Orazipone, a locally acting immunomodulator, ameliorates intestinal radiation injury: a preclinical study in a novel rat model.
OBJECTIVE
Intestinal radiation injury (radiation enteropathy) is relevant to cancer treatment, as well as to radiation accidents and radiation terrorism scenarios. This study assessed the protective efficacy of orazipone, a locally-acting small molecule immunomodulator.


METHODS
Male rats were orchiectomized, a 4-cm segment of small bowel was sutured to the inside of the scrotum, a proximal anteperistaltic ileostomy was created for intraluminal drug administration, and intestinal continuity was re-established by end-to-side anastomosis. After three weeks postoperative recovery, the intestine in the "scrotal hernia" was exposed locally to single-dose or fractionated X-radiation. Orazipone (30 mg/kg/day) or vehicle was administered daily through the ileostomy, either during and after irradiation, or only after irradiation. Structural, cellular, and molecular aspects of intestinal radiation toxicity were assessed two weeks after irradiation.


RESULTS
Orazipone significantly ameliorated histologic injury and transforming growth factor-beta immunoreactivity levels, both after single-dose and fractionated irradiation. Intestinal wall thickness was significantly reduced after single-dose and nonsignificantly after fractionated irradiation. Mucosal surface area and numbers of mast cells were partially restored by orazipone after single-dose irradiation.


CONCLUSIONS
This work (1) demonstrates the utility of the ileostomy rat model for intraluminal administration of response modifiers in single-dose and fractionated radiation studies; (2) shows that mucosal immunomodulation during and/or after irradiation ameliorates intestinal toxicity; and (3) highlights important differences between single-dose and fractionated radiation regimens.
Boerma
Marjan
M
Department of Surgery, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.
Wang
Junru
J
Richter
Konrad K
KK
Hauer-Jensen
Martin
M
D000818:Animals; D007081:Ileostomy; D007413:Intestinal Mucosa / Q000187:drug effects; D007421:Intestine, Small / Q000378:metabolism / Q000528:radiation effects*; D008297:Male; D023421:Models, Animal; D009919:Orchiectomy; D011833:Radiation Injuries, Experimental / Q000378:metabolism / Q000517:prevention & control*; D011836:Radiation Tolerance / Q000187:drug effects*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D011837:Radiation-Protective Agents; D013438:Sulfhydryl Compounds; D016212:Transforming Growth Factor beta; C502617:orazipone