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Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer
Journal article   Open access   Peer reviewed

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer

Matthew S Alexander, Justin G Wilkes, Samuel R Schroeder, Garry R Buettner, Brett A Wagner, Juan Du, Katherine Gibson-Corley, Brianne R O'Leary, Douglas R Spitz, John M Buatti, …
Cancer research (Chicago, Ill.), Vol.78(24), pp.6838-6851
12/15/2018
DOI: 10.1158/0008-5472.CAN-18-1680
PMCID: PMC6295907
PMID: 30254147
url
https://doi.org/10.1158/0008-5472.CAN-18-1680View
Published (Version of record) Open Access

Abstract

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH , i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (H O )-mediated mechanism. In this study, we demonstrate that P-AscH radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH , while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH during the radiotherapy "beam on." Specifically, treatment with P-AscH increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH -treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.
 Cell Proliferation Oxidative Stress Glutathione - metabolism Humans Middle Aged Radiation Tolerance Male Pancreatic Neoplasms - drug therapy Aged, 80 and over Female Recombinant Proteins - metabolism Cell Survival Deoxycytidine - administration & dosage Pancreatic Neoplasms - radiotherapy Treatment Outcome Radiotherapy Collagen - metabolism Disease-Free Survival Animals Mice, Nude Ascorbic Acid - pharmacology Cell Line, Tumor Aged Mice DNA Damage Deoxycytidine - analogs & derivatives

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