Radioprotection Of Normal Esophageal Tissue By Soy Isoflavone Treatment

Patients undergoing definitive or neoadjuvant chemoradiation therapy (CRT) for locally advanced lung cancer very commonly experience acute, treatment-related esophagitis, with up to 20% of patients experiencing a grade 3 or higher toxicity. Late effects of therapy can include stenosis or fistula. Our pre-clinical studies in a naïve mouse lung model indicate that the inflammatory response in the lung induced by radiation can be attenuated by treatment with soy isoflavones. In this study, we have investigated whether soy isoflavones attenuate the changes induced by radiation in the normal esophagus. We hypothesize that soy isoflavones will modulate the inflammatory response of esophageal tissues to radiation offering a protective effect. Naive BALB/c mice received 10Gy thoracic irradiation with or without soy isoflavones given orally at 1 mg per day, prior-to and continuously after radiation for 8 weeks. Soy formulation (98.16% isoflavones) was 83.3% genistein, 14.6% daidzein, and 0.26% glycitein. Esophagi were resected at 8 weeks post-radiation and processed for histology analysis by H&E staining. Using commercially available image processing software, morphometric measurements were made in the subepithelial inner esophageal layer (IEL), located between the epithelium and muscularis externa, and includes the lamina propria, muscularis mucosa, and submucosa. Measurements (total 8) were taken in 4 fields times 3 mice per group for a total of 72 measurements. A t--test was used to determine differences in values between treatment groups (radiation + soy, radiation alone, and control). Radiation caused significant thickening of the IEL, mean 66.5+/-4.3um (SEM) compared with 22.7+/-0.8um IEL thickness in control mice (p<0.0001). When radiation was combined with soy treatment, IEL thickening was significantly reduced, measuring 37.2+/-1.1um compared with radiation alone (p<0.0001). The change in IEL thickness for irradiated mice was histologically characterized by an increased presence of inflammatory cells and fibroblasts, whereas the IEL in radiation + soy treated mice showed cellularity comparable to that of control. Thoracic radiation instigated an inflammatory response in the esophagus characterized by inflammatory cell infiltrate and subepithelial thickening, which was markedly attenuated by soy treatment. Our data suggest a radioprotective effect of soy isoflavones on esophageal tissues and warrant further investigation to describe the mechanisms responsible for these findings.