CMAJ. 2006 Mar 28;174(7):937-42.
Intravenously administered vitamin C as cancer therapy: three cases.
Padayatty SJ, Riordan HD, Hewitt SM, Katz A, Hoffer LJ, Levine M.
Source
Molecular and Clinical Nutrition Section, Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md 20892-1372, USA.
Abstract
Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 micromol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50-100 g) given intravenously may result in plasma concentrations of about 14,000 micromol/L. At concentrations above 1000 micromol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with NationalCancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed.
Comment in
- The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.
www.riordanclinic.org
J Transl Med. 2012 Sep 11;10:189. doi: 10.1186/1479-5876-10-189.
Effect of high-dose intravenous vitamin C on inflammation in cancer patients.
Mikirova N, Casciari J, Rogers A, Taylor P.
Source
Riordan Clinic, 3100 North Hillside, Wichita, KS, USA. nmikirova@riordanclinic.org
Abstract
BACKGROUND:
An inflammatory component is present in the microenvironment of most neoplastic tissues. Inflammation and elevated C-reactive protein (CRP) are associated with poor prognosis and decreased survival in many types of cancer.Vitamin C has been suggested as having both a preventative and therapeutic role in a number of pathologies when administered at much higher-than-recommended dietary allowance levels.Since in vitro studies demonstrated inhibition of pro-inflammatory pathways by millimolar concentrations of vitamin C, we decided to analyze the effects of high dose IVC therapy in suppression of inflammation in cancer patients.
METHODS:
45 patients with prostate cancer, breast cancer, bladder cancer, pancreatic cancer, lung cancer, thyroid cancer, skin cancer and B-cell lymphoma were treated at the Riordan Clinic by high doses of vitamin C (7.5 g -50 g) after standard treatments by conventional methods.CRP and tumor markers were measured in serum or heparin-plasma as a routine analysis. In addition, serum samples were collected before and after the IVCs for the cytokine kit tests.
RESULTS:
According to our data positive response to treatment, which was demonstrated by measurements of C- reactive protein, was found in 75% of patients and progression of the inflammation in 25% of patients. IVC treatments on all aggressive stage cancer patients showed the poor response of treatment.There was correlation between tumor markers (PSA, CEA, CA27.29 and CA15-3) and changes in the levels of C-reactive protein.Our test of the effect of IVC on pro-inflammatory cytokines demonstrated that inflammation cytokines IL-1α, IL-2, IL-8, TNF-α, chemokine eotaxin and CRP were reduced significantly after treatments.
CONCLUSIONS:
The high dose intravenous ascorbic acid therapy affects C-reactive protein levels and pro-inflammation cytokines in cancer patients. In our study, we found that modulation of inflammation by IVC correlated with decreases in tumor marker levels.In summary, our data support the hypothesis that high dose intravenous ascorbate treatments may reduce inflammation in cancer patients. Our results suggest that further investigations into the use of IVC to reduce inflammation in diseases where inflammation is relevant are warranted.
PMID: 22963460 [PubMed – indexed for MEDLINE] PMCID: PMC3480897 Free PMC Article
www.riordanclinic.org
Cell Signal. 2005 Jan;17(1):111-9.
Activation of Raf1 and the ERK pathway in response to l-ascorbic acid in acute myeloid leukemia cells.
Park S, Park CH, Hahm ER, Kim K, Kimler BF, Lee SJ, Park HK, Lee SH, Kim WS, Jung CW, Park K, Riordan HD, Lee JH.
Source
Samsung Medical Center and Sungkyunkwan University School of Medicine, Seoul 135-710, Korea. sypark21@yumc.yonsei.ac.kr
Abstract
L-ascorbic acid (LAA) shows cytotoxicity and induces apoptosis of malignant cells in vitro, but the mechanisms by which such effects occur have not been elucidated. In the present study, we provide evidence that the ERK MAP kinase pathway is activated in response to LAA (< 1 mM) in acutemyeloid leukemia cell lines. LAA treatment of cells induces a dose-dependent phosphorylation of extracellular signal-regulated kinases (ERK) and results in activation of its catalytic domain. Our data also demonstrate that the small G protein Raf1 and MAPK-activated protein kinase 2 are activated by LAA as an upstream and a downstream regulator of ERK, respectively. Although the ERK pathway has been known to activate cell proliferation, pharmacologic inhibition of ERK reduces LAA-dependent apoptosis and growth inhibitory response of acute myeloid leukemia cell lines, suggesting that this signaling cascade positively regulates induction of apoptotic response by LAA.
