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.