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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 (K-ras^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 incidence of cancer initiation and progression. We also found that a non-toxic anti-inflammatory, anti-oxidative radioprotector (CDDO-EA) reduced H?He?Si induced oxidative stress and cancer initiation almost back to baseline. Thus, exposure to H?He?Si elicits significant changes in lung cancer initiation that can be mitigated using CDDO-EA.

SUBMITTER: Luitel K

PROVIDER: S-EPMC6991460 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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

Luitel Krishna K Kim Sang Bum SB Barron Summer S Richardson James A JA Shay Jerry W JW

Life sciences in space research 20190801

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 d ...[more]

PMID: 31987474

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Project description:There is an ongoing and significant need for radiation countermeasures to reduce morbidities and mortalities associated with exposure of the heart and lungs from a radiological or nuclear incidents. Radiation-induced late effects occur months to years after exposure, stemming from significant tissue damage and remodeling, resulting in fibrosis and loss of function. TGF-β is reported to play a role in both pulmonary and cardiac fibrosis. We investigated the ability of a small molecule TGF-β receptor 1 inhibitor, IPW-5371, to mitigate the effects of thoracic irradiation in C57L/J mice, a murine model that most closely resembles that observed in humans in the induction of fibrosis and dose response. To simulate a radiological event, radiation was administered in two doses: 5 Gy total-body irradiation (eliciting a whole-body response) and immediately after that, a thoracic "top-up" of 6.5 Gy irradiation, for a total dose of 11.5 Gy to the thorax. IPW-5371 was administered once daily, orally, starting 24 h postirradiation for 6 or 20 weeks at a dose of 10 mg/kg or 30 mg/kg. Animals were monitored for a period of 180 days for survival, and cardiopulmonary injury was assessed by echocardiography, breathing rate and arterial oxygen saturation. Exposure of the thorax (11.5 Gy) induced both pulmonary and cardiac injury, resulting in a reduced life span with median survival of 135 days. IPW-5371 treatment for 6 weeks, at both 10 mg/kg and 30 mg/kg, delayed disease onset and mortality, with median survival of 165 days. Twenty weeks of IPW-5371 treatment at 30 mg/kg preserved arterial O2 saturation and cardiac contractile reserve and resulted in significant decreases in breathing frequency and cardiac and pulmonary fibrosis. This led to dramatic improvement in survival compared to the irradiated, vehicle-treated group (P < 0.001), and was statistically insignificant from the nonirradiated group. We observed that IPW-5371 treatment resulted in decreased pSmad3 tissue levels, confirming the effect of IPW-5371 on TGF-β signaling. These results demonstrate that IPW-5371 represents a potentially promising radiation countermeasure for the treatment of radiation-induced late effects.

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

Publications

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

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