Copyright 2004 Elsevier Inc.
PMID: 15451031 [PubMed – indexed for MEDLINE]
www.riordanclinic.org
Int J Biochem Cell Biol. 2004 Nov;36(11):2180-95.
L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide mediated mechanisms.
Park S, Han SS, Park CH, Hahm ER, Lee SJ, Park HK, Lee SH, Kim WS, Jung CW, Park K, Riordan HD, Kimler BF, Kim K, Lee JH.
Source
Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Republic of Korea. seypark21@hotmail.com
Abstract
L-Ascorbic acid (LAA) is being investigated clinically for the treatment of patients with acute myeloid leukemia (AML) based on the observed effects of LAA on AML progenitor cells in vitro. However, the mechanism for LAA-induced cytoreduction remains to be elucidated. LAA at concentrations of 0.25-1.0 mM induced a dose- and time-dependent inhibition of proliferation in three AML cell lines and also in leukemic cells from peripheral blood specimens obtained from three patients with AML. In contrast, ovarian cancer cell lines were only minimally affected. Flow cytometric analysis showed that LAA at concentrations of 0.25-1.0 mM could significantly induce apoptosis in the AML cell lines. LAA induced oxidation of glutathione to oxidized form (GSSG) and subsequent H(2)O(2) accumulation in a concentration-dependent manner, in parallel to induction of apoptosis. The direct role of H(2)O(2) in the induction of apoptosis in AML cells was clearly demonstrated by the finding that catalase could completely abrogate LAA-induced apoptosis. Induction of apoptosis in LAA-treated AML cells involved a dose-dependent increase of Bax protein, release of cytochrome C from mitochondria to cytosol, activation of caspase 9 and caspase 3, and cleavage of poly[ADP-ribose]polymerase. In conclusion, LAA can induceapoptosis in AML cells, and this is clearly due to H(2)O(2) which accumulates intracellularly as a result of oxidation of reduced glutathione by LAA.
PMID: 15313465 [PubMed – indexed for MEDLINE]
www.riordanclinic.org
Ann Intern Med. 2004 Apr 6;140(7):533-7.
Vitamin C pharmacokinetics: implications for oral and intravenous use.
Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M.
Source
National Institute of Diabetes and Digestive and Kidney Diseases, the National Cancer Institut, and the Clinical Center, National Institutes of Health, Bethesda, Maryland 20892-1372, USA.
Abstract
BACKGROUND:
Vitamin C at high concentrations is toxic to cancer cells in vitro. Early clinical studies of vitamin C in patients with terminal cancer suggested clinical benefit, but 2 double-blind, placebo-controlled trials showed none. However, these studies used different routes of administration.
OBJECTIVE:
To determine whether plasma vitamin C concentrations vary substantially with the route of administration.
DESIGN:
Dose concentration studies and pharmacokinetic modeling.
SETTING:
Academic medical center.
PARTICIPANTS:
17 healthy hospitalized volunteers.
MEASUREMENTS:
Vitamin C plasma and urine concentrations were measured after administration of oral and intravenous doses at a dose range of 0.015 to 1.25 g, and plasma concentrations were calculated for a dose range of 1 to 100 g.
RESULTS:
Peak plasma vitamin C concentrations were higher after administration of intravenous doses than after administration of oral doses (P < 0.001), and the difference increased according to dose. Vitamin C at a dose of 1.25 g administered orally produced mean (+/-sd) peak plasma concentrations of 134.8 +/- 20.6 micromol/L compared with 885 +/- 201.2 micromol/L for intravenous administration. For the maximum tolerated oraldose of 3 g every 4 hours, pharmacokinetic modeling predicted peak plasma vitamin C concentrations of 220 micromol/L and 13 400 micromol/L for a 50-g intravenous dose. Peak predicted urine concentrations of vitamin C from intravenous administration were 140-fold higher than those from maximum oral doses.
LIMITATIONS:
Patient data are not available to confirm pharmacokinetic modeling at high doses and in patients with cancer.
CONCLUSIONS:
Oral vitamin C produces plasma concentrations that are tightly controlled. Only intravenous administration of vitamin C produces high plasma and urine concentrations that might have antitumor activity. Because efficacy of vitamin C treatment cannot be judged from clinical trials that use only oral dosing, the role of vitamin C in cancer treatment should be reevaluated.
Comment in
- The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version.
