title: A Novel Mouse Model to Study Image-Guided, Radiation-Induced Intestinal Injury and Preclinical Screening of Radioprotectors.
abstract: Radiation is an important treatment modality for gastrointestinal tumors, but intestinal injury is a common side effect. Here we describe a physiologically relevant model for studying the molecular determinants of radiation-induced intestinal damage and testing novel radioprotectors. The model employs a radiopaque marker implanted into the surface of the mouse jejunum, serving as a fiducial marker for precise radiation targeting. Mice were imaged with Cone-Beam CT (CBCT) and irradiated (IR) to the marked area using the Small Animal Radiation Research Platform (SARRP). IR-induced damage was acute but reversible and largely restricted to the area of the marker, leaving the surrounding tissues intact. Although whole gut irradiation with these doses caused lethal GI syndrome, focal (5 mm) radiation of the intestine did not cause any weight loss or lethality. However, fibrosis and collagen deposition 4 months post-IR indicated chronic intestinal damage. A separate cohort of mice was treated daily with curcumin, a clinically tested radioprotector, prior to and post-IR. Curcumin-treated mice showed significant decreases in both local and systemic inflammatory cytokine levels and in fibrosis, suggesting it is an effective radioprotector of the intestine. Our results indicate that this model, which emulates clinically relevant intestinal radiation-induced injury, can be used to assess radioprotectors prior to testing in the clinic.Cancer Res; 77(4); 908-17. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Ioannis I
authors.initials: II
authors.lastname: Verginadis
authors.affiliation: Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Rahul
authors.initials: R
authors.lastname: Kanade
authors.affiliation: Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Brett
authors.initials: B
authors.lastname: Bell
authors.affiliation: Department of Biology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Sravya
authors.initials: S
authors.lastname: Koduri
authors.affiliation: Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Edgar
authors.initials: E
authors.lastname: Ben-Josef
authors.affiliation: Department of Radiation Oncology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. costas.koumenis@uphs.upenn.edu.
authors.forename: Constantinos
authors.initials: C
authors.lastname: Koumenis
mesh_terms: D000818:Animals; D017209:Apoptosis; D054893:Cone-Beam Computed Tomography; D003474:Curcumin / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005770:Gastrointestinal Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D006657:Histones / Q000032:analysis; D015850:Interleukin-6 / Q000097:blood; D007422:Intestines / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D011833:Radiation Injuries, Experimental / Q000209:etiology*; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D061089:Radiotherapy, Image-Guided / Q000009:adverse effects*
chemical_list: D006657:Histones; D015850:Interleukin-6; D011837:Radiation-Protective Agents; C475961:gamma-H2AX protein, mouse; D003474:Curcumin