Dietary administration of black raspberries modulates markers of oxidative stress in patients with Barrett’s esophagus.

B34

Oxidative damage has been implicated in the progression and development of esophageal adenocarcinoma (EAC), a rapidly increasing and extremely deadly malignancy. Barrett’s esophagus (BE) is a premalignant condition in which the normal stratified squamous epithelium lining the esophagus is replaced by metaplastic columnar epithelium with goblet cells. Barrett's typically develops in the background of gastroesophageal reflux disease. BE importance lies in the fact that it confers a 30-40 fold increased risk for the development of esophageal adenocarcinoma. Thus, BE patients represent a population for whom targeted chemopreventive interventions may prove particularly beneficial. Dietary administration of lyophilized black raspberries (LBR) has inhibited chemically induced oral, esophageal, and colon carcinogenesis in animal models. LBR have reduced measures of oxidative stress, decreased DNA damage, inhibited cellular proliferation rates, and reduced levels of esophageal and colon preneoplasia in pre-clinical models. These observations lead us to hypothesize that dietary administration of LBR may modulate markers of DNA or oxidative damage associated with gastroesophageal reflux disease and in turn inhibit the progression of Barrett’s esophagus. We conducted a six month chemopreventive intervention where 32 and 45 grams of LBR (female and male, respectively) were administered daily to twenty patients with BE. Tissue, blood, and urinary biomarkers were assessed pre- and post-intervention utilizing enzyme-linked immunosorbent assays to measure urinary 8-epi-prostaglandin F2α (8-Iso-PGF2α) and 8-hydroxy-2’-deoxyguanosine (8-OHdG) and immunohistochemical methods were employed to measure GSTπ, NFκB, Ki-67 and CDX2 in Barrett’s epithelium. Urinary biomarkers were corrected for urinary creatinine levels to control for potential differences in urine volumes collected between patients. Patients experienced a statistically significant decline in mean levels of 8-Iso-PGF2α following 26 weeks of LBR consumption and 58% of patients experienced marked individual level declines. Mean concentrations of 8-Iso-PGF2α were 1.59E-10, 1.38E-10, and 1.30E-10 mg/ml urine at baseline, week 12, and week 26 of study, respectively. Conversely, mean levels of urinary 8-OHdG were not significantly reduced in this patient population at 26 weeks of study. However, all patients experiencing declines in urinary 8-OHdG also had reduced 8-Iso-PGF2α levels (r=0.82). LBR also resulted in increased expression of GSTπ in Barrett’s tissues among 37% of the patients. LBR treatment did not result in significant changes in mean Ki-67 staining levels in this cohort. Only low levels of CDX2 were detectable limiting the usefulness of this marker. NFκB analysis is ongoing. Pilot study results support that daily administration of LBR for 6 months significantly reduces urinary 8-Iso-PGF2α, a marker of oxidative stress, and that LBR increases tissue levels of the phase II enzyme GSTπ in a subset of BE patients. These results are encouraging and support conducting a randomized placebo controlled trail in this patient cohort to more fully assess LBR as inhibitors of esophageal adenocarcinogenesis.