Bone marrow and gastrointestinal mucosa are highly sensitive to radiation exposure. Radiation-induced damage to bone marrow and the gastrointestinal tract could be lethal in events such as nuclear accidents or radiation terrorism, depending on radiation doses, exposure rate and quality. No truly satisfactory radioprotective drugs are yet available. The phospholipids growth factor lsophosphatidic acid (LPA) is a prosurvival factor acting via LPA receptors. We have synthesized a LPA receptor modulator Rx100, a partial agonist for LPA1 & LPA3, and a potent agonist for LAP2 receptor. We have proof of principle that Rx100, when applied either orally or subcutaneously, 1 hr before or 3 hrs after radiation exposure effectively reduced radiation-induced lethality to mice. We propose to fully evaluate Rx100 as a radioprotectant and a radiomitigator. Our ultimate goal is to provide a highly efficient medical countermeasure against radiological and nuclear threats, and a potent radioprotectant for cancer patients. Research design: Evaluate the efficacy of Rx100 in ameliorating radiation-associated hematopoietic syndrome. (1) We will use a mouse model of whole-body radiation; (2) We will optimize dosing schedules by oral and subcutaneous routes; (3) We will compare all data to decide two final schedules: one for Rx100 administered prior to radiation exposure as a radioprotectant and one as a radiomitigator; (4) We will quantify Rx100-initiated radioprotection by dose-reduction factor (DRF). Methods: (1) whole-body radiation of mice. Conscious mice are subjected to whole-body irradiation using a Cs-137 source at a rate of 4.6 Gy/min. (2) Hematopoietic assay. The primary endpoint is 30 days overall survival. For determining DRF, mice will be subjected to graded lethal doses of radiation exposure to generate survival curves for control groups and Rx100-treated groups. DRF will be calculated by probit analysis.
Exposure to radiation could result in fatal damage to bone marrow and the gut. No truly satisfactory radioprotective drugs are available yet. We propose to develop Rx100 into a highly efficient medical countermeasure against radiological and nuclear threats, and a potent radioprotectant for cancer patients. ? ? ?
| Deng, Wenlin; Kimura, Yasuhiro; Gududuru, Veeresh et al. (2015) Mitigation of the hematopoietic and gastrointestinal acute radiation syndrome by octadecenyl thiophosphate, a small molecule mimic of lysophosphatidic acid. Radiat Res 183:465-75 |
