclear detonation near a city will be problematic:
    1. Bell WC, Dallas CE. 2007. Intl J Health Geographics 6:5
    2. British Medical Association's Board of Science and Education. 1983, The Medical Effects of Nuclear War, John Wiley & Sons, New York.
    3. Holdstock D, Waterston L. 2000. Lancet 355:1544–1547
    4. Flynn DF, Goans RE. 2006. Surg Clin North Am 86:601–636
  12. In light of the logistical realities of likely nuclear disaster scenarios, much of our current focus is on drug candidates with extremely low toxicity and ease of administration, suitable for use outside the clinic without physician supervision.
TOP OF PAGE
Previous work at AFRRI
AFRRI researchers have examined the efficacy, toxicity, and mechanisms of a number of radiation countermeasure candidates over the years. Three lines of investigation in particular have strongly influenced current practice:
  1. Weiss, Kumar, Landauer, and co-workers performed a series of studies on the toxicity of the previous "gold standard," amifostine. The effects of drug combinations on efficacy and toxicity were explored.
    1. Environmental Health Perspectives 105 Suppl 6: 1473–1478, 1997
    2. Advances in Space Research 12: 273–283, 1992
    3. Pharmacology and Therapeutics 39: 97–100, 1988
    4. Free Radicals Research Communications 3: 33–38, 1987
    5. Radiation Research 104: 182–190, 1985
  2. Neta and co-workers introduced the concept of using cytokines as radiation countermeasures. Experiments were done to determine the radioprotective roles of various cytokines in signaling cascades.
    1. Journal of Immunology 153: 1536–1543, 1994
    2. Journal of Immunology 153: 4230–4237, 1994
    3. Journal of Experimental Medicine 175: 689–694, 1992
    4. Journal of Experimental Medicine 173: 1177–1182, 1991
    5. Blood 76: 57–62, 1990
    6. Journal of Immunology 136: 2483–2485, 1986
    7. Journal of Immunology 140: 108–111, 1988
  3. MacVittie and co-workers expanded the study of cytokines to large animals. This work led directly to the current standard practice of administering G-CSF or GM-CSF off-label to radiation victims.
    1. Health Physics 89: 546–555, 2005
    2. Journal of Clinical Investigation 97: 2145–2151, 1996
    3. Blood 87: 4129–4135, 1996
    4. Hendry JH, Lord BI (eds): Radiation Toxicology: Bone Marrow and Leukaemia. London, Taylor and Francis, 1995, pp 141–194
    5. Blood 82: 3012-3018, 1993
    6. International Journal of Radiation Biology 57: 723–736, 1990
    7. Experimental Hematology 16: 344–348, 1988
TOP OF PAGE
Recent accomplishments
  1. 5-androstene steroids (first IND for an ARS countermeasure)
    1. 2012—Grace MB, Singh VK, Rhee JG, Jackson WE III, Kao T-C, Whitnall MH. 5-AED enhances survival of irradiated mice in a G-CSF-dependent manner, stimulates innate immune cell function, reduces radiation-induced DNA damage and induces genes that modulate cell cycle progression and apoptosis, J Rad Res. 53:840–853. doi: 10.1093/jrr/rrs060.
    2. 2008—Singh VK, Grace MB, Jacobsen KO, Chang CM, Parekh VI, Inal CE, Shafran RL, Whitnall AD, Kao TC, Jackson WE 3rd, Whitnall MH. Administration of 5-androstenediol to mice: Pharmacokinetics and cytokine gene expression, Exp Mol Pathol. 84:178–188.
    3. 2007—Xiao M, Inal CE, Parekh VI, Chang CM, Whitnall MH. 5-Androstenediol promotes survival of gamma-irradiated human hematopoietic progenitors through induction of nuclear factor-kappaB activation and granulocyte colony-stimulating factor expression, Mol Pharmacol. 72:370–379.
    4. 2007—Stickney DR, Dowding C, Authier S, Garsd A, Onizuka-Handa N, Reading C, Frincke JM. 5-androstenediol improves survival in clinically unsupported rhesus monkeys with radiation-induced myelosuppression, Int Immunopharmacol. 7: 500–505.
    5. 2006—Stickney DR, Dowding C, Garsd A, Ahlem C, Whitnall M, McKeon M, Reading C, Frincke J. 5-androstenediol stimulates multilineage hematopoiesis in rhesus monkeys with radiation-induced myelosuppression (Int Immunopharmacol. 6: 1706–1713.
    6. 2005—Singh VK, Shafran RL, Inal CE, Jackson WE 3rd, Whitnall MH. Effects of whole-body gamma irradiation and 5-androstenediol administration on serum G-CSF, Immunopharmacol Immunotoxicol. 27: 521–534.
