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| Radiation Countermeasures |
| Jump to: Background | Summary of accomplishments | Previous work at AFRRI | Recent accomplishments |
| Overview |
| Program advisor: Mark H. Whitnall, PhD |
| Mission: To develop pharmacological countermeasures to radiation injury that can be used by military personnel and emergency responders. |
| Strategic plan |
- Develop a better understanding of the biology of radiation injury and radiation countermeasure drugs.
- Use knowledge of processes involved in radiation injury and countermeasures to identify and assess novel drug candidates.
- 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.
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| Background |
- Ionizing radiation at certain doses damages the blood-forming system.
- This results in fewer blood cells and platelets in the circulatory system.
- White blood cells form part of the immune system: they attack infectious microorganisms. Platelets form clots and prevent uncontrolled bleeding.
- Therefore, susceptibility to infection and hemorrhage increase after exposure to radiation.
- 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.
- 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.)
- Possible countermeasures to ionizing radiation can be broadly categorized into three groups.
- Drugs that prevent the initial radiation injury
- Free radical antioxidants
- Hypoxia
- Enzymatic detoxification
- Oncogene targeting agents
- Drugs that repair the molecular damage caused by radiation
- Hydrogen transfer
- Enzymatic repair
- Drugs that stimulate proliferation of surviving stem and progenitor cells
- Immunomodulators
- Growth factors and cytokines
- Military personnel and emergency responders urgently need nontoxic countermeasures to ionizing radiation.
- 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.
- The availability of medical facilities for radiation casualties after a nuclear detonation near a city will be problematic:
- Bell WC, Dallas CE. 2007. Intl J Health Geographics 6:5
- British Medical Association's Board of Science and Education. 1983, The Medical Effects of Nuclear War, John Wiley & Sons, New York.
- Holdstock D, Waterston L. 2000. Lancet 355:1544–1547
- Flynn DF, Goans RE. 2006. Surg Clin North Am 86:601–636
- 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.
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| Summary of accomplishments |
- Radiation countermeasure candidates tested for efficacy at AFRRI are chosen based on extensive basic research, which increases chances of success.
- All four countermeasures for acute radiation syndrome with Food and Drug Administration (FDA) Investigational New Drug (IND) status are AFRRI products.
- Two (5-AED and BIO-300) were conceived, initiated, and developed at AFRRI.
- The two others (Ex-Rad and CBLB502) were the subjects of company-initiated research programs that AFRRI joined at early stages.
- A fifth candidate, which AFRRI is researching in collaboration with a company, will be the subject of an IND application in the near future.
- The current standard (off-label) treatment for acute radiation syndrome, hematopoietic cytokines such as G-CSF, was conceived, initiated, and developed at AFRRI.
- 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.
- 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.
- 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.
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| 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: |
- 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.
- Radiation Research 104: 182–190, 1985
- Free Radicals Research Communications 3: 33–38, 1987
- Pharmacology and Therapeutics 39: 97–100, 1988
- Advances in Space Research 12: 273–283, 1992
- Environmental Health Perspectives 105 Suppl 6: 1473–1478, 1997
- Advances in Space Research 12: 273–283, 1992
- 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.
- Journal of Immunology 136: 2483–2485, 1986
- Journal of Immunology 140: 108–111, 1988
- Blood 76: 57–62, 1990
- Journal of Experimental Medicine 173: 1177–1182, 1991
- Journal of Experimental Medicine 175: 689–694, 1992
- Journal of Immunology 153: 1536–1543, 1994
- Journal of Immunology 153: 4230–4237, 1994
- 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.
- Experimental Hematology 16: 344–348, 1988
- International Journal of Radiation Biology 57: 723–736, 1990
- Blood 82: 3012-3018, 1993
- Journal of Clinical Investigation 97: 2145–2151, 1996
- Blood 87: 4129–4135, 1996
- Hendry JH, Lord BI (eds): Radiation Toxicology: Bone Marrow and Leukaemia. London, Taylor and Francis, 1995, pp 141–194
- Health Physics 89: 546–555, 2005
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| Recent accomplishments |
- Introduced a novel class of radiation countermeasures (5-androstene steroids)
- Demonstrated 5-androstenediol (5-AED), a naturally-occurring steroid hormone, enhances resistance to infection and survival after exposure to ionizing radiation (International Journal of Immunopharmacology 22: 1–14, 2000)
- Showed injection of 5-AED increases the number of circulating platelets, and cells of the innate immune system: neutrophils, monocytes, and natural killer cells (International Journal of Immunopharmacology 22: 1–14, 2000), (Radiation Research 156: 283–293, 2001)
- Injection of 5-AED also caused functional activation of all three of these cell types (Radiation Research 156: 283–293, 2001)
- Found 5-AED protects against radiation when administered orally (Immunopharmacology and Immunotoxicology 24: 595–626, 2002)
- Presented evidence that 5-AED is extremely safe, even when administered at high doses (Immunopharmacology and Immunotoxicology 24: 595–626, 2002)
- 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).
