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Pancreatic Neoplasms: HELP
Articles by Brett A. Wagner
Based on 11 articles published since 2009
(Why 11 articles?)
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Between 2009 and 2019, B. A. Wagner wrote the following 11 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer. 2018

Alexander, Matthew S / Wilkes, Justin G / Schroeder, Samuel R / Buettner, Garry R / Wagner, Brett A / Du, Juan / Gibson-Corley, Katherine / O'Leary, Brianne R / Spitz, Douglas R / Buatti, John M / Berg, Daniel J / Bodeker, Kellie L / Vollstedt, Sandy / Brown, Heather A / Allen, Bryan G / Cullen, Joseph J. ·Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa. · Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa. · The Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, Iowa. · Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, The University of Iowa Carver College of Medicine, Iowa City, Iowa. · Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa. joseph-cullen@uiowa.edu. · The Veterans' Affairs Medical Center, Iowa City, Iowa. ·Cancer Res · Pubmed #30254147.

ABSTRACT: : Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH

2 Clinical Trial Pharmacological ascorbate with gemcitabine for the control of metastatic and node-positive pancreatic cancer (PACMAN): results from a phase I clinical trial. 2013

Welsh, J L / Wagner, B A / van't Erve, T J / Zehr, P S / Berg, D J / Halfdanarson, T R / Yee, N S / Bodeker, K L / Du, J / Roberts, L J / Drisko, J / Levine, M / Buettner, G R / Cullen, J J. ·Department of Surgery, 1528 JCP-UIHC, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA. ·Cancer Chemother Pharmacol · Pubmed #23381814.

ABSTRACT: BACKGROUND: Treatment for pancreatic cancer with pharmacological ascorbate (ascorbic acid, vitamin C) decreases tumor progression in preclinical models. A phase I clinical trial was performed to establish safety and tolerability of pharmacological ascorbate combined with gemcitabine in patients with biopsy-proven stage IV pancreatic adenocarcinoma. DESIGN: Nine subjects received twice-weekly intravenous ascorbate (15-125 g) employing Simon's accelerated titration design to achieve a targeted post-infusion plasma level of ≥350 mg/dL (≥20 mM). Subjects received concurrent gemcitabine. Disease burden, weight, performance status, hematologic and metabolic laboratories, time to progression and overall survival were monitored. RESULTS: Mean plasma ascorbate trough levels were significantly higher than baseline (1.46 ± 0.02 vs. 0.78 ± 0.09 mg/dL, i.e., 83 vs. 44 μM, p < 0.001). Adverse events attributable to the drug combination were rare and included diarrhea (n = 4) and dry mouth (n = 6). Dose-limiting criteria were not met for this study. Mean survival of subjects completing at least two cycles (8 weeks) of therapy was 13 ± 2 months. CONCLUSIONS: Data suggest pharmacologic ascorbate administered concurrently with gemcitabine is well tolerated. Initial data from this small sampling suggest some efficacy. Further studies powered to determine efficacy should be conducted.

3 Article Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer. 2019

Alexander, Matthew S / O'Leary, Brianne R / Wilkes, Justin G / Gibson, Adrienne R / Wagner, Brett A / Du, Juan / Sarsour, Ehab / Hwang, Rosa F / Buettner, Garry R / Cullen, Joseph J. ·a   Department of Surgery, University of Iowa, Iowa City, Iowa. · b   Free Radical and Radiation Biology Program, University of Iowa, Iowa City, Iowa. · c   Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. · d   The University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa. · e   Veterans Affairs Medical Center, Iowa City, Iowa. ·Radiat Res · Pubmed #30376411.

ABSTRACT: Pharmacologic ascorbate (P-AscH

4 Article Tumor cells have decreased ability to metabolize H 2016

Doskey, Claire M / Buranasudja, Visarut / Wagner, Brett A / Wilkes, Justin G / Du, Juan / Cullen, Joseph J / Buettner, Garry R. ·Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA. · Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA. · Department of Surgery, The University of Iowa, Iowa City, IA 52242, USA. · Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA; Department of Surgery, The University of Iowa, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Veterans Affairs Medical Center, Iowa City, IA 52246, USA. · Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA; Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA. Electronic address: garry-buettner@uiowa.edu. ·Redox Biol · Pubmed #27833040.

