The gastrointestinal (GI) tract is highly sensitive to radiation damage. Substantial injury to the GI tract after radiation exposure results in death. There is an urgent need to develop specific countermeasures against the lethality caused by intestinal exposure to radiation.
The aim of this project is to study three promising drugs that are likely to significantly improve GI recovery after lethal dose irradiation using the well-established dog model. The drugs are: keratinocyte growth factor (KGF), lithium carbonate (Li2CO3), and a GI-specific formulation of beclomethasone dipropionate (BDP) to be given alone or in combination after exposure to lethal doses of total body irradiation (TBI) administered at a high dose rate. KGF stimulates intestinal epithelium cell proliferation and has anti-apoptotic activity on epithelial cells. Lithium specifically inhibits glycogen synthase kinase 3 beta (GSK-3?) which activates intestinal stem cell proliferation via the wnt / ? catenin signaling pathway. We propose that gut-localized BDP can reduce the inflammatory cytokine storm induced by the radiation damaged GI tract. The dog model of radiation exposure for GI and hematopoietic injury is robust, and the model has a strong track record of translating preclinical findings to the clinical setting.
In Aim 1, the drugs to mitigate the GI radiation syndrome will be given after TBI, and in Aim 2, the drugs will be given before and after TBI to achieve survival of dogs with good GI tract recovery. Based on our prior work in this model, we will begin with a TBI dose of 10 Gy at 0.7 Gy/min dose rate, and we will treat dogs with autologous bone marrow plus standard supportive care including broad spectrum antibiotics, blood transfusion support, and intravenous fluids. This permits us to focus on treating the GI radiation syndrome, rather than on treating complications of the hematopoietic syndrome. The study end point is survival at day 30 and recovery from GI radiation syndrome. In this model, a GI radioprotective drug is defined as achieving significantly improved survival (= 70%) compared to standard supportive care alone. In the subsequent experiments, the TBI dose will be successively increased by 2 Gy increments, and dogs will be treated with single-drug or combined radioprotective drugs.
In Aim 3 we will study dogs given TBI without autologous bone marrow support given both (a) the optimal combination of GI radioprotection treatment and (b) optimal cytokine treatment for recovery from the radiation hematopoietic syndrome, based on the results of concurrent studies in AI-066498 Project Bioshield """"""""Cytokines for immune protection from acute radiation."""""""" Upon study completion, we will have identified the optimal drug treatment for the GI syndrome and the highest dose of TBI that can be reliably survived both with and without hematopoietic stem cell support. ? ? ? ?
