No satisfactory medical interventions for radiation enteritis are available yet. We have demonstrated that polyamine inhibition by a-difluoromethylornithine orDFMO, a selective and irreversible inhibitor of ornithine decarboxylase (ODC, the primary rate-limiting enzyme in the production of polyamines) significantly protects the gastrointestinal (GI) tract from whole-body radiation exposure. Here we propose to further develop it into a highly efficient radioprotector/radiomitigator for indications (1) radiotherapy associated enteritis and (2) GI injury due to nuclear accidents or incidents.
Aim #1. Evaluate the radioprotecting/mitigating effect of DFMO on GI injury Aim #2. Evaluate the effect of DFMO on cancer radiosensitivity Methods: (1) For efficacy studies under Aim #1, we will use a mouse model of abdomen-pelvis irradiation. Morphological evaluations include crypt survival and crypt-villus recovery. Intestinal barrier integrity will be evaluated by measuring plasma citrulline and serum endotxoin levels. (2) Under Aim #2, we will first evaluate the effect of DFMO on cancer growth and radiosensitivity in HCT116 and HT29 cell lines, and then move to mouse models of colon cancer and simulate abdomen-pelvis radiotherapy. Methods involved are cell culture, in vitro clonogenic assay of tumor cell growth, Xenograft implantation of HCT116 cells and HT29 cells and measuring tumor volume Relevance to public health: The concept proposed in this project, if proved, will lead to a full-scale development program to advance DFMO into a highly efficient drug for managing radiation enteritis in cancer patients as well as GI injury due to unintended radiation exposure.
