No abstract

Purpose-To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N′-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with SOD mimetic properties reduces the severity of radiation-induced injury to the lung from single dose irradiation (RT) of 28 Gy.Materials/Methods-Animals were randomly divided into four different dose groups (0, 1, 10 and 30 mg/kg/day of AEOL 10150), receiving either short (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Animals received single dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology and immunohistochemistry were used to assess lung damage.Results-There was no significant difference in any of the study endpoints between the irradiated controls and the 3 groups receiving RT and short-term administration of AEOL 10150. For the long term administration functional determinants of lung damage 20 weeks post radiation were significantly worse for RT+PBS and RT+1mg/kg/day of AEOL 10150 as compared to the irradiated groups treated with higher doses of AEOL 10150 (10 or 30mg/kg/day), Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in animals receiving 10 or 30mg/kg/day after radiation in comparison to RT+PBS and 1mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress and hypoxia in animals receiving AEOL 10150 (10 or 30mg/kg/day) after lung irradiation compared to RT+PBS and 1mg/kg/day groups. Conclusion-The chronic administration of novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events following irradiation and adding drug prior to irradiation and its short-term administration have no significant additional benefits.

Previous studies indicate that carbohydrate intake influences prostate cancer biology, as mice fed a no-carbohydrate ketogenic diet (NCKD) had significantly smaller xenograft tumors and longer survival than mice fed a Western diet. As it is nearly impossible for humans to consume and maintain NCKD, we determined whether diets containing 10% or 20% carbohydrate kcal showed similar tumor growth as NCKD. A total of 150 male severe combined immunodeficient mice were fed a Western diet ad libitum, injected with the human prostate cancer cell line LAPC-4, and then randomized 2 weeks later to one of three arms: NCKD, 10% carbohydrate, or 20% carbohydrate diets. Ten mice not injected were fed an ad libitum low-fat diet (12% fat kcal) serving as the reference in a modified-paired feeding protocol. Mice were sacrificed when tumors reached 1,000 mm3. Despite consuming extra calories, all mice receiving low-carbohydrate diets were significantly lighter than those receiving a low-fat diet (P < 0.04). Among the low-carbohydrate arms, NCKD-fed mice were significantly lighter than the 10% or 20% carbohydrate groups (P < 0.05). Tumors were significantly larger in the 10% carbohydrate group on days 52 and 59 (P < 0.05), but at no other point during the study. Diet did not affect survival (P = 0.34). There were no differences in serum insulin-like growth factor-I or insulin-like growth factor binding protein-3 at sacrifice among the low-carbohydrate arms (P = 0.07 and P = 0.55, respectively). Insulin was significantly lower in the 20% carbohydrate arm (P = 0.03). LAPC-4 xenograft mice fed a low-carbohydrate diet (10–20% carbohydrate kcal) had similar survival as mice consuming NCKD (0% carbohydrate kcal).