    7. 2005—U.S. Food and Drug Administration (FDA) granted Investigational New Drug (IND) status to 5-Androstenediol (NEUMUNE™), i.e., the FDA determined it was safe to proceed with Phase I clinical trials in the United States. A Phase I trial was already underway in the Netherlands.
    8. 2005—Whitnall MH, Villa V, Seed TM, Benjack J, Miner V, Lewbart ML, Dowding CA, Jackson WE 3rd. Molecular specificity of 5-androstenediol as a systemic radioprotectant in mice, Immunopharmacol Immunotoxicol. 27: 15–32.
    9. 2002—Entered into Cooperative Research and Development Agreement (CRADA) with Hollis-Eden Pharmaceuticals to jointly develop 5-androstenediol (referred to as HE2100 or NEUMUNE™) for eventual approval as a radiation countermeasure by the Food and Drug Administration (FDA).
    10. 2002—Whitnall MH, Wilhelmsen CL, McKinney L, Miner V, Seed TM, Jackson WE 3rd. Radioprotective efficacy and acute toxicity of 5-androstenediol after subcutaneous or oral administration in mice, Immunopharmacol Immunotoxicol. 24: 595–626.
    11. 2001—Whitnall MH, Inal CE, Jackson WE 3rd, Miner VL, Villa V, Seed TM. In vivo radioprotection by 5-androstenediol: Stimulation of the innate immune system, J Radiat Res. 156: 283–293.
    12. 2000—Whitnall MH, Elliott TB, Harding RA, Inal CE, Landauer MR, Wilhelmsen CL, McKinney L, Miner VL, Jackson WE 3rd, Loria RM, Ledney GD, Seed TM. Androstenediol stimulates myelopoiesis and enhances resistance to infection in gamma-irradiated mice, Int J Immunopharmacol 22: 1–14.

      Marrow treated with F-AED        Marrow treated with a placebo
      Bone marrow from a mouse treated with 5-AED (above, left), compared with marrow from a mouse treated with placebo (right). The many small, round, dark objects in the control section are nuclei in progenitors of red blood cells. Progenitors of granulocytes (mostly neutrophils) and monocytes possess lighter nuclei, often horseshoe-shaped. Four days after 5-AED treatment, there was a proliferation of granulocyte/ monocyte progenitors.

  2. Animal models
    1. 2014—Moroni M, Elliott TB, Deutz NE, Olsen CH, Owens R, Christensen C, Lombardini E, Whitnall MH. Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal acute radiation syndrome (GI)-ARS: Early hematological changes and systemic inflammatory response syndrome in minipig. Int J of Radiat Biol (in press).
    2. 2013—Moroni M, Whitnall MH. Gottingen minipig model of the acute radiation syndrome. In: Proceedings of NATO RTO HFM-223 Symposium "Biological Effects of Ionizing Radiation Exposure and Countermeasures: Current Status and Future Perspectives," Slovenia 2012. www.cso.nato.int/Pubs/rdp.asp?RDP=STO-MP-HFM-223
    3. 2013—Moroni M, Ngudiankama BF, Christensen C, Olsen CH, Owens R, Lombardini ED, Holt RK, Whitnall MH. The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body γ-irradiation. Int J Radiat Oncol Biol Phys. 86(5):986–992.
    4. 2013—Moroni M, Maeda D, Whitnall MH, Bonner WM, Redon CE. Evaluation of the gamma-H2AX assay for radiation biodosimetry in a swine model. Int J Mol Sci. 14:14119–14135, doi:10.3390/ijms140714119.
    5. 2012—Hulet SW, Moroni M, Whitnall MH and Mioduszewski RJ. The minipig in chemical, biological, and radiological research. In: McAnulty PA, Dayan AD, Ganderup NC, Hastings KL (eds.) The Minipig in Biomedical Research. CRC Press, Boca Raton, FL: 533–547.
    6. 2011—Moroni M, Lombardini E, Salber R, Kazemzedeh M, Nagy V, Olsen C, Whitnall MH. Hematological changes as prognostic indicators of survival: Similarities between Gottingen minipigs, humans, and other large animal models. PLoS ONE. 2011;6:e25210. Epub 2011 Sep 28.
    7. 2011—Moroni M, Coolbaugh TV, Lombardini ED, Mitchell JM, Moccia KD, Shelton LJ, Nagy V, Whitnall MH. Hematopoietic radiation syndrome in the Gottingen minipig, Radiat Res. 176:89-101.
