Caloric Restriction Decreases Radiation-Induced Normal Tissue Toxicity

Abstract

<h3>Purpose/Objective(s)</h3> Improvements in radiation delivery are limited by normal tissue toxicity. Studies show that the patient's metabolic state affects radiation toxicity. It has previously been shown that caloric restriction can be used to induce radiation sensitivity in treating breast and prostate tumors. Here we investigate the effect of caloric restriction on radiation induced normal tissue toxicity in two murine models. <h3>Materials/Methods</h3> To determine the role of diet on radiation induced normal tissue toxicity two toxicity models were used to assess mice fed either an ad libitum (AL), caloric restriction (CR: 30% reduction of calories) or ketogenic diet (KD: 60mg fat). A leg shortening model was used to assess acute and long-term skin toxicity by treating one leg of 9-week old Balb/c mice with a single- fraction of 30Gy of irradiation (320kV) with the rest of the body shielded and the contralateral leg serving as an unirradiated control. Measurements of leg length of irradiated compared with control leg length were performed. To assess differences in bone marrow, gastrointestinal and cardiac toxicity, total body radiation was administered to Balb/c mice using a dose of 6.5Gy (LD 50/30) with cohorts from each experimental diet. Histologic evaluation of small intestines and bone marrow was performed after tissue collection at 0, 1, 72 hours as well as 16-18 days post TBI. Small intestinal histology was reviewed by a gastrointestinal pathologist. Serum was evaluated for cardiac troponin 1 levels using ELISA at the same time points. Statistical comparisons were made using students t-test. <h3>Results</h3> The leg shortening model revealed radiation acute skin toxicity at 2 weeks post an ad libitum or ketogenic diet with skin peeling, hair loss, and moist desquamation that lasted 3 weeks compared to the mice treated with CR that had a delayed acute skin toxicity that only lasted 1 week. Long term, the irradiated leg was notably shortened and decreased by 22% and 20% relative to the contralateral leg in the AL and KD groups with 14% leg shortening and decreased fibrosis at 120 days post treatment in the CR groups (p<0.01). Gastrointestinal toxicity was decreased after TBI in mice on CR diet with less denuded villi epithelium and less obvious change in villi length at 72 hours compared to AL diet. The CR mice at 72 hours also had less variation in nuclear size within the epithelium and less changes in Paneth cells. Bone marrow was more hypocellular in the TBI mice on ad libitum diet compared with mice in the CR cohort. Acute cardiac toxicity was evaluated with serum troponin and was less elevated 72 hours post radiation in the CR group, 0.16ng/ml compared to 0.25ng/ml in the AL mice (p=0.03). <h3>Conclusion</h3> Dietary changes impact radiation induced toxicity. Our data show that caloric restriction decreases acute skin toxicity, fibrosis, gastrointestinal and cardiac toxicity. Future research is warranted to translate this strategy to decrease radiation induced normal tissue toxicity.