Lung cancer progression using fast switching multiple ion beam radiation and countermeasure prevention

Abstract

Most of the research in understanding space radiation-induced cancer progression and risk assessment has been performed using mono-energetic single-ion beams. However, the space radiation environment consists of a wide variety of ion species with a various range of energies. Using the fast beam switching technology developed at the NASA Space Radiation Laboratory (NSRL) at Brookhaven National Laboratory (BNL), ion species can be switched rapidly allowing investigators to use multiple ions with different energies to simulate more closely the radiation environment found in space. Here, we exposed a lung cancer susceptible mouse model (Kras LA−1 ) to three sequential ion beams: Proton (H) (120 MeV/n) 20 cGy, Helium (He) (250 MeV/n) 5.0 cGy, and Silicon (Si) (300 MeV/n) 5.0 cGy with a dose rate of 0.5 cGy/min. Using three ion beams we performed whole body irradiation with a total dose of 30 cGy in two different orders: 3B-1 (H→He→Si) and 3B-2 (Si→He→H) and used 30 cGy H single-ion beam as a reference. In this study we show that whole-body irradiation with H→He→Si increases the incidence of premalignant lesions and systemic oxidative stress in mice 100 days post-irradiation more than (Si→He→H) and H only irradiation. Additionally, we observed an increase in adenomas with atypia and adenocarcinomas in H→He→Si irradiated mice but not in (Si→He→H) or H (30 cGy) only irradiated mice. When we used the H→He→Si irradiation sequence but skipped a day before exposing the mice to Si, we did not observe the increased

Heavy-Ion-Induced Lung Tumors: Dose- & LET-Dependence

“…However, mixed beam studies are nevertheless far more complicated in that, in addition to dose/fluence, the temporal sequence, dose rate and composition of the mixed beams must be taken into consideration. In a recent study, lung cancer tumorigenesis in K-ras LA-1 mice was reported to be dependent on the sequence of H + He + Si vs. Si + He + H [ 38 ]. H + He + Si showed increased incidences of premalignant lesions and systemic oxidative stress in mice 100 days post irradiation when compared to Si + He + H or H alone.…”

Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure

“…CDDO is of particular CNS interest due to proven therapeutic intervention for mouse models of Huntington’s disease, malaria, and ischemic injury (Stack et al, 2010; Crowley et al, 2017; Xu et al, 2017; Lei et al, 2020). In addition, dietary CDDO-EA (400mg/Kg) has proven as an effective countermeasure against GCR-induced lung tumors in tumorigenic mice exposed to 30cGy of a 3-beam mixed field (Luitel et al, 2020). The exact mechanism of charged-particle radiation toxicity on neurons remains unclear, though oxidative stress, being the primary source of radiation interaction with tissues remains a primary therapeutic target.…”

“…CDDO is of particular interest for CNS research due to effective pre-clinical therapeutic intervention for mouse models of Huntington's disease, malaria, and ischemic injury [16][17][18][19]. In addition, dietary CDDO-EA (400mg/Kg) is an effective countermeasure against GCR-induced lung tumors in tumorigenic male mice exposed to 30cGy of a 3-beam mixed field [15]. CDDO-EA was therefore a promising intervention as it offers a multifaceted protective approach by targeting the Nrf-2 pathways, which have protective downstream effects on oxidative stress management, microglial activation, and blood-brain barrier integrity, all of which are adversely affected in the CNS of mice following radiation [77,78].…”

“…One such compound with a long biological half-life is the triterpenoid 2-cyano-3, 12-dioxooleana-1, 9-dien-28-oic acid (CDDO)-ethylamide (CDDO-EA), which targets the Nrf-2/ARE pathway, upregulates endogenous oxidative stress response elements, and potentially quenches the dense oxidative stress produced by particle radiation [14]. CDDO-EA is an effective countermeasure against 1 H+ 4 He+ 28 Si-induced blood plasma lipid peroxidation and lung cancer initiation after an acute, 30cGy, whole-body dose [15]. In the CNS, CDDO-EA and structurally similar variants (such as CDDO-Imidazole or CDDO-Methyl) improve pathological symptoms in mouse models of Huntington's disease, ischemic injury, cerebral malaria, and amyotrophic lateral sclerosis via their anti-inflammatory/antioxidant actions [14,[16][17][18][19].…”

How certain are we? Development of an ensemble based framework for assessing astronaut cancer risks from space radiation

“…Likewise, it is assumed that the biological response from a mixed-field irradiation (in particle type and energy), as would be found in space, can be determined by simple additivity or by directly adding responses from individual ions and energies. However, results for Harderian gland tumorigenesis [Siranart et al 2016] and lung cancer tumorigenesis [Luitel et al 2020] in murine models suggest that synergies between particles may exist and that more complex additivity models need to be considered. Emerging models for non-targeted effects (NTE), which have a significant influence on low-dose extrapolations expressed through RBEs, are being developed and have been shown to significantly impact radiation quality factors Cacao 2017, Matsuya et al 2018].…”