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

Welsh, Jessemae L.; Wagner, Brett A.; Erve, Thomas J van't; Zehr, Pamela; Berg, Daniel J.; Halfdanarson, Thorvardur R.; Yee, Nelson S.; Bodeker, Kellie L.; Du, Juan; Roberts, L. Jackson; Drisko, Jeanne; Levine, Mark; Buettner, Garry R.; Cullen, Joseph J.

doi:10.1007/s00280-013-2070-8

Cited by 253 publications

(357 citation statements)

References 25 publications

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“…The benefit of high doses of ascorbate in broad-spectrum cancer treatment was initially reported by Cameron and Pauling [77]; however, subsequent trials have either shown promising benefits in certain circumstances, or have provided no detectable advantages at all [78][79][80][81][82][83][84]. Nevertheless, it remains possible that vitamin C supplementation can reverse global loss of 5hmC [6] and hypermethylation of tumor-suppressor genes [75,76].…”

Section: Reprogrammingmentioning

confidence: 98%

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Hore

2017

Epigenomics

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Vitamins A and C represent unrelated sets of small molecules that are essential to the human diet and have recently been shown to intensify erasure of epigenetic memory in naive embryonic stem cells. These effects are driven by complementary enhancement of the ten-eleven translocation (TET) demethylases -vitamin A stimulates TET expression, whereas vitamin C potentiates TET catalytic activity. Vitamin A and C cosupplementation synergistically enhances reprogramming of differentiated cells to the naive state, but overuse may exaggerate instability of imprinted genes. As such, optimizing their use in culture media will be important for regenerative medicine and mammalian transgenics. In addition, mechanistic perception of how these vitamins interact with the epigenome may be relevant for understanding cancer and improving patient treatment. Figure 1A), and both are associated with a long recorded history. Nightblindness, an early symptom of vitamin A deficiency, and its cure through liver consumption, was known to Egyptians in the prehistoric period [1]. Equally, the debilitating effects of scurvy (vitamin C deficiency) among sailors, and its treatment with oranges, was registered as far back as 1498 [2]. Vitamins A and C also have a lengthy and rich history in scientific literature; in 1753 James Lind described the first controlled clinical trial where various antiscorbutic treatments were tested on British seamen and in 1929, Frederick Gowland Hopkins was co-awarded the Nobel Prize in Medicine for the 'discovery of vitamins' following milk supplementation experiments in vitamin A deficient mice [3]. Eventual isolation of the respective compounds underlying both vitamins led to Nobel Prizes in Chemistry and Medicine in 1937 [4]. Since this time, a considerable amount of scientific progress (and at times conjecture) has been associated with vitamins A and C, and their respective biological effects touch disciplines as divergent as development and dermatology.One of the most recently discovered fields that vitamins A and C impact upon is epigenetics [5][6][7]. New research has shown that both vitamins drive active removal of DNA methylation in embryonic stem cells (ESCs) by enhancing the same family of ten-eleven translocation (TET) enzymes, and in doing so, help erase DNA methylation and the epigenetic memory encoded by it to improve the reprogramming of differentiated cells to an embryonic-like state. Here I review the effects of vitamins A and C on DNA methylation and epigenetic memory in stem cells, and outline their significance for the fields For reprint orders, please contact: reprints@futuremedicine.com

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Section: Reprogrammingmentioning

confidence: 98%

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Hore

2017

Epigenomics

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“…Encouraging data emerged from a recent phase I trial at the University of Iowa examining toxicity and effects of intravenous ascorbate plus gemcitabine in patients with stage IV pancreatic adenocarcinoma (79). Nine patients completed at least one 4-week treatment cycle and were evaluable.…”

Section: Safetymentioning

confidence: 99%

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Parrow

Leshin

Levine

2013

Antioxidants & Redox Signaling

110

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Significance: Ewan Cameron reported that ascorbate, given orally and intravenously at doses of up to 10 g/day, was effective in the treatment of cancer. Double-blind placebo-controlled clinical trials showed no survival advantage when the same doses of ascorbate were given orally, leading the medical and scientific communities to dismiss the use of ascorbate as a potential cancer treatment. However, the route of administration results in major differences in ascorbate bioavailability. Tissue and plasma concentrations are tightly controlled in response to oral administration, but this can be bypassed by intravenous administration. These data provide a plausible scientific rationale for the absence of a response to orally administered ascorbate in the Mayo clinic trials and indicate the need to reassess ascorbate as a cancer therapeutic. Recent Advances: High dose ascorbate is selectively cytotoxic to cancer cell lines through the generation of extracellular hydrogen peroxide (H 2 O 2 ). Murine xenograft models confirm a growth inhibitory effect of pharmacological concentrations. The safety of intravenous ascorbate has been verified in encouraging pilot clinical studies. Critical Issues: Neither the selective toxicity of pharmacologic ascorbate against cancer cells nor the mechanism of H 2 O 2 -mediated cytotoxicity is fully understood. Despite promising preclinical data, the question of clinical efficacy remains. Future Directions: A full delineation of mechanism is of interest because it may indicate susceptible cancer types. Effects of pharmacologic ascorbate used in combination with standard treatments need to be defined. Most importantly, the clinical efficacy of ascorbate needs to be reassessed using proper dosing, route of administration, and controls.

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“…The therapeutic potential of pharmacological doses of ascorbate alone has already been demonstrated in several preclinical and clinical trials (46,61,83,127) and is based on the increased production of reactive species due to ascorbate oxidation, catalyzed by endogenous metalloproteins (36). MnPs, however, are advantageous, as their redox properties can be optimized in order to achieve the maximal rate of ascorbate oxidation.…”

Section: Tovmasyan Et Almentioning

confidence: 99%

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

Tovmasyan

Rebouças

Benov

2014

Antioxidants & Redox Signaling

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Significance: Half a century of research provided unambiguous proof that superoxide and species derived from it-reactive oxygen species (ROS)-play a central role in many diseases and degenerative processes. This stimulated the search for pharmaceutical agents that are capable of preventing oxidative damage, and methods of assessing their therapeutic potential. Recent Advances: The limitations of superoxide dismutase (SOD) as a therapeutic tool directed attention to small molecules, SOD mimics, that are capable of catalytically scavenging superoxide. Several groups of compounds, based on either metal complexes, including metalloporphyrins, metallocorroles, Mn(II) cyclic polyamines, and Mn(III) salen derivatives, or non-metal based compounds, such as fullerenes, nitrones, and nitroxides, have been developed and studied in vitro and in vivo. Very few entered clinical trials. Critical Issues and Future Directions: Development of SOD mimics requires in-depth understanding of their mechanisms of biological action. Elucidation of both molecular features, essential for efficient ROS-scavenging in vivo, and factors limiting the potential side effects requires biologically relevant and, at the same time, relatively simple testing systems. This review discuses the advantages and limitations of genetically engineered SOD-deficient unicellular organisms, Escherichia coli and Saccharomyces cerevisiae as tools for investigating the efficacy and mechanisms of biological actions of SOD mimics. These simple systems allow the scrutiny of the minimal requirements for a functional SOD mimic: the association of a high catalytic activity for superoxide dismutation, low toxicity, and an efficient cellular uptake/biodistribution. Antioxid. Redox Signal. 20, 2416Signal. 20, -2436

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

Cited by 253 publications

References 25 publications

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

Parenteral Ascorbate As a Cancer Therapeutic: A Reassessment Based on Pharmacokinetics

Simple Biological Systems for Assessing the Activity of Superoxide Dismutase Mimics

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