Radiotherapy is a major treatment modality typically used in conjunction with surgery and/or chemotherapy in treating a variety of cancers. While effective in controlling or eliminating localized tumors or preventing recurrence, radiation does induce a host of normal tissue toxicities. Gastrointestinal (GI) side effects from radiation treatment are very common; often this limits the dose of radiation that can be delivered to GI tumors and thereby its effectiveness. Thus, the discovery and clinical implementation of the use of bowel radioprotectors and mitigators could have significant clinical impact.
The purpose of this study was to develop a novel method of inflicting localized radiation-induced GI damage in order to establish a more physiological model of damage and aid the development of radioprotectors. Current models, while useful in elucidating the pathophysiological characteristics of broad field radiation, are hampered by complex surgical procedures (exteriorizing the rat intestine and then irradiating the herniated loop of bowel) which can introduce confounding factors such as infection, inflammation and fibrosis or involve whole abdominal irradiation, recapitulating a pathophysiology that is not relevant to clinical practice.
Here we surgically glued a 2mm diameter radiopaque marker made of bismuth subcarbonate onto the surface of the mouse (C57BL/6) jejunum to serve as a target for radiation treatment. One-week post-surgery the mice were imaged with cone-beam CT to locate the marker, and irradiated with 12Gy on the marker using the Small Animal Radiation Research Platform (SARRP®) using a 5×5mm collimator. Mice were sacrificed at various time points post-RT and intestinal tissue directly under, adjacent to, and distal to the marker were collected to assess both morphological and molecular features of radiation-induced damage and inflammation. These included levels of γ-H2AX, multiple cytokines, EdU incorporation, TUNEL assay and intestinal stem cell marker analysis.
Our findings suggest that our image-guided radiation injury mouse model is feasible since we observed a high survival rate post-surgery (approx. 90%). DNA damage, cell-cycle arrest, intestinal crypt apoptosis and inflammation were all significantly higher in the irradiated mice and confined to the immediately irradiated or adjacent area. However, IR-induced damage at 12Gy over 5mm appeared to be transient, as we observed regeneration of the majority of crypts at later time points post- IR. We are currently extending these findings with higher doses of radiation in the presence and absence of clinically used radioprotectors such as curcumin. Our model constitutes a new tool to rapidly evaluate multiple biological markers of DNA damage in the mouse intestine and we believe it will be valuable in future screens for radiation response modifiers and the study of molecular aspects of IR damage.
Citation Format: Ioannis Verginadis, Rahul Kanade, Edgar Ben-Josef, Constantinos Koumenis. Development of a novel mouse model to study image-guided radiation-induced gastrointestinal injury and its application in pre-clinical research. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1662.