Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC, USA.
Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA.
Sci Rep. 2021 Jun 1;11(1):11449. doi: 10.1038/s41598-021-91067-9.
To date, the United States Food and Drug Administration (FDA) has approved four drugs to mitigate hematopoietic acute radiation syndrome and all four are repurposed radiomitigators. There are several additional drug candidates currently under evaluation that may also be helpful for use during a widespread emergency. One possible candidate is Ex-Rad, also known as ON01210, a chlorobenzyl sulfone derivative (organosulfur compound), which is a novel, small-molecule kinase inhibitor with demonstrated efficacy in the murine model. In this study, we have evaluated the metabolomic and lipidomic profiles in serum samples of nonhuman primates (NHPs) treated with Ex-Rad after exposure to ionizing radiation. Two different dose administration schedules (Ex-Rad I administered 24 and 36 h post-irradiation, and Ex-Rad II administered 48 and 60 h post-irradiation), were used and evaluated using a global molecular profiling approach. We observed alterations in biochemical pathways relating to inflammation and oxidative stress after radiation exposure that were alleviated in animals that received Ex-Rad I or Ex-Rad II. The results from this study lend credence to the possible radiomitigative effects of this drug possibly via a dampening of metabolism-based tissue injury, thus aiding in recovery of vital, radiation-injured organ systems.
截至目前，美国食品和药物管理局（FDA）已批准了四种用于减轻造血急性辐射综合征的药物，这四种药物均为重新定位的辐射缓解剂。目前还有几种候选药物正在评估中，在发生广泛紧急情况时可能也会有所帮助。一种可能的候选药物是 Ex-Rad，也称为 ON01210，是一种氯苄基砜衍生物（有机硫化合物），它是一种新型小分子激酶抑制剂，在小鼠模型中显示出疗效。在这项研究中，我们评估了接受电离辐射后接受 Ex-Rad 治疗的非人类灵长类动物（NHP）的血清样本中的代谢组学和脂质组学特征。使用两种不同的剂量给药方案（Ex-Rad I 在辐照后 24 和 36 小时给药，Ex-Rad II 在辐照后 48 和 60 小时给药），并使用全局分子分析方法进行了评估。我们观察到辐射暴露后与炎症和氧化应激有关的生化途径发生了变化，而接受 Ex-Rad I 或 Ex-Rad II 治疗的动物的这些变化得到了缓解。这项研究的结果为这种药物可能具有的辐射缓解作用提供了依据，可能是通过抑制基于代谢的组织损伤来实现的，从而有助于辐射损伤的重要器官系统的恢复。
