title: Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.
abstract: The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: John A
authors.initials: JA
authors.lastname: Cieslak
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Jessemae L
authors.initials: JL
authors.lastname: Welsh
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Zita A
authors.initials: ZA
authors.lastname: Sibenaller
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Bryan G
authors.initials: BG
authors.lastname: Allen
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Brett A
authors.initials: BA
authors.lastname: Wagner
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Kalen
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Doskey
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Strother
authors.affiliation: Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Button
authors.affiliation: Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Mott
authors.affiliation: Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Susan
authors.initials: S
authors.lastname: Tsai
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: James
authors.initials: J
authors.lastname: Mezhir
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Prabhat C
authors.initials: PC
authors.lastname: Goswami
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
authors.affiliation: Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Buettner
authors.affiliation: Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. Veterans Affairs Medical Center, Iowa City, Iowa. joseph-cullen@uiowa.edu.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cullen
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology*; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D059248:Chemoradiotherapy; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008819:Mice, Nude; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011839:Radiation, Ionizing; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D011838:Radiation-Sensitizing Agents; D006861:Hydrogen Peroxide; D005978:Glutathione; D001205:Ascorbic Acid; D019803:Glutathione Disulfide