Somatostatin Analogs as Countermeasures against Intestinal Radiation Toxicity

骨髓和胃肠(GI)的损伤是决定术后存活的主要因素 暴露在电离辐射中。在造血放射治疗方面取得进展 受伤。相比之下，GI辐射毒性的管理仍然不发达，应采取的对策 特别是针对肠道辐射损伤是迫切需要的。我们发现一种新型的生长抑素 类似物，SOM230，大大降低了死亡率，延长了生存时间，并减少了两种结构性肠道损伤 全身照射(TBI)后小鼠细菌移位。我们还证明了这种机制 包括抑制胰腺外分泌进入肠腔。最值得注意的是，SOM230保留了它的 致命性保护属性，即使在TBI后48小时以上开始给药，这是一个现实的时间框架 大量人员伤亡的情况。因此，SOM230是改善/恢复肠道的有效辐射减少剂 结构和功能在最初损坏发生后很久才发生。该项目将推动SOM230获得食品和药物管理局(FDA)的批准，解决与其作为辐射缓释剂属性相关的机械方面的问题，并试图进一步加强物流和/或功效。我们建议确定1)GI与造血损伤的相对重要性；2)生长抑素2型受体的特殊要求；3)是否可以通过与长效生长抑素类似物联合使用来减少注射次数；以及4)是否可以通过与γ-生育三烯醇(GT3)的联合使用来进一步增强缓解特性。这项工作有坚实的初步数据基础，并利用成熟的辐射模型和生理分析与当代分子技术相结合。它与该计划中的其他项目高度协作，并利用了它的几个核心。这些研究将推动SOM230朝着FDA批准的药物开发道路迈进，作为应对辐射紧急情况的医学对策，并将对人类健康产生重大和直接的影响。

Injuries to the bone marrow and gastrointestinal (GI) tract are the prinnary determinants of survival after exposure to ionizing radiation. Progress has been made in the management of hematopoietic radiation injury. In contrast, the management of GI radiation toxicity remains underdeveloped, and countermeasures specifically against intestinal radiation injury are urgently needed. We discovered that a novel somatostatin analog, SOM230, substantially reduces lethality, prolongs survival, and reduces both structural bowel injury and bacterial translocation in mice after total body irradiation (TBI). We also showed that the mechanism involves inhibition of exocrine pancreatic secretion into the gut lumen. Most remarkably, SOM230 retains its lethality-protecting properties even when administration begins 48+ hours after TBI, a realistic time-frame in a mass casualty situation. Thus, SOM230 is an effective radiation mitigator that ameliorates/restores gut structure and function long after the initial damage has occurred. This project will advance SOM230 toward approval by the Food and Drug Administration (FDA) by addressing mechanistic aspects related to its properties as a radiation mitigator and attempting to further enhance logistics and/or efficacy. We proposed to determine 1) the relative significance of GI versus hematopoietic injury; 2) the specific requirement for somatostatin type 2 receptor; 3) if the number of injections can be reduced by the combination with a longacting somatostatin analog; and 4) whether the mitigating properties can be further enhanced by the combination with gamma-tocotrienol (GT3), a unique vitamin E analog that is currently in advanced development as a radioprophylactic agent. This work has a strong basis in preliminary data and utilizes well established radiation models and physiological assays combined with contemporary molecular techniques. It is highly collaborative with other projects in this program and utilizes several of its cores. These studies will move SOM230 fonward on the drug development path toward FDA approval as a medical countermeasure against radiological emergencies and will have a significant and immediate impact on human health.