High-dose vitamin C and cancer
In this article
High-dose vitamin C therapy has been widely debated and attracted great interest recently. High dose means 7-10 grams daily or more. Since its discovery, vitamin C has been among the most promoted dietary components for healthy living. Frequent consumption of vitamin-C-rich vegetables and fruits may be the health advice we hear most often. It is therefore easy to claim exaggerated benefits for a compound so strongly associated with health. Vitamin C undoubtedly has many benefits, but according to studies to date, cancer treatment is not among them. Although some laboratory and animal experiments were positive, human clinical studies have not confirmed them or demonstrated a clear cancer benefit.
Although high doses are claimed harmless because vitamin C is water-soluble and not stored, the literature reports many side effects and drug interactions. Nevertheless, alternative practitioners present it as a miracle and administer it to cancer patients. Considering possible harms and interactions, such claims should not be trusted, and this therapy should currently be avoided until its effects are clearly established.
What is vitamin C, and what are its functions?
Also called ascorbic acid and ascorbate, vitamin C is an essential water-soluble compound. Most animals and plants produce it, but humans cannot and must obtain it externally. It is required for various enzymes and acts as an antioxidant by neutralizing free oxygen products that damage tissues. It is also important in collagen synthesis. Collagen forms the main structure of connective and supporting tissues such as skin, cartilage, bone, tendons and ligaments. Severe deficiency therefore causes scurvy, characterized by receding gums, fatigue, drowsiness, easy bleeding and bruising. Symptoms result from weakened collagen, which vitamin C administration strengthens.
What are vitamin C sources?
The World Health Organization (WHO) recommends daily intake of 45 mg. for healthy adults. Fresh fruits and vegetables are the richest sources of this widely occurring vitamin. Fruits richest in it include lemons, oranges, grapefruit, strawberries, pineapple, kiwi, melon, watermelon and currants, particularly citrus (lemon, orange, grapefruit). Vegetable sources include rosehips, cauliflower, cabbage, broccoli, peppers, onions, spinach, potatoes and tomatoes. Liver is a rich animal source; supplements are another. Cooking or prolonged storage reduces content. Microwaving and steaming reduce losses, but fresh, raw consumption is ideal for preserving vitamin C.
What is vitamin C's history, and where do cancer effectiveness claims originate?
The discovery that citrus prevented scurvy in 1753 paved the way for vitamin C; in 1912, Casimir Funk called this compound in fruit and vegetables the antiscorbutic vitamin. In 1920, British biochemist Jack Drummond used the name vitamin C. Its use against cancer emerged from a study in 1959 claiming that cancer might involve connective tissue changes related to vitamin C deficiency. High doses were first tested in cancer patients in the 1970s by Scottish surgeon Ewan Cameron. Nobel-winning chemist Linus Pauling later joined him, attracting great attention. Although they claimed high doses might be a potential treatment for advanced cancer, their studies were subsequently found flawed.
What are the possible side effects and risks of high-dose vitamin C?
Despite claims that high doses are harmless because the vitamin is water-soluble and not stored, many side effects and interactions are reported. High doses may increase hemolytic anemia risk in glucose-6-phosphate dehydrogenase deficiency and kidney failure risk in people with kidney problems. Because vitamin C can increase iron utilization, it is not recommended in hemochromatosis (iron storage disease). It may also reduce B12 and copper absorption. Acidification of urine can cause kidney stones, while oxalic acid produced by metabolism can cause hyperoxaluria, excessive urinary oxalate that may produce stones. A study published in 2000 first established a tolerable upper limit of 2 grams and reported diarrhea beyond it. Diarrhea is indeed the most common high-dose side effect.
Studies also show greater side effects when combined with some chemotherapy drugs. Unexpected effects have forced researchers to stop some studies early.
What are the laboratory results on high-dose vitamin C's cancer effects?
Some laboratory studies show reduced proliferation in cell lines of various cancers. Mechanistic studies found killing through hydrogen-peroxide-producing chemical reactions. High doses enhanced arsenic trioxide in ovarian cancer cells, gemcitabine in pancreatic cells, and gemcitabine plus epigallocatechin-3-gallate (EGCG) in mesothelioma (lung lining cancer) cells. A study in 2012 reported greater radiotherapy sensitivity in glioblastoma multiforme (brain cancer) cells. Conversely, some studies reported reduced effectiveness when combined with chemotherapy drugs such as doxorubicin, methotrexate and cisplatin.
What are the clinical results on high-dose vitamin C's cancer effects?
The first clinical studies were performed in the 1970s by Ewan Cameron and Linus Pauling. They claimed intravenous high doses significantly prolonged survival in advanced cancer. Later review by the National Cancer Institute found poor design and errors. Furthermore, 3 Mayo Clinic studies, from one of the world's most prestigious medical institutions, did not confirm these findings.
