Polypharmacy to Mitigate Acute and Delayed Radiation Syndromes

Abstract

There is a need for countermeasures to mitigate lethal acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). In WAG/RijCmcr rats, ARS occurs by 30-days following total body irradiation (TBI), and manifests as potentially lethal gastrointestinal (GI) and hematopoietic (H-ARS) toxicities after >12.5 and >7 Gy, respectively. DEARE, which includes potentially lethal lung and kidney injuries, is observed after partial body irradiation >12.5 Gy, with one hind limb shielded (leg-out PBI). The goal of this study is to enhance survival from ARS and DEARE by polypharmacy, since no monotherapy has demonstrated efficacy to mitigate both sets of injuries. For mitigation of ARS following 7.5 Gy TBI, a combination of three hematopoietic growth factors (polyethylene glycol (PEG) human granulocyte colony-stimulating factor (hG-CSF), PEG murine granulocyte-macrophage-CSF (mGM-CSF), and PEG human Interleukin (hIL)-11), which have shown survival efficacy in murine models of H-ARS were tested. This triple combination (TC) enhanced survival by 30-days from ∼25% to >60%. The TC was then combined with proven medical countermeasures for GI-ARS and DEARE, namely enrofloxacin, saline and the angiotensin converting enzyme inhibitor, lisinopril. This combination of ARS and DEARE mitigators improved survival from GI-ARS, H-ARS, and DEARE after 7.5 Gy TBI or 13 Gy PBI. Circulating blood cell recovery as well as lung and kidney function were also improved by TC + lisinopril. Taken together these results demonstrate an efficacious polypharmacy to mitigate radiation-induced ARS and DEARE in rats.

Time- and sex-dependent delayed effects of acute radiation exposure manifest via miRNA dysregulation

“…These models enable analyses to be conducted under standardized conditions and can yield conclusive evidence regarding the proposed sex-specific radiation sensitivity. 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 33 In this study, we performed a robust 30-day animal studies with 6 escalating radiation doses (7–9 Gy) and find that females are more radioresistant than males. Probit analysis of the lethal dose curves shows that LD50/30 is 7.76 Gy for male mice and 8.08 Gy for female mice.…”

“…Likewise, DEARE studies also disclosed different effects on male and female mice. 24 , 25 , 26 This implies that sex-related factors may play a role in the long-term response to radiation exposure. Nonetheless, the associated cellular and molecular mechanisms for these variations in sensitivity and long-term response to radiation exposure remain unclear.…”

Delayed effects of radiation exposure in a C57L/J mouse model of partial body irradiation with ~2.5% bone marrow shielding

“…Chronic kidney disease following irradiation develops clinically, and both PBI rat ( 23 ) and PBI NHP ( 20 ) models develop K-DEARE either concurrent to, or following, L-DEARE. In the C57L/J mouse model described herein, there is a lack of evidence for the development of K-DEARE, and this is consistent with the similar C57L/J model developed by Gibbs et al ( 10 ).…”

Considerations of Medical Preparedness to Assess and Treat Various Populations During a Radiation Public Health Emergency

“…The authors concluded that major differences in vasculopathy, inflammation, oxidative imbalance, and senescence between the heart and kidney suggest the need for different MCMs in different organs to be administered at different times post-irradiation. Further support for the concept of a time-dependent polypharmacy approach to mitigating ARS and DEARE comes from a study employing PBI in a rat model (150). In this study, a triple combination of H-ARS mitigators were used to support survival through H-ARS.…”