Preclinical Evaluation of SOM230 as a Radiation Mitigator in a Mouse Model: Postexposure Time Window and Mechanisms of Action

Abstract

The somatostatin analog SOM230 has potent radioprophylactic and radiation mitigating properties that are unrelated to cytoprotection but appear to be due to suppression of secretion of pancreatic enzymes into the intestinal lumen. To determine the maximal postirradiation time window for administration, male CD2F1 mice were exposed to 8.5–11 Gy total-body radiation; SOM230 (0.5, 2 or 5 mg/kg) or vehicle was given by twice daily subcutaneous injections for 14 days, beginning 24–72 h after irradiation, and 30-day animal survival was recorded. The contribution of the gut to systemic cytokine levels was estimated by analyzing plasma samples obtained simultaneously from the portal vein and carotid artery. The effect of SOM230 on cell trypsin secretion was assessed in vitro and intestinal proteolytic activity was measured in vivo. SOM230 was associated with a 40–60% absolute improvement in overall postirradiation survival when treatment was started 48 h after irradiation and even exhibited a statistically significant survival benefit when started at 72 h. SOM230 ameliorated the radiation-induced decrease in chemokine (C-X-C motif) ligand 9 (CXCL9). SOM230 inhibited pancreatic acinar cell trypsin secretion in vitro in a dose-dependent fashion and reduced intraluminal and intestinal tissue proteolytic activity in vivo. SOM230 is an excellent radiation mitigator with a postirradiation time window in excess of 48 h. The mechanism likely involves preservation of intestinal barrier function due to decreased secretion of pancreatic enzymes into the bowel lumen.

Radiation enteropathy—pathogenesis, treatment and prevention

“…These interventions seek to increase radiation tolerance, ameliorate secondary normal tissue injury, or enhance repair capacity. Such approaches include, for example, various immune-modulating drugs 74,75 , enterotrophic agents 76–83 , compounds that modulate intraluminal contents 84,85 , and a variety of other strategies 86–91 . Interventions that target downstream radiation effects may be generally more appealing in the cancer treatment situation because they do not interfere directly with the mechanism of radiation.…”

Challenges and Benefits of Repurposing Products for Use during a Radiation Public Health Emergency: Lessons Learned from Biological Threats and other Disease Treatments

“…These drugs fall into several major classes, associated with their known mechanisms of action. These categories include, but are not limited to antibiotics (21,22), anti-inflammatories [e.g., celecoxib (23) and steroids (https://bit.ly/2vyt08B)], 6 growth factors and mimetics (24)(25)(26)(27), hormones [e.g., somatostatin (28) and parathyroid hormone (https://bit.ly/2AWSi5A)], interleukins (29)(30)(31), statins (32) and angiotensin-converting-enzyme (ACE) inhibitors (33,34).…”

Correction: Radiation enteropathy—pathogenesis, treatment and prevention

“…These interventions seek to increase radiation tolerance, ameliorate secondary normal tissue injury, or enhance repair capacity. Such approaches include, for example, various immunemodulating drugs 74,75 , enterotrophic agents [76][77][78][79][80][81][82][83] , compounds that modulate intraluminal contents 84,85 , and a variety of other strategies [86][87][88][89][90][91] . Interventions that target downstream radiation effects may be generally more appealing in the cancer treatment situation because they do not interfere directly with the mechanism of radiation.…”