ABSTRACT: Ascorbate (AscH

5 Article Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. 2015

Du, Juan / Cieslak, John A / Welsh, Jessemae L / Sibenaller, Zita A / Allen, Bryan G / Wagner, Brett A / Kalen, Amanda L / Doskey, Claire M / Strother, Robert K / Button, Anna M / Mott, Sarah L / Smith, Brian / Tsai, Susan / Mezhir, James / Goswami, Prabhat C / Spitz, Douglas R / Buettner, Garry R / Cullen, Joseph J. ·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. · Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. · Holden Comprehensive Cancer Center, Iowa City, Iowa. · Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. · 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. ·Cancer Res · Pubmed #26081808.

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.

6 Article Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer. 2015

Cieslak, John A / Strother, Robert K / Rawal, Malvika / Du, Juan / Doskey, Claire M / Schroeder, Samuel R / Button, Anna / Wagner, Brett A / Buettner, Garry R / Cullen, Joseph J. ·Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA. · Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. · Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. · Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: joseph-cullen@uiowa.edu. ·Free Radic Biol Med · Pubmed #25725418.

ABSTRACT: Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.

7 Article Loss of SOD3 (EcSOD) Expression Promotes an Aggressive Phenotype in Human Pancreatic Ductal Adenocarcinoma. 2015

O'Leary, Brianne R / Fath, Melissa A / Bellizzi, Andrew M / Hrabe, Jennifer E / Button, Anna M / Allen, Bryan G / Case, Adam J / Altekruse, Sean / Wagner, Brett A / Buettner, Garry R / Lynch, Charles F / Hernandez, Brenda Y / Cozen, Wendy / Beardsley, Robert A / Keene, Jeffery / Henry, Michael D / Domann, Frederick E / Spitz, Douglas R / Mezhir, James J. ·Department of Surgery, University of Iowa, Iowa City, Iowa. · Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. · Department of Pathology, University of Iowa, Iowa City, Iowa. · Department of Biostatistics, University of Iowa, Iowa City, Iowa. · National Cancer Institute, Bethesda, Maryland. · Department of Epidemiology, University of Iowa, Iowa City, Iowa. · University of Hawaii Cancer Center, Honolulu, Hawaii. · University of Southern California, Los Angeles, California. · Galera Therapeutics, Malvern, Pennsylvania. · Department of Microbiology, University of Iowa, Iowa City, Iowa. · Department of Surgery, University of Iowa, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa, Iowa City, Iowa. james-mezhir@uiowa.edu. ·Clin Cancer Res · Pubmed #25634994.

ABSTRACT: PURPOSE: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. EXPERIMENTAL DESIGN: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. RESULTS: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. CONCLUSIONS: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease.

8 Article Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer. 2013

Moser, Justin C / Rawal, Malvika / Wagner, Brett A / Du, Juan / Cullen, Joseph J / Buettner, Garry R. ·Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA. · Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA ; Department of Surgery, The University of Iowa, Iowa City, IA, USA ; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA. · Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA ; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA. ·Redox Biol · Pubmed #24396727.

ABSTRACT: Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors.

9 Article Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation. 2013

Rawal, Malvika / Schroeder, Samuel R / Wagner, Brett A / Cushing, Cameron M / Welsh, Jessemae L / Button, Anna M / Du, Juan / Sibenaller, Zita A / Buettner, Garry R / Cullen, Joseph J. ·Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA, USA. ·Cancer Res · Pubmed #23764544.

ABSTRACT: Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

10 Article Regulation of pancreatic cancer growth by superoxide. 2013

Du, Juan / Nelson, Elke S / Simons, Andrean L / Olney, Kristen E / Moser, Justin C / Schrock, Hannah E / Wagner, Brett A / Buettner, Garry R / Smith, Brian J / Teoh, Melissa L T / Tsao, Ming-Sound / Cullen, Joseph J. ·Departments of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. ·Mol Carcinog · Pubmed #22392697.

ABSTRACT: K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O 2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O 2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O 2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O 2.-, and treatment with the small molecule O 2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O 2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.

11 Article Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. 2010

Du, Juan / Martin, Sean M / Levine, Mark / Wagner, Brett A / Buettner, Garry R / Wang, Sih-han / Taghiyev, Agshin F / Du, Changbin / Knudson, Charles M / Cullen, Joseph J. ·Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. ·Clin Cancer Res · Pubmed #20068072.

ABSTRACT: PURPOSE: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%. EXPERIMENTAL DESIGN: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks. RESULTS: There was a time- and dose-dependent increase in measured H(2)O(2) production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H(2)O(2). Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival. CONCLUSIONS: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer.