*Armed Forces Radiobiology Research Institute, Bethesda, MD; †Department of Radiation Biology, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD; ‡Tech Micro Services, 4417 Maple Avenue, Bethesda, MD.
Health Phys. 2014 Jun;106(6):689-98. doi: 10.1097/HP.0000000000000089.
The authors demonstrate the efficacy of a bridging therapy in a preclinical animal model that allows the lymphohematopoietic system of severely immunocompromised individuals exposed to acute, high-dose ionizing irradiation to recover and to survive. CD2F1 mice were irradiated acutely with high doses causing severe, potentially fatal hematopoietic or gastrointestinal injuries and then transfused intravenously with progenitor-enriched, whole blood, or peripheral blood mononuclear cells from mice injected with tocopherol succinate- and AMD3100- (a chemokine receptor anatogonist used to improve the yield of mobilized progenitors). Survival of these mice over a 30-d period was used as the primary measured endpoint of therapeutic effectiveness. The authors demonstrate that tocopherol succinate and AMD3100 mobilize progenitors into peripheral circulation and that the infusion of mobilized progenitor enriched blood or mononuclear cells acts as a bridging therapy for lymphohematopoietic system recovery in mice exposed to whole-body ionizing irradiation. The results demonstrate that infusion of whole blood or blood mononuclear cells from tocopherol succinate (TS)- and AMD3100-injected mice improved the survival of mice receiving high radiation doses significantly. The efficacy of TS-injected donor mice blood or mononuclear cells was comparable to that of blood or cells obtained from mice injected with granulocyte colony-stimulating factor. Donor origin-mobilized progenitors were found to localize in various tissues. The authors suggest that tocopherol succinate is an optimal agent for mobilizing progenitors with significant therapeutic potential. The extent of progenitor mobilization that tocopherol succinate elicits in experimental mice is comparable quantitatively to clinically used drugs such as granulocyte-colony stimulating factor and AMD3100. Therefore, it is proposed that tocopherol succinate be considered for further translational development and ultimately for use in humans.
作者在一个临床前动物模型中证明了桥接治疗的疗效，该模型使暴露于急性高剂量电离辐射的严重免疫功能低下个体的淋巴血液系统得以恢复并存活。CD2F1 小鼠接受急性大剂量照射，导致严重的、潜在致命的造血或胃肠道损伤，然后静脉输注富含祖细胞的全血或外周血单个核细胞，这些祖细胞来自注射生育酚琥珀酸和 AMD3100 的小鼠（一种趋化因子受体拮抗剂，用于提高动员祖细胞的产量）。这些小鼠在 30 天期间的存活被用作治疗效果的主要测量终点。作者证明生育酚琥珀酸和 AMD3100 将祖细胞动员到外周循环中，并且输注富含动员祖细胞的血液或单核细胞作为暴露于全身电离辐射的小鼠淋巴血液系统恢复的桥接治疗。结果表明，输注来自生育酚琥珀酸（TS）和 AMD3100 注射小鼠的全血或单核细胞可显著提高接受高剂量辐射的小鼠的存活率。TS 注射供体小鼠血液或单核细胞的疗效与注射粒细胞集落刺激因子的小鼠血液或细胞相当。发现供体来源的动员祖细胞定位于各种组织中。作者认为生育酚琥珀酸是一种动员祖细胞的理想药物，具有显著的治疗潜力。生育酚琥珀酸在实验小鼠中引起的祖细胞动员程度在数量上与临床上使用的药物（如粒细胞集落刺激因子和 AMD3100）相当。因此，建议进一步考虑将生育酚琥珀酸用于转化开发，并最终用于人类。
