Adenocarcinoma of the pancreas is the fourth leading cause of cancer death in the United States and is increasing in incidence. Intravenous ascorbate (i.e., ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations, which are in the range that are cytotoxic to tumor cells. Studies from our currently funded 2 year U01 grant CA166800 Ascorbate-induced radiosensitization in pancreatic cancer have demonstrated that ascorbate, in doses achievable in humans, synergizes with ionizing radiation in decreasing viability and proliferation in all pancreatic cancr cell lines examined, via a H2O2-mediated mechanism. Our recently completed phase I study demonstrated that pharmacological ascorbate combined with gemcitabine is safe and well-tolerated and may lead to overall clinical benefit in patients with stage IV pancreatic cancer. Thi proposal focuses on improvement of the therapeutic ratio of a standard anti-cancer therapy (ionizing radiation) using a complementary approach (high dose ascorbate), in the treatment of pancreatic cancer. If pancreatic cancer cells (relative to normal cells) are more susceptible to ascorbate-induced cytotoxicity due to increased ascorbate auto-oxidation leading to increased H2O2 production, then ascorbate would be expected to be efficacious and well-tolerated adjuvant to chemo-radiation in patients. Furthermore, increasing the rate of auto- oxidation of ascorbate with redox active metal catalysts to generate more H2O2 should selectively increase ascorbate-induced radiosensitization and oxidative stress. Finally, ascorbate-induced radiosensitization would be expected to sensitize tumor cells to clinically relevant pharmacological agents that inhibit the removal of H2O2. The current proposal will test the hypothesis that production of H2O2 via the metal ion catalyzed auto- oxidation of ascorbate mediates ascorbate-induced cytotoxicity and chemo-radiosensitization in human pancreatic cancer. We will test our hypothesis with the following three Specific Aims. 1) Determine in a phase I trial the safety of administering pharmacological ascorbate during concurrent gemcitabine-radiation therapy for the treatment of non-resectable pancreatic cancer; 2) Determine if ascorbate-induced radiosensitization can be selectively enhanced by redox active metal catalysts; 3) Determine if the ascorbate-induced radiosensitization can be enhanced by clinically relevant pharmacological inhibitors of glucose and hydroperoxide metabolism. The phase I trial will quantify adverse events and determine changes in systemic parameters indicative of oxidative stress in patients. The preclinical studies will use biochemistry/molecular biology techniques to determine ascorbate-induced radiosensitization and oxidative stress and employ a non- invasive in vivo index of cell proliferation. If we can rigorously demonstrate that the radiosensitization mediated by pharmacological ascorbate induces preferential oxidative stress and subsequent cytotoxicity in human pancreatic cancer cells, then the results of this proposed research program will provide a foundation for the rational design of a novel combined modality cancer therapy for pancreatic cancer.

Public Health Relevance

Intravenous ascorbate produces high plasma concentrations in the range that is cytotoxic to pancreatic tumor cells. Pharmacological ascorbate has been hypothesized to be a pro-drug for formation of hydrogen peroxide (H2O2). Our proposal investigates mechanisms to enhance radiosensitivity of human pancreatic cancer cells by the flux of H2O2 generated by treatment with pharmacological ascorbate.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Radiation Therapeutics and Biology Study Section (RTB)
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Buchsbaum, Jeffrey
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University of Iowa
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Iowa City
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O'Leary, Brianne R; Houwen, Frederick K; Johnson, Chase L et al. (2018) Pharmacological Ascorbate as an Adjuvant for Enhancing Radiation-Chemotherapy Responses in Gastric Adenocarcinoma. Radiat Res 189:456-465
Alexander, Matthew S; Wilkes, Justin G; Schroeder, Samuel R et al. (2018) Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. Cancer Res 78:6838-6851
Alexander, Matthew S; Cullen, Joseph J (2018) Treating pancreatic cancer: more antioxidants more problems? Expert Rev Gastroenterol Hepatol 12:849-851
Wilkes, Justin G; O'Leary, Brianne R; Du, Juan et al. (2018) Pharmacologic ascorbate (P-AscH-) suppresses hypoxia-inducible Factor-1? (HIF-1?) in pancreatic adenocarcinoma. Clin Exp Metastasis 35:37-51
Schoenfeld, Joshua D; Sibenaller, Zita A; Mapuskar, Kranti A et al. (2017) O2?- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell 31:487-500.e8
Xi, Dan; Bao, Ting; Chen, Qi et al. (2017) State of the Science: Cancer Complementary and Alternative Medicine Therapeutics Research-NCI Strategic Workshop Highlights of Discussion Report. J Natl Cancer Inst Monogr 2017:
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Cieslak, John A; Sibenaller, Zita A; Walsh, Susan A et al. (2016) Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy. Radiat Res 185:31-8
Doskey, Claire M; Buranasudja, Visarut; Wagner, Brett A et al. (2016) Tumor cells have decreased ability to metabolize H2O2: Implications for pharmacological ascorbate in cancer therapy. Redox Biol 10:274-284

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