    8. 2011—Moroni M, Coolbaugh TV, Mitchell JM, Lombardini E, Moccia KD, Shelton LJ, Nagy V, Whitnall MH. Vascular access port implantation and serial blood sampling in a Gottingen minipig (Sus scrofa domestica) model of acute radiation injury, J Am Assoc Lab Anim Sci. 50:65–72.
    9. 2010—Moccia KD, Olsen CH, Mitchell JM, Landauer MR. Evaluation of hydration and nutritional gels as supportive care after total-body irradiation in mice (Mus musculus), J Am Assoc Lab Anim Sci. 49:323–328.
    10. 2007—Parra NC, Ege CA, Ledney GD. Retrospective analyses of serum lipids and lipoproteins and severity of disease in 60Co-irradiated Sus scrofa domestica and Macaca mulatta, Comp Med 57:298–304.
    11. 2006—Ege CA, Parra NC, Johnson TE. Noninfectious complications due to vascular access ports (VAPs) in Yucatan minipigs (Sus scrofa domestica), J Am Assoc Lab Anim Sci. 45:27–34.
    12. 2004—Jacobsen KO, Villa V, Miner VL, Whitnall MH. Effects of anesthesia and vehicle injection on circulating blood elements in C3H/HeN male mice, Contemporary Topics 43: 9–14.
  3. Antibiotics
    1. 2002—Kumar KS, Srinivasan V, Toles RE, Miner VL, Jackson WE, Seed TM. High-dose antibiotic therapy is superior to a 3-drug combination of prostanoids and lipid A derivative in protecting irradiated canines. J Radiat Res. 43:361–370.
  4. Cellular therapies
    1. 2012—Singh VK, Christensen J, Fatanmi OO, Gille D, Ducey EJ, Wise SY, Karsunky H, Sedello AK. Myeloid progenitors: A radiation countermeasure that is effective when initiated days after irradiation. J Radiat Res. 177:781–791.
    2. 2011—Singh, VK, Brown, DS, Singh, PK, Seed, TM. Progenitor cells as a bridging therapy for radiation casualties. Defence Science Journal 61: 118–124.
  5. Cytokines and growth factors
    1. 2012—Singh VK, Fatanmi OO, Singh PK, Whitnall MH. Role of radiation-induced granulocyte colony-stimulating factor in recovery from whole body gamma-irradiation. Cytokine. 58:406–414. Epub 2012 Apr 8.
    2. 2011—Satyamitra M, Lombardini E, Graves J, Mullaney C, Ney P, Hunter J, Johnson K, Tamburini P, Wang Y, Springhorn JP, Srinivasan V. A TPO receptor agonist, ALXN4100TPO, mitigates radiation-induced lethality and stimulates hematopoiesis in CD2F1 mice, J Radiat Res. 175(6):746–58.
    3. 2005—Singh VK, Srinivasan V, Seed TM, Jackson WE, Miner VE, Kumar KS. Radioprotection by N-palmitoylated nonapeptide of human interleukin-1beta, Peptides 26:413–418.
  6. Delayed effects
    1. 2011—Miller AC, Cohen S, Stewart M, Rivas R, Lison P. Radioprotection by the histone deacetylase inhibitor phenylbutyrate. Radiat Environ Biophys. 50:585–96. Epub 2011 Sep 3.
    2. 2002—Miller AC, Ainsworth EJ, Lui L, Wang TJ, Seed TM. Development of chemopreventive strategies for radiation-induced cancer: Targeting radiation-induced genetic alterations, Mil Med. 167 Suppl. 1: 54–56.
  7. Enzyme mimetics and inhibitors
    1. 2010—Davis TA, Landauer MR, Mog SR, Barshishat-Kupper M, Zins SR, Amare MF, Day RM. Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation, Exp Hematol. 38:270–281.
    2. 2008—Srinivasan V, Doctrow S, Singh VK, Whitnall MH. Evaluation of EUK-189, a synthetic superoxide dismutase/catalase mimetic as a radiation countermeasure, Immunopharmacol Immunotoxicol. 30:271–290.
  8. Ex-RAD®
    1. 2012—Ghosh SP, Kulkarni S, Perkins MW, Hieber K, Pessu RL, Gambles K, Maniar M, Kao T-C, Seed TM, Kumar KS. Amelioration of radiation-induced hematopoietic and gastrointestinal damage by Ex-RAD® in mice. J Radiat Res. doi: 10.1093/jrr/rrs001.
    2. 2009—Ghosh SP, Perkins MW, Hieber K, Kulkarni S, Kao T-C, Reddy EP, Reddy MVR, Maniar M, Seed T, Kumar KS. Radiation protection by a new chemical entity, Ex-Rad™: Efficacy and mechanism, Radiation Research 171:173–179.
