Modulation of Radiation Injury

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Science  30 Apr 2004:
Vol. 304, Issue 5671, pp. 693-694
DOI: 10.1126/science.1095956

Ionizing radiation is present all around us; exposure to background radiation from cosmic rays and naturally occurring isotopes is unavoidable. We are exposed during diagnostic and therapeutic medical procedures and in certain occupations. Radiation therapy for cancer allows for precise, focused delivery, with improved quality of life; nonetheless, some exposure of normal tissue is unavoidable. As a result, many millions of cancer survivors will live for decades but will be at risk for adverse consequences such as tissue atrophy and secondary tumors (1).

Further, the devastating events of 11 September 2001 underscore the potential for radiation exposure from nuclear and radiological terrorism, which could result in large-scale casualties from improvised nuclear devices or nuclear weapons (24).

The acute radiation syndrome (ARS) occurs after whole-body exposure to radiation doses greater than 1 Gy. ARS is categorized into syndromes named for the organ system showing the most prominent symptoms. The central nervous system is affected within hours of exposures of more than 15 Gy, and fatalities occur within about 2 days. Gastrointestinal effects occur within a week after doses of 8 to 12 Gy; with only supportive care, most casualties will die within 10 days (4). After doses of 1 to 7 Gy, the hematopoietic (also lymphatic and immunologic) system syndrome appears in weeks to 2 months. Survival is likely at the lower end of this range and may be possible at the higher end with administration of cytokines, antibiotics, and fluids and electrolytes (4).

Radiation causes injury of normal tissue by a dynamic, evolving process involving cell killing, altered cell-to-cell communication, inflammatory responses, compensatory tissue hypertrophy of remaining normal tissue, and tissue repair processes (5, 6). Changes in cytokines can be detected over time (68) and, indeed, radiation fibrosis may be partly reversible (9). The genetic characteristics of the exposed organism can influence the exact nature of the radiation response (10).

To develop approaches to prophylaxis, mitigation, and treatment of radiation injuries, we need appropriate models to integrate the complex influences that occur in the radiation-exposed organism. This challenge was addressed in a recent workshop, “Models and Procedures for Evaluating Radioprotectors,” sponsored by the Radiation Research Program of the National Cancer Institute on 3 and 4 December 2003.

At present, no agents approved by the U.S. Food and Drug Administration are available for the treatment of ARS, although amifostine is approved for prophylaxis of dry mouth (xerostomia) from radiotherapy, and cytokines are used without approval for treatment of ARS. New research findings presented at the meeting, however, promise improvements in survival after whole-body radiation and reductions in the risk of adverse effects of radiotherapy.

The new approaches fall into one or more of several categories (3, 11). Some of the substances act as free-radical scavengers (for example, amifostine and tempol) and act on the initial radiochemical events. To be effective, they must be present at the time of irradiation and so must be administered before exposure. These compounds provide protection in a broad range of cellular and tissue systems.

Several agents are now under investigation that prevent or reduce progression of radiation damage, or reduce symptoms of radiation injury, when given to the patient after exposure [for example, pentoxifylline, angiotensin-converting enzyme inhibitors, and angiotensin II (AII) receptor antagonists]. The precise mechanisms by which these drugs act remain to be determined, although pentoxifylline targets fibrosis and AII antagonists ameliorate kidney and possibly lung injury (3, 6).

Complementing the drugs that interfere with the progression of damage are agents that facilitate recovery from radiation-induced injuries: hematopoietic cytokines such as granulocyte and granulocyte-macrophage colony-stimulating factors, mucosa-stimulating growth factors such as keratinocyte growth factor, and stimulators of the immune response or bone marrow such as 5-androstenediol. These cytokines have been used to treat the hematopoietic system syndrome in accident victims (4). Studies in nonhuman primates point to the promise of 5-androstenediol as a therapeutic agent (12).

Finally, some relatively nontoxic agents (for instance, soy isoflavones and vitamin analogs) are being evaluated for prolonged treatment. For example, genistein, a soy isoflavone, promotes survival in mice if given orally before and after exposure (13).

Although the mechanisms of action for most of these agents are as yet unclear, they generally seem to operate at a whole-animal rather than cellular level. Therefore, research on prevention, mitigation, and treatment of radiation injuries will require whole-animal models. Mice and rats are the best characterized animal models for initial assessment of therapeutic agents, but large animal models also will be necessary for development of drugs for human use.

The discovery and delivery of effective radiation modulators will require input from experts in radiation biology, inflammation, immunology, tissue injury, drug development, and clinical radiation oncology (7, 11, 14). This meeting laid the groundwork for these collaborations and for future research.


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