Evaluation and Development of Radiation Countermeasures at AFRRI

Leukopenia after ionizing radiation is due largely to free radical injury to stem cells and progenitors in hematopoietic tissue. Recovery depends on the ability of the remaining stem cells and progenitors to proliferate and differentiate sufficiently to reconstitute the immune system before a lethal infection takes hold. Proliferation and differentiation of hematopoietic progenitor cells (HPC) are dependent on factors produced by cells in the hematopoietic microenvironment or niche. We recently introduced a novel class of radiation countermeasures, the 5-androstene steroids. The prototype compound is 5-androstenediol (5-AED), a natural steroid that enhances survival in irradiated animals. We demonstrated that 5-AED stimulates hematopoiesis, ameliorates neutropenia, activates immune cells, and induces cytokine expression. Pilot studies in non-human primates have shown positive results and have led us to enter a phase of advanced drug development with this compound. To develop 5-AED for use in humans, it is necessary to better understand the mechanisms by which 5-AED produces these effects. A detailed mechanistic understanding is important because the pivotal efficacy studies involving whole-body irradiation will be performed in non-human primates, under the U.S. Food and Drug Administration’s “Animal Efficacy Rule.” A thorough analysis of mechanisms of action of 5AED is required by the FDA in order to predict efficacy in humans. Knowledge of 5-AED’s mechanisms of efficacy also will be helpful in guiding the discovery and evaluation of other classes of radiation countermeasure candidates. We are investigating induction of cytokine expression and modulation of apoptotic signaling pathways by 5-AED in blood-forming tissue, on the mRNA and protein levels. We are also exploring the effects of 5-AED on the various cell lineages of the immune system, and testing the possible role of specific niche cells in 5-AED’s stimulation of hematopoiesis. A similar process of baseline assessment, detailed evaluation, and advanced drug development is being undertaken at AFRRI for a portfolio of promising countermeasure candidates. Our criteria for admitting drug candidates into this program are evidence for radioprotectant, immunostimulatory, or cancer-preventative activity, representation of different mechanisms in the program, low toxicity, a practical administration route, and pre-existing human safety data. Compounds being evaluated at AFRRI include soy isoflavones, vitamin E-related compounds, phenylacetate, phenylbutyrate, epigallocatechin gallate (EGCG), benzyl styryl sulfones, CpG oligonucleotides, a superoxide dismutase mimetic, statins, dipeptidyl peptidase inhibitors, and truncated flagellin. 1.0 INTRODUCTION The risk of civilians and emergency responders being exposed to lethal doses of ionizing radiation is greater now than it was during the cold war. Nuclear proliferation, terrorist activity, and the distribution of nuclear Paper presented at the Human Factors and Medicine Panel Research Task Group 099 “Radiation Bioeffects and Countermeasures” meeting, held in Bethesda, Maryland, USA, June 21-23, 2005, and published in AFRRI CD 05-2. NATO RTG-099 2005 15–1 Report Documentation Page Form Approved OMB No. 0704-0188 Public reporting burden for the collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to a penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. 1. REPORT DATE 2005 2. REPORT TYPE 3. DATES COVERED 4. TITLE AND SUBTITLE Evaluation and Development of Radiation Countermeasures at AFRRI 5a. CONTRACT NUMBER