    3. 2008—Ex-RAD® obtained IND status with the FDA as an acute radiation syndrome countermeasure.
  9. Guidance and reviews
    1. 2013—Kumar KS, Kiang JG, Whitnall MH, Hauer-Jensen M. Perspectives in radiological and nuclear countermeasures. In: Textbook of Military Medicine: Medical Consequences of Radiological and Nuclear Weapons. Department of Defense, Office of The Surgeon General, US Army, Borden Institute, Washington, DC.
    2. 2013—Whitnall MH. Mitigating radiation adverse effects: State of the art and challenges. In: Proceedings of NATO RTO HFM-223 Symposium "Biological Effects of Ionizing Radiation Exposure and Countermeasures: Current Status and Future Perspectives," Slovenia 2012. www.cso.nato.int/Pubs/rdp.asp?RDP=STO-MP-HFM-223
    3. 2012—Singh VK, Ducey EJ, Brown DS, Whitnall MH. A review of radiation countermeasure work ongoing at the Armed Forces Radiobiology Research Institute. Int J Radiat Biol. 88(4):296-310. Epub 2012 Feb 9.
    4. 2012—Whitnall MH, Ngudiankama BF, Cary LH, Moroni M, Landauer MR, Singh VK, Ghosh SP, Kumar KS, Miller AC, Srinivasan V, Xiao M. United States Armed Forces Radiobiology Research Institute countermeasures program and related policy questions. In: Report from the 2011 Hirosaki University Radiation Emergency Medicine International Symposiumm, page 40.
    5. 2011—Chang CM, Ghosh SP, Grace MB, Hauer-Jensen M, Kao TC, Kumar KS, Landauer MR, Miller AC, Mog SR, Pellmar TC, Singh VK, Srinivasan V, Whitnall MH, Xiao M. Chapter 9—Prophylaxis and therapy. In NATO RTO Technical Report, HFM Panel-099 RTG-033 Activity: Radiation Bioeffects and Countermeasures, pp 9.1–9.21.
    6. 2009—Weiss JF, Landauer MR. History and development of radiation-protective agents, Int J Radiat Biol. 2009 Jul;85(7):539–73.
    7. 2009—Xiao M, Whitnall MH. Pharmacological countermeasures for the acute radiation syndrome, Curr Mol Pharmacol. 2(1):122–133.
    8. 2008—Pellmar TC. Development of Radiation Countermeasures. In: Voeller JG (ed), Wiley Handbook of Science and Technology for Homeland Security, John Wiley & Sons, Inc. ISBN: 978-0-471-76130-3.
    9. 2008—Hauer-Jensen M, Kumar KS, Wang J. Intestinal Toxicity in Radiation and Combined Injury: Significance, Mechanisms, and Countermeasures. In: Larche RA (ed), Global Terrorism Issues and Developments, Nova Science Publishers, Inc., pp. 61–100. ISBN: 978-1600219306.
    10. 2007—Jarrett DG, Sedlak RG, Dickerson WE, Reeves GI. Medical treatment of radiation injuries—current U.S. status, Radiat Meas. 42(6–7):1063–1074
    11. 2007—Whitnall MH, Pellmar TC. New directions in development of pharmacological countermeasures for the acute radiation syndrome. In: Kasid UN, Notario V, Haimovitz-Friedman A, and Bar-Eli M (eds), Reviews in Cancer Biology & Therapeutics, Kerala, India: Transworld Research Network, 193–209; ISBN: 978-81-7895-285-7.
    12. 2006—Pellmar TC. Radiological/Nuclear Preparedness. Military Medical Technology, Online Edition, 10(3).
    13. 2005—Singh VK, Yadav VS. Role of cytokines and growth factors in radioprotection, Exp Mol Pathol. 78(2):156–169.
    14. 2005—Pellmar TC, Rockwell S, Radiological/Nuclear Threat Countermeasures Working Group. Priority list of research areas for radiological nuclear threat countermeasures, J Radiat Res. 163:115–123.
    15. 2005—Goans RE, Waselenko JK. Medical management of radiological casualties, Health Phys. 89(5):505–512.
    16. 2005—Augustine AD, Gondre-Lewis T, McBride W, Miller L, Pellmar TC, Rockwell S. Animal models for radiation injury, protection and therapy, J Radiat Res. 164:100–109.
    17. 2004—Coleman CN, Stone HB, Moulder JE, Pellmar TC. Medicine. Modulation of radiation injury, Science 304(5671):693–694.
