Mitigation of radiation-induced lung injury by genistein and EUK-207

Abstract

Purpose We examined the effects of genistein and/or Eukarion (EUK)-207 on radiation-induced lung damage and investigated whether treatment for 0–14 weeks (wks) post-irradiation (PI) would mitigate late lung injury. Materials and Methods The lungs of female Sprague-Dawley (SD) rats were irradiated with 10 Gy. EUK-207 was delivered by infusion and genistein was delivered as a dietary supplement starting immediately after irradiation (PI) and continuing until 14 wks PI. Rats were sacrificed at 0, 4, 8, 14 and 28 wks PI. Breathing rate was monitored and lung fibrosis assessed by lung hydroxyproline content at 28 wks. DNA damage was assessed by micronucleus (MN) assay and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. The expression of the cytokines Interleukin (IL)-1α, IL-1β, IL-6, Tumor necrotic factor (TNF)-α and Transforming growth factor (TGF)-β1, and macrophage activation were analysed by immunohistochemistry. Results Increases in breathing rate observed in the irradiated rats were significantly reduced by both drug treatments during the pneumonitis phase and the later fibrosis phase. The drug treatments decreased micronuclei (MN) formation from 4–14 wks but by 28 wks the MN levels had increased again. The 8-OHdG levels were lower in the drug treated animals at all time points. Hydroxyproline content and levels of activated macrophages were decreased at 28 wks in all drug treated rats. The treatments had limited effects on the expression of the cytokines. Conclusion Genistein, and EUK-207 can provide partial mitigation of radiation-induced lung damage out to at least 28 wks PI even after cessation of treatment at 14 wks PI.

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…The protective effect of EUK207 applied during the early phase after irradiation was associated with a partial mitigation of the radiation-induced vascular injury and reduction in blood vessel density observed as a late effect of TBI of mice with 11 Gy (29), highlighting a role of oxidative stress for radiation-induced vascular injury. In line with these findings, continuous administration of EUK207 via implanted subcutaneous infusion pumps from 1 h until 14 weeks after irradiation also mitigated radiation-induced lung damage in rats (49). Even, when given after irradiation, a single injection of the SOD mimetic EUK189 had a small but mitigating effect in rodents, especially in the lung (48).…”

Short-Term Treatment with a SOD/Catalase Mimetic, EUK-207, Mitigates Pneumonitis and Fibrosis after Single-Dose Total-Body or Whole-Thoracic Irradiation

“…Despite the fact that the pathogenesis of radiation lung injury is incompletely understood, many studies have described promising mitigators, such as angiotensin converting enzyme (ACE) inhibitors (3,9), genistein (10), manganese porphyrins (11)(12)(13)(14) and salen Mn complexes (15).…”

“…SODs dismutate superoxide to form hydrogen peroxide (H 2 O 2 ) (16), and catalase (17) decomposes H 2 O 2 into water and oxygen. EUK-207 and other salen Mn complexes, such as the older compound EUK-189, have been reported to mitigate radiation injury in vivo in multiple tissues including the lung (15,18,19). EUK-207 and EUK-189 also inhibit apoptosis induced by ionizing radiation in capillary endothelial cell cultures (20).…”

“…Recently, Mahmood et al (15) reported that EUK-207 mitigated pulmonary fibrosis in Sprague Dawley rats when given subcutaneously (by implanted infusion pumps) starting within 1 h after thoracic irradiation and continuing for 98 days. Our goal is to mitigate radiation-induced lung injury after total-body irradiation (TBI) as well as after wholethoracic irradiation, both of which are scenarios that are likely to occur in a radiological terrorism event or nuclear accident.…”

Drug therapy to prevent and diminish radiation injury of the lungs

“…EUK 207 (Eukarion), также обладающий способ ностью ликвидировать активные формы кислорода, применялся у крыс путем ежедневной подкожной инъекции с момента начала и до 14 й недели после тотального облучения грудной клетки [43,44]. Пре парат обеспечил частичное смягчение симптомов лучевых повреждений легких в фазе пневмонита и поздней фазе фиброза (снижение уровня окисли тельного повреждения и количества активирован ных макрофагов), отмечен ограниченный эффект на экспрессию цитокинов.…”