title: Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer.
abstract: Conventional treatment approaches have had little impact on the course of pancreatic cancer, which has the highest fatality rate among cancers. Gemcitabine, the primary therapeutic agent for pancreatic carcinoma, produces minimal survival benefit as a single agent. Therefore, numerous efforts have focused on gemcitabine combination treatments. Using a ratio design, this study established that combining pharmacologically achievable concentrations of ascorbate with gemcitabine resulted in a synergistic cytotoxic response in eight pancreatic tumor cell lines. Sensitization was evident regardless of inherent gemcitabine resistance and epithelial-mesenchymal phenotype. Our analysis suggested that the promiscuous oxidative actions of H(2)O(2) derived from pharmacologic ascorbate can culminate in synergism independent of the cancer cell's underlying phenotype and resistance to gemcitabine monotherapy. Gemcitabine-ascorbate combinations administered to mice bearing pancreatic tumor xenografts consistently enhanced inhibition of growth compared to gemcitabine alone, produced 50% growth inhibition in a tumor type not responsive to gemcitabine, and demonstrated a gemcitabine dose-sparing effect. These data support the testing of pharmacologic ascorbate in adjunctive treatments for cancers prone to high failure rates with conventional therapeutic regimens, such as pancreatic cancer.
authors.affiliation: Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michael Graham
authors.initials: MG
authors.lastname: Espey
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Brian
authors.initials: B
authors.lastname: Chalmers
authors.forename: Jeanne
authors.initials: J
authors.lastname: Drisko
authors.forename: Andrew Y
authors.initials: AY
authors.lastname: Sun
authors.forename: Mark
authors.initials: M
authors.lastname: Levine
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001205:Ascorbic Acid / Q000008:administration & dosage*; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D001205:Ascorbic Acid; D000093542:Gemcitabine