Somatostatin analogues as countermeasures against intestinal radiation toxicity

辐射恐怖主义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的狭窄时间窗口内使用；与性能降级毒性有关；或不适合在大规模伤亡情况下储存和/或使用。因此，迫切需要新的对策。骨髓和胃肠道的损伤是中等剂量电离辐射后存活的主要决定因素。随着生长因子、造血干细胞、抗生素和支持性护理在治疗造血辐射损伤方面的进展，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，有效和安全的肠道 辐射响应修饰剂还不可用。因此，有必要制定具体的 针对肠道辐射致死性和放射性肠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的、无毒的、易于管理的对抗肠道辐射损伤的对策。我们的研究表明，奥曲肽对大鼠局部小肠照射后的结构性损伤以及放射性粘膜炎、上皮屏障破坏和其他早期和延迟肠道损伤的细胞和分子方面具有显著的保护作用。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系数；2)确定 奥曲肽给药的最佳剂量、持续时间和治疗时间窗口；3)检验奥曲肽主要通过减少肠腔中胰蛋白酶含量发挥肠道保护作用的假设；以及4)对一种新型生长抑素类似物SOM230进行初步疗效测试。与奥曲肽相比，SOM230具有更广泛的受体特异性和更大的代谢稳定性，但其肠道保护作用尚不清楚。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卫生保护工作，还可能有助于避免不利的长期影响。 肠道辐射暴露的风险。由于奥曲肽被联邦药物管理局批准用于其他适应症，这项研究将产生可以迅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.