    18. 2004—Stone HB, Moulder JE, Coleman CN, Ang KK, Anscher MS, Barcellos-Hoff MH, Dynan WS, Fike JR, Grdina DJ, Greenberger JS, Hauer-Jensen M, Hill RP, Kolesnick RN, Macvittie TJ, Marks C, McBride WH, Metting N, Pellmar T, Purucker M, Robbins ME, Schiestl RH, Seed TM, Tomaszewski JE, Travis EL, Wallner PE, Wolpert M, Zaharevitz D. Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3–4, 2003, J Radiat Res. 162(6):711–728.
    19. 2004—Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman N, Seed T, Lowry P, Armitage JO, Dainiak N. Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group, Ann Intern Med. 140: 1037–1051.
    20. 2003—Weiss JF, Landauer MR. Protection against ionizing radiation by antioxidant nutrients and phytochemicals, Toxicology 189:1–20.
    21. 2002—Seed TM, Fry SA, Neta R, Weiss JF, Jarrett DG, Thomassen D. Prevention and treatments: summary statement, Mil Med. 167(2 Suppl):87–93.
    22. 2000—Weiss JF, Landauer MR. Radioprotection by antioxidants, Ann NY Acad Sci 899:44–60.
  10. Mechanisms of injury and recovery
    1. 2013—Ghosh SP, Singh R, Chakraborty K, Kulkarni S, Uppal A, Luo Y, Kaur P, Pathak R, Kumar KS, Hauer-Jensen M, Cheema AK. Metabolomic changes in gastrointestinal tissues after whole body radiation in a murine model. Mol BioSyst. [Epub ahead of print]. (doi: 10.1039/c3mb25454b)
    2. 2012—Li XH, Ha CT, Fu D, Xiao M. Micro-RNA30c negatively regulates REDD1 expression in human hematopoietic and osteoblast cells after gamma-irradiation. PLoS One. 7(11):e48700. doi: 10.1371/journal.pone.0048700.
    3. 2012—Li XH, Ha CT, Fu D, Xiao M. REDD1 protects osteoblast cells from gamma radiation-induced premature senescence. PLoS ONE. 2012;7(5): e36604.
    4. 2010—Cui L, Pierce D, Light KE, Melchert RB, Fu Q, Kumar KS, Hauer-Jensen M. Sublethal total body irradiation leads to early cerebellar damage and oxidative stress, Curr Neurovasc Res. 7:125–35.
    5. 2010—Garg S, Boerma M, Wang J, Fu Q, Loose DS, Kumar KS, Hauer-Jensen M. Influence of sublethal total-body irradiation on immune cell populations in the intestinal mucosa, J Radiat Res. 173:469–478.
    6. 2009—Xiao M, Inal CE, Parekh VI, Li XH, Whitnall MH. Role of NF-kappaB in hematopoietic niche function of osteoblasts after radiation injury, Experimental Hematology 37:52–64.
  11. Nutraceuticals
    1. Genistein
      1. 2013—Ha CT, Li XH, Fu D, Xiao M, Landauer MR. Genistein nanoparticles protect mouse hematopoietic system and prevent proinflammatory factors after gamma irradiation. Radiat Res. 180:316–325. doi: 10.1667/RR3326.1.
      2. 2013—Day RM, Davis TA, Barshishat-Kupper M, McCart EA, Tipton AJ, Landauer MR. Enhanced hematopoietic protection from radiation by the combination of genistein and captopril. Int Immunopharmacol. pii: S1567–5769(13)00002-7. doi: 10.1016/j.intimp.2012.12.029. [Epub ahead of print]
      3. 2009—Singh VK, Grace MB, Parekh VI, Whitnall MH, Landauer MR. Effects of genistein administration on cytokine induction in whole-body gamma irradiated mice, Int Immunopharmacol. 9:1401–1410.
      4. 2008—Day RM, Barshishat-Kupper M, Mog SR, McCart EA, Prasanna PGS, Davis TA, Landauer MR. Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation, Radiation Research 49:361–372.
      5. 2008—Landauer MR. Radioprotection by the soy isoflavone genistein. In: R. Arora (ed), Herbal Radiomodulators: Applications in Medicine, Homeland Defense and Space, Wallingford, England: CABI Publishing, 163–173; ISBN: 978-1845933951.
      6. 2007—Grace MB, Blakely WF, Landauer MR. Genistein-induced alterations of radiation-responsive gene expression, Radiation Measurements 42:1152–1157.