- Elucidated molecular specificity of 5-AED in radioprotection, indicating which chemical groups on the molecule are beneficial, supporting the hypotheses that 5-AED is the active molecule after systemic administration, and that efficacy is not due to activation of sex steroid receptors (Immunopharmacology and Immunotoxicology 27: 15–32, 2005)
- 2005: U.S. Food and Drug Administration (FDA) granted Investigational New Drug (IND) status to 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.
- Documented 5-AED-induced increases in circulating granulocyte colony-stimulating factor (G-CSF) in irradiated and unirradiated mice (Immunopharmacology and Immunotoxicology 27: 521–534, 2005)
- Demonstrated 5-AED-induced shortening of duration of severe neutropenia, thrombocytopenia, and anemia in irradiated rhesus macaques (International Immunopharmacology 6: 1706–1713, 2006)
- Showed 5-AED enhanced survival in irradiated rhesus macaques. Prediction of survival correlated most closely with days of thrombocytopenia, not neutropenia (International Immunopharmacology 7: 500–505, 2007)
- Reported 5-AED promotes survival of gamma-irradiated human hematopoietic progenitors through induction of NF-kappa B activation and G-CSF expression (Molecular Pharmacology, 72: 370–379, 2007)
- Analyzed pharmacokinetics and cytokine gene expression in irradiated mice after 5-AED administration (Experimental and Molecular Pathology, 84:178–188, 2008)
- Development of enzyme mimetics: Demonstration of radiation countermeasure efficacy of a superoxide dismutase/catalase mimetic (Immunopharmacology and Immunotoxicology 30: 271–290, 2008)
- Hematopoietic microenvironment mechanisms: Elucidation of signaling molecules involved in hematopoietic niche function of human osteoblasts after radiation injury Experimental Hematology 37: 52–64, 2009)
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| Bone marrow from a mouse treated with 5-AED (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. |
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- Advanced nutraceuticals as radioprotectants
- Evaluated vitamin E as an effective radioprotectant (Military Medicine 167 Suppl. 1: 57–59, 2002)
- Characterized radioprotectant properties of soy-derived isoflavones (Journal of Applied Toxicology, 23: 379–385, 2003)
- 2003 and 2005: 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
- January 2007: The Food and Drug Administration granted Investigational New Drug (IND) status to BIO-300, a Humanetics radiation countermeasure developed at the Armed Forces Radiobiology Research Institute with collaborators at the National Institutes of Health (NIH)
- Demonstrated induction of cytokines by Vitamin E-related analogs (Experimental and Molecular Pathology, 81: 55–61, 2006)
- Assessed effects of genistein on hematopoietic progenitor cell recovery in irradiated mice (International Journal of Radiation Biology 83: 141–151, 2007)
- Documented effects of genistein on radiation-responsive gene expression (Radiation Measurements 42: 1152–1157, 2007)
- Demonstrated genistein protects against delayed radiation effects in lung (Radiation Research 49: 361–372, 2008)
- Effects of genistein administration on cytokine induction in whole-body gamma irradiated mice (Int Immunopharmacol. 9: 1401–1410, 2009)
- Tocopherol succinate: a promising radiation countermeasure (Int Immunopharmacol. 9:1423–1430, 2009)
- Gamma-tocotrienol, a tocol antioxidant as a potent radioprotector (Int J Radiat Biol. 85:598–606, 2009 )
- Preclinical development of a bridging therapy for radiation casualties (Exp Hematol. 38: 61–70, 2010)
- Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor (Int J Radiat Biol 86:12–21, 2010)
- Kinase inhibitors: Documented protection by a new chemical entity, Ex-Rad™ (Radiation Research 171: 173–179, 2009)
- Developed chemopreventive strategies for radiation-induced cancer: targeting radiation-induced genetic alterations (Military Medicine 167 Suppl. 1: 54–56, 2002)
- Contributed to guidance for medical management of the Acute Radiation Syndrome following terrorist acts (Annals of Internal Medicine 140: 1037–1051, 2004)
- Analyzed the effects of isoflurane anesthesia on numbers of circulating white blood cells (Contemporary Topics 43: 9–14, 2004)
- Demonstrated beneficial effects of N-palmitoylation of IL-1 radioprotective domain (Immunopharmacology and Immunotoxicology 26: 193–202, 2004) (Peptides 26: 413–418, 2005)
- Recent studies of radioprotective thiols:
- Characterized delivery of amifostine with subcutaneous pellets (International Journal of Radiation Biology 78: 535–543, 2002)
- Developed electrochemical detection method for measurement of thiols (Journal of AOAC International 85: 551–554, 2002)
- Investigated effects of thiols on LPS-induced NO production in macrophages (Experimental and Molecular Pathology 74: 68–73, 2003)
- Developed oral formulation of amifostine nanoparticles (Journal of Pharmacy and Pharmacology 56: 1119–1125, 2004)
- Protectans
- 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
- 2008: Protectan CBLB502 obtained IND status with the FDA as an acute radiation syndrome countermeasure
- Captopril
- Timing of captopril administration determines radiation protection or radiation sensitization in a murine model of total body irradiation (Exp Hematol.; Epub ahead of print, 2010)
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