Environmental Health Perspectives 105, Supplement 6, December 1997

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Pharmacologic Approaches to Protection against Radiation-induced Lethality and Other Damage

Joseph F. Weiss

Office of International Health Programs, U.S. Department of Energy, Germantown, Maryland

Abstract
Studies on mechanisms of radioprotection are leading to a more rational use of protectors for different applications. In considering the feasibility of radioprotectors that act through various mechanisms, it is necessary to distinguish the application needed, e.g., protection against accidental external or internal exposures, acute high-dose radiation injury or low doses over a long period, high-LET radiation exposures during space flight, and protection of normal tissues of cancer patients who are undergoing therapy. Protectors generally are classified as either sulfhydryl compounds, other antioxidants, or receptor-mediated agents (e.g., bioactive lipids, cytokines, and growth factors). This review focuses on comparative radioprotection and toxicity studies in mice using the most effective phosphorothioate agents designated as WR-compounds and other classes of protectors. The superiority of phosphorothioates (WR-2721, WR-151327) as radioprotectors appears to be related to their high affinity for DNA and the similarity in structure of phosphorothioate metabolites to polyamines, and their effects on processes related to DNA structure and synthesis. Drug tolerance levels are available from clinical trials using WR-2721 (amifostine) and provide a basis for discussions of the disadvantages of phosphorothioate administration outside a clinical setting. In this regard, arguments are presented against the current use of WR-2721 by Department of Energy personnel for planned radiation exposures during emergencies. Future research may demonstrate, however, that pharmacologic agents could be useful in accident scenarios, especially when used in combination with therapeutic measures. Assessment of potential prophylactic measures should consider compatibility with therapeutic measures currently in use or ones that might be available in the future for the treatment of radiation injuries. These include antiemetics, purified stem cells, granulocyte colony-stimulating factor, and other cytokines. Their potential usefulness against radiation-induced mutagenesis of pre- and postexposure administration of phosphorothioates and other classes of protectors should be corroborated in humans. -- Environ Health Perspect 105(Suppl 6):1473-1478 (1997)

Key words: radioprotection, WR-2721, WR-151327, toxicity, antioxidants, aminothiols, growth factors, eicosanoids, receptor-mediated protection

This paper is based on a presentation at the International Conference on Radiation and Health held 3-7 November 1996 in Beer Sheva, Israel. Abstracts of these papers were previously published in Public Health Reviews 24(3-4):205-431 (1996). Manuscript received at EHP 23 June 1997; accepted 19 August 1997.

Address correspondence to Dr. J. Weiss, Office of International Health Programs, U.S. Department of Energy, EH-63/270CC, 19901 Germantown Road, Germantown, MD 20874-1290. Telephone: (301) 903-1846. Fax: (301) 903-1413. E-mail: joseph.weiss@hq.doe.gov

Views presented in this paper are those of the author. Many of the reviewed animal studies were done at the Armed Forces Radiobiology Research Institute (AFRRI), Bethesda, MD, and were conducted according to the principles in the Guide for the Care and Use of Laboratory Animals prepared by the Institute of Laboratory Animal Resources, National Research Council. The contributions of the AFRRI staff are gratefully acknowledged.

Abbreviations used: DMF, dose-modifying factor; G-CSF, granulocyte colony-stimulating factor; GI, gastrointestinal; GM-CSF, granulocyte-macrophage colony-stimulating factor; MPG, 2-mercaptopropionylglycine; MTD, maximum tolerated dose; WR-compounds, numerical designations of Walter Reed Army Institute of Research; WRAIR, Walter Reed Army Institute of Research; WR-1065, 2-(3-aminopropylamino)ethanethiol; WR-2721, Ethyol, amifostine, ethiofos, gammaphos, S-2-(3-aminopropylamino)ethylphosphorothioic acid; WR-3689, S-2-(3-methylaminopropylamino)ethylphosphorothioic acid; WR-151326, 3-(3-methylaminopropylamino)propanethiol; WR-151327, S-3-(3-methylaminopropylamino)propylphosphorothioic acid.

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