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.

FIG. 1

Mouse model for blood collection from the carotid artery and portal vein. Left panel: cartoon of the model. Right panel: photograph from the model showing cannulas in the carotid artery (top) and portal vein (bottom).

FIG. 2

Dose-dependent radiation-mitigating effects of SOM230. Kaplan-Meier survival curves from mice exposed to 8.5, 9 and 9.5 Gy radiation (SOM230 administration beginning 24 h after TBI). SOM230 significantly reduced lethality in a dose-dependent manner across radiation doses (P < 0.0001). n = 8.

FIG. 3

Postexposure time window for SOM230. Kaplan-Meier survival curves from mice exposed to 9 and 9.5 Gy radiation (n = 8). SOM230 (2 mg/kg bid) significantly reduced lethality when administration commenced 24 h (P < 0.004) or 48 h after TBI (P = 0.005). Even when the start of administration was delayed by 72 h, the difference in survival between vehicle-treated and SOM230-treated animals across the two radiation doses was borderline significant (P = 0.05).

FIG. 4

Difference in chemokine (CXCL9) levels from portal vein draining the intestines and carotid artery (systemic circulation) as a function of SOM230 treatment. Difference between portal vein and systemic levels of the chemokine, monokine induced by gamma-interferon (MIG, CXCL9), from vehicle-treated (left) and SOM230-treated (right) mice. SOM230 injection was started 2 days prior to TBI and continued through the termination of the experiment at 7 days. Samples were taken before irradiation and 1 and 7 days after 8.5 Gy TBI. While vehicle-treated mice have significantly higher CXCL9 levels in portal blood than in the systemic circulation after TBI, the difference was not significant in mice treated with SOM230. **P = 0.006; *P = 0.001; SOM230 dose 5 mg/kg bid. CA, carotid artery; PV, portal vein. n = 5–7.

FIG. 5

Inhibition of trypsin secretion in vitro by SOM230. Trypsin (normalized to baseline) secreted by rat pancreatic acinar cells after 24 h treatment with SOM230. Trypsin secretion was inhibited in a highly significant, dose-dependent manner (P = 0.0001). n = 4.

FIG. 6

Inhibition of intestinal proteolytic activity in vivo by SOM230. Proteolytic activity in the intestinal lumen (luminal washings, left) and in intestinal tissue (right) from unirradiated mice after treatment with vehicle or SOM230. Treatment with SOM230 was associated with a highly significant reduction in proteolytic activity both intraluminally (P = 0.004) and in intestinal tissue (P = 0.0003). n = 5.