Presentations

Abstract

Introduction:

Patients undergoing radiation therapy, especially those with underlying metabolic dysfunction from obesity or diabetes, frequently suffer from radiation-induced toxicities including dermatitis and long-term fibrosis. These toxicities not only decrease patient quality of life but also decrease adherence to treatment regimens, resulting in unfavorable outcomes. Our laboratory has previously shown metabolic reprogramming augments the radiation response via downregulation of the IGF-1R pathway. Since IGF-1R is also implicated in radiation-induced toxicity, we sought to determine the role of dietary interventions in minimizing radiation- induced dermatitis and fibrosis.

Methods:

The leg shortening fibrosis model was used to determine the effect of metabolism on radiation-induced fibrosis. Mice with either a normal baseline metabolism or diabetes (induced by injection with Streptozotocin (STZ) 75 mg/kg in PBS via intraperitoneal injection for 5 consecutive days) were treated with a single 30 Gy dose of RT to the right hind leg, while the contralateral leg was used as control. The mice were then randomized to a) Ad Libitum diet, b) Caloric Restriction (30% reduced calorie diet), or c) Ketogenic diet. Progression of acute skin toxicities (erythema, hair loss and desquamation) were noted daily for 30 days and fibrosis was determined by measuring changes in length of the irradiated leg at 2 weeks, 30 days, 90 days and 120 days. Skin and muscle of both irradiated and control legs were collected at 120 days for histological analysis.

Results:

AL mice developed acute skin toxicities 2 weeks post-RT, which resolved within 4 weeks. CR altered the acute dermatitis and delayed signs of acute toxicity by 1 week post-RT (and resolving after 1 week), while KD fed mice had acute toxicity 2 weeks post-RT (and resolving after 6 weeks with persistent hair loss). Evaluating radiation-induced fibrosis, leg measurements at 120 days post-RT in the AL group were 10% shorter than the CR group (RT-78% vs CR-86%, p =0.01). Length percent changes of the irradiated AL and KD mice legs were comparable and not significantly different. Acute dermatitis was notably worse in diabetic mice compared to normal metabolism mice; however diabetic CR mice had delayed skin toxicities compared to the control. STZ mice developed acute toxicities 2 weeks post-RT and resolved after 2 weeks. STZ+CR mice developed acute toxicities 3 weeks post-RT, and resolved after 1 week. Additionally STZ+CR mice measured a 33% decrease in average blood glucose change compared to the control, and a 29% decrease in average body weight fluctuations. At 7 days, legs of mice in the STZ group were significantly shorter than STZ+CR (STZ-78% vs STZ+CR-90%, p=0.05). IHC staining with IGF-1R confirmed that CR reduced radiation-induced IGF-1R expression in the epidermis.

Discussion:

Radiation-induced acute skin toxicity and long-term skin fibrosis were alleviated in the setting of caloric restriction. Although mice with diabetes had worse acute skin toxicity, caloric restriction was able to mitigate the toxicity, as well as induce resistance to changes in both blood glucose and body weight. In the future, we will seek to elucidate the potential role of IGF-1R in the toxicity process and explore the effects of CR in other tissue types.