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用途有限，因为它们必须在相对于辐射而言较窄的时间窗口内施用;与降低性能的毒性有关;或者不适合储存和/或在大规模伤亡情况下施用。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。由于在造血放射损伤的管理与生长因子，造血干细胞，抗生素和支持性治疗的进展，肠道作为一个关键器官在辐射照射的情况下，相对重要性有所增加。然而，有效和安全的肠道 辐射响应调节剂还不能得到。因此，有必要制定具体的 针对肠辐射致死性和针对辐射诱导的肠毒性的病理生理学表现的对策。我们实验室的数据表明，合成生长抑素类似物奥曲肽是一种有效、无毒、易于管理的肠道辐射损伤对策。我们的研究表明，奥曲肽对大鼠小肠局部照射后的结构损伤，以及对放射性粘膜炎，上皮屏障破坏和早期和延迟性肠道损伤的其他细胞和分子方面具有显著的保护作用。本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降低因子; 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的含量发挥其肠保护作用的假设;和4）进行SOM 230（一种新型生长抑素类似物）的初始功效测试。与奥曲肽相比，SOM 230具有更广泛的受体特异性和更高的代谢稳定性，但其肠保护作用尚不清楚。这些研究的战略和指导可能直接导致在未来的辐射事故或恐怖主义情况下改善健康保护工作，也可能有助于避免不利的长期影响 肠道辐射暴露。由于奥曲肽已被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早期结果，可以迅速采取行动和实施。

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.