      7. 2007—Davis TA, Clarke TK, Mog SR, Landauer MR. Subcutaneous administration of genistein prior to lethal irradiation supports multilineage, hematopoietic progenitor cell recovery and survival, International Journal of Radiation Biology 83:141–151.
      8. 2007 (Jan.)—The Food and Drug Administration granted Investigational New Drug (IND) status to genistein (BIO-300), a Humanetics radiation countermeasure developed at the Armed Forces Radiobiology Research Institute with collaborators at the National Institutes of Health (NIH).
      9. 2005 and 2003—Entered into Cooperative Research and Development Agreements (CRADAs) with Humanetics Corporation to jointly develop oral agents that show promise in supporting and protecting the immune system against challenges from exposure to radiation.
      10. 2003—Landauer MR, Srinivasan V, Seed TM. Genistein treatment protects mice from ionizing radiation injury, Journal of Applied Toxicology, 23:379–385.
    2. Tetrahydrobiopterin
      1. 2013—Pathak R, Pawar SA, Fu Q, Gupta PK, Berbée M, Garg S, Sridharan V, Wang W, Biju PJ, Krager KJ, Boerma M, Ghosh SP, Cheema AK, Hendrickson HP, Aykin-Burns N, Hauer-Jensen M. Characterization of transgenic Gfrp knock-in mice: Implications for tetrahydrobiopterin in modulation of normal tissue radiation responses. Antioxidants and Redox Signaling. doi: 10.1089/ars.2012.5025 [Epub ahead of print].
      2. 2010—Berbée M, Fu Q, Kumar KS, Hauer-Jensen M. Novel strategies to ameliorate radiation injury: A possible role for tetrahydrobiopterin, Curr Drug Targets. 11:1366–74.
    3. Tocols (Vitamin E components and analogs)
      1. 2014—Singh VK, Wise SY, Scott JR, Romaine, LP, Newman VL, Fatanmi OO. Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor. Life Sci. 98:113–122.
      2. 2014—Singh VK, Wise SY, Fatanmi OO, Beattie, L, Seed TM. Preclinical development of a bridging therapy for radiation casualities. Health Physics (in press).
      3. 2014—Singh VK, Wise SY, Fatanmi OO, Beattie L, Ducey EJ, Seed TM. Alpha-tocopherol succinate- and AMD3100-mobilized progenitors mitigate radiation combined injury in mice. J. Radiat. Res. 55:41–53.
      4. 2013—Compadre CM, Singh A, Thakkar S, Zheng G, Breen PH, Ghosh S, Kiaie M, Boerma M, Varughese KI, Hauer-Jensen M (2013) Molecular dynamics guided design of tocoflexol: A new radioprotectant tocotrienol with enhanced bioavailability. Drug Develop Res. 75:10–22.
      5. 2013—Li XH, Ghosh SP, Ha CT, Fu D, Elliott TB, Bolduc DL, Villa V, Whitnall MH, Landauer MR, Xiao M. Delta-tocotrienol protects mice from radiation-induced gastrointestinal injury. Radiat Res. 180:649–657.
      6. 2013—Suman S, Datta K, Chakraborty K, Kulkarni SS, Doiron K, Fornace AJ Jr, Sree Kumar K, Hauer-Jensen M, Ghosh SP. Gamma tocotrienol, a potent radioprotector, preferentially upregulates expression of anti-apoptotic genes to promote intestinal cell survival. Food Chem Toxicol. 60:488–96. doi: 10.1016/j.fct.2013.08.011.
      7. 2013—Kulkarni S, Chaikraborty K, Kumar KS, Kao T-C, Hauer-Jensen M, Ghosh SP. Synergistic radioprotection by gamma-tocotrienol and pentoxifylline: Role of cAMP signaling. ISRN Radiology, Volume 2013, article ID 390379.
      8. 2013—Kulkarni S, Singh PK, Ghosh S, Posarac A, Singh VK. Granulocyte colony-stimulating factor antibody abrogates radioprotective efficacy of gamma-tocotrienol, a promising radiation countermeasure. Cytokine 62:278–285.
      9. 2013—Ray S, Kulkarni SS, Chakraborty K, Pessu R, Hauer-Jensen M, Kumar KS, Ghosh SP. Mobilization of progenitor cells into peripheral blood by gamma-tocotrienol: A promising radiation countermeasure. Int Immunopharmacol. 2013 Feb 12. pii:S1567–5769(13)00037–4. doi:10.1016/j.intimp.2012.12.034. [Epub ahead of print].
      10. 2013—Singh VK, Beattie L, Seed TM. Vitamin E: Tocopherols and tocotrienols as potential radiation countermeasures. J Radiat Res. 54:973–988.
