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Pancreatic Neoplasms: HELP
Articles by Mark N. Levine
Based on 7 articles published since 2009
(Why 7 articles?)
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Between 2009 and 2019, M. Levine wrote the following 7 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Clinical Trial High Dose Parenteral Ascorbate Inhibited Pancreatic Cancer Growth and Metastasis: Mechanisms and a Phase I/IIa study. 2017

Polireddy, Kishore / Dong, Ruochen / Reed, Gregory / Yu, Jun / Chen, Ping / Williamson, Stephen / Violet, Pierre-Christian / Pessetto, Ziyan / Godwin, Andrew K / Fan, Fang / Levine, Mark / Drisko, Jeanne A / Chen, Qi. ·Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA. · Integrative Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. · Department of Internal Medicine, Hematology and Oncology Division, University of Kansas Medical Center, Kansas City, KS, 66160, USA. · National Institute of Diabetes, Digestive and Kidney Diseases, the National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. · Integrative Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. jdrisko@kumc.edu. · Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, 66160, USA. qchen@kumc.edu. · Integrative Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. qchen@kumc.edu. ·Sci Rep · Pubmed #29215048.

ABSTRACT: Pancreatic cancer is among the most lethal cancers with poorly tolerated treatments. There is increasing interest in using high-dose intravenous ascorbate (IVC) in treating this disease partially because of its low toxicity. IVC bypasses bioavailability barriers of oral ingestion, provides pharmacological concentrations in tissues, and exhibits selective cytotoxic effects in cancer cells through peroxide formation. Here, we further revealed its anti-pancreatic cancer mechanisms and conducted a phase I/IIa study to investigate pharmacokinetic interaction between IVC and gemcitabine. Pharmacological ascorbate induced cell death in pancreatic cancer cells with diverse mutational backgrounds. Pharmacological ascorbate depleted cellular NAD+ preferentially in cancer cells versus normal cells, leading to depletion of ATP and robustly increased α-tubulin acetylation in cancer cells. While ATP depletion led to cell death, over-acetylated tubulin led to inhibition of motility and mitosis. Collagen was increased, and cancer cell epithelial-mesenchymal transition (EMT) was inhibited, accompanied with inhibition in metastasis. IVC was safe in patients and showed the possibility to prolong patient survival. There was no interference to gemcitabine pharmacokinetics by IVC administration. Taken together, these data revealed a multi-targeting mechanism of pharmacological ascorbate's anti-cancer action, with minimal toxicity, and provided guidance to design larger definitive trials testing efficacy of IVC in treating advanced pancreatic cancer.

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 Clinical Trial Phase I evaluation of intravenous ascorbic acid in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. 2012

Monti, Daniel A / Mitchell, Edith / Bazzan, Anthony J / Littman, Susan / Zabrecky, George / Yeo, Charles J / Pillai, Madhaven V / Newberg, Andrew B / Deshmukh, Sandeep / Levine, Mark. ·Myrna Brind Center of Integrative Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania, United States of America. ·PLoS One · Pubmed #22272248.

ABSTRACT: BACKGROUND: Preclinical data support further investigation of ascorbic acid in pancreatic cancer. There are currently insufficient safety data in human subjects, particularly when ascorbic acid is combined with chemotherapy. METHODS AND FINDINGS: 14 subjects with metastatic stage IV pancreatic cancer were recruited to receive an eight week cycle of intravenous ascorbic acid (three infusions per week), using a dose escalation design, along with standard treatment of gemcitabine and erlotinib. Of 14 recruited subjects enrolled, nine completed the study (three in each dosage tier). There were fifteen non-serious adverse events and eight serious adverse events, all likely related to progression of disease or treatment with gemcitabine or erlotinib. Applying RECIST 1.0 criteria, seven of the nine subjects had stable disease while the other two had progressive disease. CONCLUSIONS: These initial safety data do not reveal increased toxicity with the addition of ascorbic acid to gemcitabine and erlotinib in pancreatic cancer patients. This, combined with the observed response to treatment, suggests the need for a phase II study of longer duration. TRIAL REGISTRATION: Clinicaltrials.gov NCT00954525.

