Chief, Surgical Services, VA Medical Center
Professor of Surgery
- Gastrointestinal, Minimally-invasive and Bariatric Surgery
Primary Office: 1528 JCP
Iowa City, IA 52242
Web: Research website
MD, University of Iowa
BS, Loras College
Residency, General Surgery, University of Iowa
Fellowship, Digestive Disease, NIH Fellow, Mayo Clinic
Licensure and Certifications
Iowa Medical License (permanent), Iowa Board of Medicine
Board Certified, General Surgery, American Board of Surgery
Education/Training Program Affiliations
Free Radical and Radiation Biology Graduate Program
Interdisciplinary Graduate Program in Translational Biomedicine
Medical Scientist Training Program
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 cancer 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. This 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.
Cieslak III J,
Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer.
Free Radical Biology and Medicine.
2014 April. 69:357-66.
Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.
2013 August 15. 73(16):5232-5241.
Regulation of pancreatic cancer growth by superoxide.
2013 July. 52(7):555-567.
van 't Erve T,
Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): Results from a phase I clinical trial.
Cancer Chemotherapy and Pharmacology.
2013 March. 71(3):765-775.
Ascorbic acid: chemistry, biology and the treatment of cancer.
BBA Reviews on Cancer.
2012 December. 1826(2):443-457.
Role of Rac1-dependent NADPH oxidase in the growth of pancreatic cancer.
Cancer Gene Therapy.
2011 February. 18(2):135-143.
Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer.
Clinical Cancer Research.
2010 January 15. 16(2):509-520.
Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue.
2010 January. 5(1):51-66.
Enhancing the antitumor activity of adriamycin and ionizing radiation.
2009 May 15. 69(10):4294-4300.
Mitochondrial production of reactive oxygen species mediate dicumarol-induced cytotoxicity in cancer cells.
Journal of Biological Chemistry.
2006 December 8. 281(49):37416-37426.
Date Last Modified: 10/09/2015 -