Somatostatin analogues as countermeasures against intestinal radiation toxicity

放射性和核恐怖主义已成为重大威胁。目前可用的医疗对策的用途有限，因为它们必须在相对于辐射而言很窄的时间窗口内实施；与降低性能的毒性有关；或不适合在大规模伤亡情况下储存和/或管理。因此，迫切需要新的对策。骨髓和胃肠道损伤是中等剂量电离辐射后生存的主要决定因素。由于使用生长因子、造血干细胞、抗生素和支持治疗治疗造血辐射损伤方面取得的进展，肠道作为辐射暴露情况下的关键器官的相对重要性有所增加。然而，有效且安全的肠道 辐射响应调节剂尚不可用。因此，需要制定专门的 针对肠道辐射致死性和辐射引起的肠道毒性的病理生理表现的对策。我们实验室的数据表明，合成的生长抑素类似物奥曲肽是一种有效、无毒且易于施用的针对肠道辐射损伤的对策。我们的研究表明，奥曲肽可显着防止大鼠局部小肠照射后的结构损伤，以及放射性粘膜炎、上皮屏障破坏以及早期和迟发性肠道损伤的其他细胞和分子方面的损伤。该项目将把这些结果扩展到 1) 确定奥曲肽在全身照射情况下的剂量减少因子； 2）确定 奥曲肽给药的最佳剂量、持续时间和治疗时间窗； 3)检验奥曲肽主要通过降低肠腔中胰腺蛋白酶含量发挥其肠道保护作用的假设； 4) 对新型生长抑素类似物 SOM230 进行初步功效测试。 SOM230 比奥曲肽具有更广泛的受体特异性和更高的代谢稳定性，但其肠道保护作用仍不清楚。这些研究的策略和指导可能会直接改善未来辐射事故或恐怖主义情况下的健康保护工作，也可能有助于避免不利的长期影响 肠道辐射暴露。由于奥曲肽已获得美国联邦药物管理局批准用于其他适应症，因此这项研究将产生可以快速采取行动和实施的早期结果。

Radiological and nuclear terrorism have emerged as significant threats. Currently available medical countermeasures are of limited use because they must be administered within a narrow time window relative to radiation; are associated with performance-degrading toxicities; or are unsuitable for stockpiling and/or administration in mass casualty situations. Hence, novel countermeasures are urgently needed. Injuries to the bone marrow and gastrointestinal tract are the primary determinants of survival after moderate doses of ionizing radiation. As a result of progress in the management of hematopoietic radiation injury with growth factors, hematopoietic stem cells, antibiotics, and supportive care, the relative importance of the intestine as a critical organ in radiation exposure situations has increased. However, effective and safe intestinal radiation response modifiers are not yet available. Hence, there is a need to develop specific countermeasures against intestinal radiation lethality and against the pathophysiological manifestations of radiation-induced bowel toxicity. Data from our laboratory demonstrate that the synthetic somatostatin analogue, octreotide, is an effective, non-toxic, and easy-to-administer countermeasure against intestinal radiation injury. Our studies show that octreotide protects strikingly against structural injury after localized small bowel irradiation in rats, as well as against radiation mucositis, epithelial barrier breakdown, and other cellular and molecular aspects of early and delayed gut injury. This project will extend these results to 1) determine the dose-reduction factor for octreotide in the total body irradiation situation; 2) determine the optimal dose, duration, and therapeutic time window for octreotide administration; 3) test the hypothesis that octreotide exerts its enteroprotective effects primarily by reducing the content of pancreatic proteases in the bowel lumen; and 4) perform initial efficacy testing of SOM230, a novel somatostatin analogue. SOM230 has broader receptor specificity and greater metabolic stability than octreotide, but its enteroprotective effects are still unknown. Strategies and guidance from these studies may lead directly to improving health protection efforts in future radiation accidents or terrorism situations and may also help avoid adverse long-term effects of intestinal radiation exposure. Because octreotide is approved by the Federal Drug Administration for other indications, this research will generate early results that can be rapidly acted upon and implemented.