Pharmacologic Ascorbate as Radioprotector of Normal Tissue in Pancreatic Cancer Treatment

INTRODUCTION: Radiation (IR) is an integral part of pancreatic ductal adenocarcinoma (PDAC) treatment but is limited by toxicity to nearby organs. Pharmacologic ascorbate (P-AscH–, high-dose, intravenous vitamin C) synergizes with IR to increase toxicity in PDAC cells but may protect normal cells. We hypothesize that inhibition of oxidative stress in normal cells is involved in the radioprotective mechanism of P-AscH–. METHODS: Duodenal samples from pancreaticoduodenectomy specimens of patients who underwent IR and gemcitabine were compared with patients who received P-AscH– with gemcitabine and IR. Trichrome staining and 4HNE as a marker of protein oxidation were evaluated. PDAC cells (MIA PaCa-2) and normal pancreatic ductal epithelial cells (H6c7) were treated with IR at 2, 4, 6 Gy with and without P-AscH–, probed with BODIPY C-11 to determine lipid peroxidation. RESULTS: Average villi length was significantly greater in the duodenum from patients who received P-AscH- (5.3 ± 0.3 vs 6.3 ± 0.4, means ± SEM, p = 0.05). 4HNE immunofluorescence was also lower in the duodenum of patients that received P-AscH– treatment (23.9% vs 10.1%, p = 0.04). In vitro MIA PaCa-2 cells had increased BODIPY oxidation with P-AscH- at 2, 4, and 6 Gy (ANOVA p < 0.05), but H6c7 cells showed no meaningful changes between all groups. CONCLUSION: Consistent with previous in vivo studies, P-AscH– ameliorates IR-induced damage to normal cells. This mechanism of radioprotection of normal cells by P-AscH– may be due to inhibition of oxidative stress.