Somatostatin Analogs as Countermeasures against Intestinal Radiation Toxicity

骨髓和胃肠道（GI）损伤是治疗后生存的主要决定因素。 暴露于电离辐射。造血放射治疗的管理已取得进展 损伤与此相反，胃肠道辐射毒性的管理仍然不发达， 特别是针对肠辐射损伤。我们发现一种新的生长抑素 类似物，SOM 230，大大降低了致死率，存活率，并减少了结构性肠损伤 和细菌移位。我们还发现， 涉及抑制胰腺分泌物外分泌到肠腔中。最值得注意的是，SOM 230保留了其 即使在TBI后48小时以上开始给药，也具有致死保护特性，这是一个现实的时间范围， 大规模伤亡的情况因此，SOM 230是改善/恢复肠道的有效辐射缓解剂 结构和功能在初始损伤发生后很长时间内。该项目将通过解决与其作为辐射缓解剂的特性相关的机械方面，并试图进一步提高物流和/或功效，推动SOM 230获得美国食品药品监督管理局（FDA）的批准。我们建议确定1）GI与造血损伤的相对意义; 2）生长抑素2型受体的特异性需求; 3）是否可以通过与长效生长抑素类似物的组合来减少注射次数;和4）是否可以通过与γ-生育三烯酚（GT 3）的组合进一步增强缓解性能，一种独特的维生素E类似物，目前正处于放射预防剂的高级开发阶段。这项工作有一个坚实的基础，在初步的数据，并利用完善的辐射模型和生理分析结合当代分子技术。它与该计划中的其他项目高度协作，并利用其几个核心。这些研究将推动SOM 230在FDA批准的药物开发道路上向前发展，作为应对放射性紧急情况的医疗对策，并将对人类健康产生重大而直接的影响。

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.