4 Article Treatment of pancreatic cancer with intravenous vitamin C: a case report. 2018

Drisko, Jeanne A / Serrano, Oscar K / Spruce, Lisa R / Chen, Qi / Levine, Mark. ·Department of Internal Medicine, Division of KU Integrative Medicine. · Department of Surgery, Division of Transplantation, University of Minnesota, Minneapolis, Minnesota. · Association of Perioperative Registered Nurses, Director of Evidence-Based Perioperative Practice, Denver, Colorado. · Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Health System, Kansas City, Kansas. · National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Clinical Nutrition Section, Bethesda, Maryland, USA. ·Anticancer Drugs · Pubmed #29438178.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and is often discovered at an advanced stage with few therapeutic options. Current conventional regimens for PDA are associated with significant morbidity, decreased quality of life, and a considerable financial burden. As a result, some patients turn to integrative medicine therapies as an alternate option after a diagnosis of PDA. Intravenous pharmacologic ascorbic acid (PAA) is one such treatment. The use of PAA has been passionately debated for many years, but more recent rigorous scientific research has shown that there are significant blood concentration differences when ascorbic acid is given parenterally when compared to oral dosing. This pharmacologic difference appears to be critical for its role in oncology. Here, we report the use of PAA in a patient with poorly differentiated stage IV PDA as an exclusive chemotherapeutic regimen. The patient survived nearly 4 years after diagnosis, with PAA as his sole treatment, and he achieved objective regression of his disease. He died from sepsis and organ failure from a bowel perforation event. This case illustrates the possibility of PAA to effectively control tumor progression and serve as an adjunct to standard of care PDA chemotherapy regimens. Our patient's experience with PAA should be taken into consideration, along with previous research in cell, animal, and clinical experiments to design future treatment trials.

5 Article Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. 2011

Espey, Michael Graham / Chen, Ping / Chalmers, Brian / Drisko, Jeanne / Sun, Andrew Y / Levine, Mark / Chen, Qi. ·Molecular and Clinical Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ·Free Radic Biol Med · Pubmed #21402145.

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.

6 Article Assessing the volume-outcome hypothesis and region-level quality improvement interventions: pancreas cancer surgery in two Canadian Provinces. 2010

Simunovic, Marko / Urbach, David / Major, Diane / Sutradhar, Rinku / Baxter, Nancy / To, Teresa / Brown, Adalsteinn / Davis, Dave / Levine, Mark N. ·Department of Surgery, Hamilton Health Sciences, McMaster University, Hamilton, ON, Canada. marko.simunovic@jcc.hhsc.ca ·Ann Surg Oncol · Pubmed #20625843.

ABSTRACT: BACKGROUND: The volume-outcome hypothesis suggests that if increased provider procedure volume is associated with improved patient outcomes, then greater regionalization to high-volume providers should improve region-level outcomes. Quality improvement interventions for pancreas cancer surgery implemented in year 1999 in Ontario, Canada were designed to regionalize surgery to high-volume hospitals and decrease operative mortality. Similar interventions were not used in Quebec, Canada. We assessed the volume-outcome hypothesis and the impact of the Ontario quality improvement interventions. MATERIALS AND METHODS: Administrative databases helped identify pancreatic resections from years 1994 to 2004 and relevant patient and hospital characteristics. Hospitals were high-volume if they provided ≥10 procedures in a given calendar year. Outcomes were regionalization of surgery to high-volume providers and rates of operative mortality. RESULTS: From 1994 to 2004 the percentage of cases in high-volume hospitals increased from 33 to 71% in Ontario and from 36 to 76% in Quebec. Annual rates of operative mortality dropped in Ontario (10.4-2.2% or less) and changed little in Quebec (7.2-9.8%). Changes in measures over time in both provinces were similar before and after year 1999. CONCLUSIONS: Regionalization was associated with improved operative mortality in Ontario but not in Quebec, undermining the volume-outcome hypothesis. The Ontario quality improvement interventions likely were of little influence since patterns in regionalization and operative mortality were similar before and after year 1999.

7 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.