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...

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Bibliographic Details
Main Authors: Srinivasan, V, Kumar, K S, Landauer, M R, Grace, M B, Miller, A C, Singh, V K, Seed, T M, Chang, C M, Inal, C E, Villa, V, Parekh, V L, Shafran, R L, Jackson, III, W E, Frincke, J M, Stickney, D R, Dowding, C, Shitnall, M H
Format: Report
Language:English
Subjects:
5-AED(5-ANDROSTENEDIOL)
COMPONENT REPORTS
Countermeasures
EXPOSURE(PHYSIOLOGY)
HEMATOPOIETIC SYSTEM
IONIZING RADIATION
LEUKOPENIA
NATO FURNISHED
RADIATION
Radiobiology
STEM CELLS
SYMPOSIA
WHOLE BODY IRRADIATION
WOUNDS AND INJURIES
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Summary: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. The original document contains color images. Presented at the Human Factors and Medicine Panel Research Task Group 099 (NATO RTG-099 2005), Radiation and Bioeffects and Countermeasures Meeting held in Bethesda, MD on 21-23 June 2005. Published in Armed Forces Radiobiology Research Institute (AFRRI)-CD-05-2, p15-1-15-10, 2005.