      11. 2013—Singh VK, Singh PK, Wise SY, Posarac A, Fatanmi OO. Radioprotective properties of tocopherol succinate against ionizing radiation in mice. J Radiat Res. 54:210–220. doi: 10.1093/jrr/rrs088.
      12. 2013—Singh VK, Wise SY, Singh PK, Posarac A, OO Fatanmi, Ducey EJ, Bolduc DL, Elliott TB, Seed TM. Alpha-tocopherol succinate-mobilized progenitors improve intestinal integrity after whole body irradiation. Int J Rad Biol. 89: 334–345. doi:10.3109/09553002.2013.762137.
      13. 2012—Singh A, Breen PJ, Ghosh SP, Kumar KS, Varughese KI, Crooks PA, Hauer-Jensen M, and Compadre CM. Structural modifications of tocotrienols to improve bioavailability. In Tocotrienols: Vitamin E beyond tocopherols, Boca Raton: CRC Press, 359-370.
      14. 2012—Kulkarni SS, Cary LH, Gambles K, Hauer-Jensen M, Kumar KS, Ghosh SP. Gamma-tocotrienol, a radiation prophylaxis agent, induces high levels of granulocyte colony-stimulating factor. Int Immunopharmacol. 14:495–503.
      15. 2012—Satyamitra M, Ney P, Graves J, Mullaney C, V Srinivasan V. Mechanism of radioprotection by δ-tocotrienol: Pharmacokinetics, pharmacodynamics and modulation of signalling pathways. Br J Radiol. 2012 Jun 6. [Epub ahead of print].
      16. 2012—Singh PK, Wise SY, Ducey EJ, Fatanmi OO, Elliott TB, Singh VK. α-Tocopherol succinate protects mice against radiation-induced gastrointestinal injury. J Radiat Res. 177:133–45. Epub 2011 Oct 20.
      17. 2012—Singh VK, Wise SY, Singh PK, Ducey EJ, Fatanmi OO, Seed TM. α-Tocopherol succinate and AMD3100-mobilized progenitors mitigate radiation-induced gastrointestinal injury in mice. Exp Hematol. 40:407–417. Epub 2012 Jan 10.
      18. 2011—Satyamitra MM, Kulkarni S, Ghosh SP, Mullaney CP, Condliffe D, Srinivasan V. Hematopoietic recovery and amelioration of radiation-induced lethality by the Vitamin E isoform δ-tocotrienol, J Radiat Res. 175:736–45.
      19. 2011—Singh PK, Wise SY, Ducey EJ, Brown DS, Singh VK. Radioprotective efficacy of tocopherol succinate is mediated through granulocyte-colony stimulating factor. Cytokine. 56:411–21.
      20. 2011—Singh VK, Brown DS, Singh PK, Seed TM. Progenitor cells as a bridging therapy for radiation casualties. Defence Science Journal 61:118–124.
      21. 2011—Singh VK, Parekh VI, Brown DS, Kao TC, Mog SR. Tocopherol succinate: Modulation of antioxidant enzymes and oncogene expression, and hematopoietic recovery, Int J Radiat Oncol Biol Phys. 79:571–8.
      22. 2011—Singh VK, Singh PK, Wise SY, Seed TM. Mobilized progenitor cells as a bridging therapy for radiation casualties: A brief review of tocopherol succinate-based approaches, Int Immunopharmacol. 11:842–47.
      23. 2010—Ghosh SP, Kulkarni S, Hauer-Jensen M, and Kumar KS. Gamma-tocotrienol as a radiation countermeasure drug: Comparison with alpha-tocopherol. Proceedings of the 37th Annual Meeting of the European Radiation Research Society, Prague, Czech Republic, August 26–29, 2009.
      24. 2010—Li XH, Fu D, Latif NH, Mullaney CP, Ney PH, Mog SR, Whitnall MH, Srinivasan V, Xiao M. Delta-tocotrienol protects mouse and human hematopoietic progenitors from gamma-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling, Haematologica 95:1996–2004.
      25. 2010—Kulkarni S, Ghosh SP, Hauer-Jensen M, Kumar KS. Hematological targets of radiation damage, Curr Drug Targets. 11:1375–85.
      26. 2010—Hauer-Jensen M, Kumar KS. Targets of potential radioprotective drugs, Curr Drug Targets. 11:1351.
      27. 2010—Kulkarni S, Ghosh SP, Satyamitra M, Mog S, Hieber K, Romanyukha L, Gambles K, Toles R, Kao T-C, Hauer-Jensen M, Kumar KS. Gamma-tocotrienol protects hematopoietic stem and progenitor cells in mice after total-body irradiation, J Radiat Res. 17:738–47.
