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.

Public Health Relevance

This research focuses on developing medical drugs that can be used to protect the public in the event of a radiological emergency situation. The overall goal is to test the efficacy of a particular compound (SOM230), which has the remarkable property that it works well, even if administration begins as late as 2 days after radiation exposure. These studies will have a significant and immediate impact on human health.

National Institute of Health (NIH)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Duke University
United States
Zip Code
Batinic-Haberle, Ines; Tovmasyan, Artak; Roberts, Emily R H et al. (2014) SOD therapeutics: latest insights into their structure-activity relationships and impact on the cellular redox-based signaling pathways. Antioxid Redox Signal 20:2372-415
Spitz, Douglas R; Hauer-Jensen, Martin (2014) Ionizing radiation-induced responses: where free radical chemistry meets redox biology and medicine. Antioxid Redox Signal 20:1407-9
Himburg, Heather A; Yan, Xiao; Doan, Phuong L et al. (2014) Pleiotrophin mediates hematopoietic regeneration via activation of RAS. J Clin Invest 124:4753-8
Johnson, Jason N; Hornik, Christoph P; Li, Jennifer S et al. (2014) Cumulative radiation exposure and cancer risk estimation in children with heart disease. Circulation 130:161-7
Cheema, Amrita K; Pathak, Rupak; Zandkarimi, Fereshteh et al. (2014) Liver metabolomics reveals increased oxidative stress and fibrogenic potential in gfrp transgenic mice in response to ionizing radiation. J Proteome Res 13:3065-74
Lee, Chang-Lung; Lento, William E; Castle, Katherine D et al. (2014) Inhibiting glycogen synthase kinase-3 mitigates the hematopoietic acute radiation syndrome in mice. Radiat Res 181:445-51
Hauer-Jensen, Martin (2014) Toward development of interleukin-11 as a medical countermeasure for use in radiological/nuclear emergencies. Dig Dis Sci 59:1349-51
Tovmasyan, Artak; Carballal, Sebastian; Ghazaryan, Robert et al. (2014) Rational design of superoxide dismutase (SOD) mimics: the evaluation of the therapeutic potential of new cationic Mn porphyrins with linear and cyclic substituents. Inorg Chem 53:11467-83
Gauter-Fleckenstein, Benjamin; Reboucas, Julio S; Fleckenstein, Katharina et al. (2014) Robust rat pulmonary radioprotection by a lipophilic Mn N-alkylpyridylporphyrin, MnTnHex-2-PyP(5+). Redox Biol 2:400-10
Stanton, Ian N; Belley, Matthew D; Nguyen, Giao et al. (2014) Europium- and lithium-doped yttrium oxide nanocrystals that provide a linear emissive response with X-ray radiation exposure. Nanoscale 6:5284-8

Showing the most recent 10 out of 131 publications