Cytokine-based treatment of accidentally irradiated victims and new approaches.

A major goal of medical management of acute radiation syndrome following accidental exposures to ionizing radiation (IR) is to mitigate the risks of infection and hemorrhage related to the period of bone marrow aplasia. This can be achieved by stimulating the proliferation and differentiation of residual hematopoietic stem and progenitor cells (HSPC) related to either their intrinsic radioresistance or the heterogeneity of dose distribution. This is the rationale for treatment with hematopoietic growth factors. In fact, apoptosis has recently been shown to play a major role in the death of the continuum of more or less radiosensitive HSPC, soon after irradiation. Therefore, administration of antiapoptotic cytokine combinations such as stem cell factor, Flt-3 ligand, thrombopoietin, and interleukin-3 (4F), may be important for multilineage recovery, particularly when these factors are administered early. Moreover, acute exposure to high doses of IR induces sequential, deleterious effects responsible for a delayed multiple organ dysfunction syndrome. These considerations strongly suggest that therapeutics could include tissue-specific cytokines, such as keratinocyte growth factor, and pleiotropic agents, such as erythropoietin, in addition to hematopoietic growth factors to ensure tissue damage repair and mitigate the inflammatory processes. Noncytokine drugs have also been proposed as an alternative to treat hematopoietic or nonhematopoietic radiation effects. To develop more effective treatments for radiation injuries, basic research is required, particularly to improve understanding of stem cell needs within their environment. In the context of radiological terrorism and radiation accidents, new growth promoting molecules need to be approved and available cytokines stockpiled.