      28. 2010—Singh VK, Brown DS, Kao T-C. Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor, Int J Radiat Biol. 86:12–21.
      29. 2010—Singh VK, Brown DS, Kao T-C, Seed TM. Preclinical development of a bridging therapy for radiation casualties, Exp Hematol. 38:61–70.
      30. 2009—Ghosh SP, Kulkarni S, Hieber K, Toles R, Romanyukha L, Kao TC, Hauer-Jensen M, Kumar KS. Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector, Int J Radiat Biol. 85:598–606.
      31. 2009—Singh VK, Brown DS, Kao T-C. Tocopherol succinate: A promising radiation countermeasure, Int Immunopharmacol. 9:1423–1430.
      32. Ghosh SP, Hauer Jensen M, and Kumar KS. Chemistry of tocotrienols In Tocotrienols: Vitamin E beyond tocopherols, Boca Raton: CRC Press, 85–96.
      33. 2008—Kumar KS, Ghosh SP, and Hauer Jensen M. Gamma-tocotrienol: Potential as a countermeasure against radiological threat. In Tocotrienols: Vitamin E beyond tocopherols, Boca Raton: CRC Press, 379–398.
      34. 2006—Singh VK, Shafran RL, Jackson WE 3rd, Seed TM, Kumar KS. Induction of cytokines by radioprotective tocopherol analogs, Experimental and Molecular Pathology, 81:55–61.
      35. 2002—Kumar KS, Srinivasan V, Toles R, Jobe L, Seed TM. Nutritional approaches to radioprotection: Vitamin E, Military Medicine 167 Suppl. 1:57–59.
  12. Radiation quality
    1. 2012—Cary LH, Ngudiankama BF, Salber RE, Ledney GD, Whitnall MH. Efficacy of radiation countermeasures depends on radiation quality. J Radiat Res. 177:663–675.
  13. Thiols
    1. 2014—Seed TM, Inal CE, Singh VK. Radioprotection of hematopoietic progenitors by low dose amifostine prophylaxis. Int J Rad Biol. (Epub ahead of print).
    2. 2004—Pamujula S, Graves RA, Freeman T, Srinivasan V, Bostanian LA, Kishore V, Mandal TK. Oral delivery of spray dried PLGA/amifostine nanoparticles, J Pharm Pharmacol. 56: 1119–1125.
    3. 2003—Kumar KS, Singh VK, Jackson W, Seed TM. Inhibition of LPS-induced nitric oxide production in RAW cells by radioprotective thiols, Exp Mol Pathol. 74: 68–7.
    4. 2002—Srinivasan V, Pendergrass JA Jr, Kumar KS, Landauer MR, Seed TM. Radioprotection, pharmacokinetic and behavioural studies in mouse implanted with biodegradable drug (amifostine) pellets, Int J Radiat Biol. 78: 535–543.
    5. 2002—Pendergrass JA Jr, Srinivasan V, Kumar KS, Jackson WE III, Seed TM. Determination of WR-1065 and WR-33278 by liquid chromatography with electrochemical detection, J AOAC Int. 85: 551–554.
  14. Toll-like receptor agonists
    1. 2012—Krivokrysenko V, Shakhov A, Singh V, Bone F, Kononov Y, Shyshynova i, Cheney A, Maitra R, Purmal A, Whitnall M, Gudkov AV, Feiinstein E. Identification of G-CSF and IL-6 as candidate biomarkers of CBLB502 efficacy as a medical radiation countermeasure. J Pharmacol Exp Ther. 343:497–508. doi: 10.1124/jpet.112.196071.
    2. 2012—Shakhov AN, Singh VK, Bone F, Cheney A, Kononov Y, et al. Prevention and mitigation of acute radiation syndrome in mice by synthetic lipopeptide agonists of Toll-like receptor 2 (TLR2). PLoS ONE 7(3): e33044, doi:10.1371/journal.pone.0033044
    3. 2012—Singh VK, Ducey EJ, Fatanmi OO, Singh PK, Brown DS, Purmal A, Shakhova VV, Gudkov AV, Feinstein E, Shakhov A CBLB613: A TLR 2/6 agonist, natural lipopeptide of Mycoplasma arginini, as a novel radiation countermeasure. J Radiat Res. 177:628–642.
    4. 2008—Protectan CBLB502 obtained IND status with the FDA as an acute radiation syndrome countermeasure.
    5. 2004—Entered into Cooperative Research and Development Agreement with Cleveland BioLabs to develop Protectans, drug candidates that protect normal tissues from acute stresses such as radiation.
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