Abstract 3730: 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigates the hematopoietic syndrome of lethal acute radiation syndrome in mice

Abstract

Abstract The acute radiation syndrome (ARS) is a broad term used to describe a range of signs and symptoms that reflect severe damage to specific organ systems and that can lead to death within hours or several months after exposure. In this study, we investigated the efficacy of EC-18 for the development of a medical countermeasure for ARS by analyzing IR-induced mortality and morbidity. First, we established a murine model of the ARS by exposing eleven week old male and female BALB/c mice to 6.0-6.5 Gy doses of total body irradiation (TBI; γ-ray, 60Co, 1553 R/min ), and assessed for 30 day survival, mean survival time and lethality dose (LD). The LD70/30 with confidence interval (CI) was 6.11Gy (5.98-6.22Gy). To determine the efficacy of EC-18 in IR-induced mortality, we exposed BALB/c mice to a 6.11Gy dose (LD70/30) of TBI and orally administered 10-250 mg/kg/day of EC-18, starting one day after irradiation. As a result, 6.11Gy of γ-radiation caused the death of 80% of the animals of positive control group within 23 days, with an average life span (ALS) of 17.9 days. The percentages of survival of the irradiated mice with EC-18 10, 50, and 250 mg/kg were 20%, 40%, and 80% with ALS of 19.3, 22.3, and 28.2 days, respectively. Moreover, the LD70/30 dose of γ-ray irradiation caused a substantial decrease in the body weight of the mice. The administration of EC-18 effectively prevented severe weight loss induced by irradiation. Next, we investigated the efficacy of EC-18 for hematopoietic ARS (H-ARS) by analyzing the kinetics of white blood cells (WBC), red blood cells (RBC), and platelets. A single whole body exposure of γ-radiation (6.11Gy) rapidly exhausted all kinds of WBC counts, and the administration of EC-18 significantly attenuated γ-radiation-induced depletion of WBCs in the irradiated mice. Especially, the administration of EC-18 substantially reduced γ-radiation-induced reduction of the ANC. The mean first day of neutropenia (ANC<500cells/μL) of control and EC-18-treated cohorts was 1.8±1.09 and 2.2±1.09 days, respectively. Although EC-18 did not protect the irradiated mice from experiencing severe neutropenia, it effectively reduced the duration of severe neutropenia from 13.0 days to 7.2±1.79 days. In addition, EC-18 significantly increased the mean nadir of ANC after γ-ray irradiation from 4.0±5.48 cells/μL to 20.0±10.00 cells/μL. In addition, the administration of EC-18 in the irradiated mice remarkably attenuated the rapid reduction of RBCs and hemoglobin. When exposed to a supra-lethal dose (8Gy) of γ-radiation, the two of five mice in the control cohort experienced severe skin discoloration and edema formation on the front right feet and hemorrhagic telangiectasia on the tales on day 10. EC-18 remarkably improved γ-radiation-induced skin damage in the irradiated mice. Based on the observations in this study, we concluded that EC-18 has potential as a medial countermeasure for ARS. Citation Format: Yong-Jae Kim, Jinseon Jeong, Ki-Young Sohn, Do Young Lee, Sun Young Yoon, Jae Wha Kim. 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol mitigates the hematopoietic syndrome of lethal acute radiation syndrome in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3730.