In two clinical studies of oral high doses, patients were divided into 2 groups: one received daily 10 gr Vitamin C, the other none. No significant difference in survival or quality of life was found. Later research showed maximum blood levels depend on administration route. Oral levels are tightly controlled, while intravenous administration bypasses this and achieves higher levels. Some studies therefore claimed intravenous levels could produce effects unavailable orally and kill cancer cells. However, subsequent well-designed clinical trials found no such benefit from intravenous high doses either.
Studies combining high doses with other cancer treatments have also been inconsistent. In 2014, patients with stage 3-4 ovarian cancer, 27 in total, were divided into 2 groups receiving chemotherapy alone (carboplatin+paclitaxel) or chemotherapy plus high-dose vitamin C. There was no survival or progression-free survival (time without worsening) difference. Only grade 1-2. chemotherapy side effects were significantly less frequent; grade 3-4. effects, the main problems causing treatment interruptions, were not reduced. Studies combining vitamin C with arsenic trioxide are conflicting. Similar combinations in leukemia, advanced colorectal cancer and melanoma skin cancer have caused serious side effects and disease progression.
A review published in 2010 compiling 33 years of research concluded: “It is unknown whether high-dose vitamin C is effective against cancer and, if so, at what doses and in which cancer types.” The American Cancer Society also states that current clinical evidence demonstrates no benefit. Despite this, complementary and alternative practitioners use it widely. At American complementary and alternative medicine conferences in 2006 and 2008, surveys found that of 199 participants, 172 said they administered high doses to patients.
In conclusion, there is currently no clear evidence that high-dose vitamin C treats cancer. Positive laboratory and animal findings are not confirmed clinically. Intravenous administration achieves higher blood concentrations and is therefore more likely to be effective than oral use, but this has not been proven either. Ongoing studies focus on whether intravenous vitamin C improves chemotherapy, radiotherapy and other regimens. Some benefit may be possible here. Nevertheless, until studies finish and any real benefits are clearly demonstrated, possible side effects make avoiding this treatment advisable at present.
*
- Herbal Treatment, Phytotherapy: Sound Science or Big Business?
Sources
2) Naidu KA. Vitamin C in human health and disease is still a mystery? An overview. Nutr J. 2003;2:7.
3) World Health Organization.Vitamin and mineral requirements in human nutrition (2nd ed.). 2004;138.
4) Gropper SS, Smith JL, Grodd JL. Advanced nutrition and human metabolism. Belmont, CA: Thomson Wadsworth. 2005;260–275.
5) Preedy VR, Watson RR, Sherma Z. Dietary Components and Immune Function (Nutrition and Health). Totowa, NJ: Humana Press. 2010:36;52.
6)Padayatty S, Espey MG, Levine M: Vitamin C. eds: Encyclopedia of Dietary Supplements. 2nd ed. New York, NY: Informa Healthcare. 2010;821-31.
7) Abou-Jawde RM, Reed J, Kelly M, Walker E, Andresen S, Baz R, Karam MA, Hussein M. Efficacy and safety results with the combination therapy of arsenic trioxide, dexamethasone, and ascorbic acid in multiple myeloma patients: a phase 2 trial. Med Oncol. 2006;23:263-72.
8) Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS. A phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of relapsed or refractory multiple myeloma. Clin Cancer Res. 2007;13:1762-8.
9) Welch JS, Klco JM, Gao F, Procknow E, Uy GL, Stockerl-Goldstein KE, Abboud CN, Westervelt P, DiPersio JF, Hassan A, Cashen AF, Vij R. Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. Am J Hematol. 2011;86:796-800.
10)Subbarayan PR, Lima M, Ardalan B. Arsenic trioxide/ascorbic acid therapy in patients with refractory metastatic colorectal carcinoma: a clinical experience. Acta Oncol. 2007;46:557-61.
11)Lind J. A Treatise of the Scurvy. London: A. Millar. 1753:149.
12)Rosenfeld L. Vitamine--vitamin. The early years of discovery. Clin. Chem. 1997;43:680–5.
13)Drummond JC. The nomenclature of the so-called accessory food factors (vitamins). Biochem J 1920;14:660.
14) McCORMICK WJ. Cancer: a collagen disease, secondary to a nutritional deficiency. Arch Pediatr. 1959;76:166-71.
15)Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 73 (10): 3685-9, 1976.
16)Cameron E, Pauling L: Supplemental ascorbate in the supportive treatment of cancer: reevaluation of prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A.1976;73:3685-9.
17)Cameron E, Campbell A: The orthomolecular treatment of cancer. II. Clinical trial of high-dose ascorbic acid supplements in advanced human cancer. Chem Biol Interact. 1974;9:285-315.
18) Vitamin C. American Cancer Society.
19)Cabanillas F. Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later? Puerto Rico health sciences journal. 2010;29:215–7.
20)Cameron E, Pauling L: The orthomolecular treatment of cancer. I. The role of ascorbic acid in host resistance. Chem Biol Interact. 1974;9:273-83.
21) Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One. 2010;5:e11414.
22)Rees DC, Kelsey H, Richards JD. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ. 1993; 306:841-2.
23) Barton JC, McDonnell SM, Adams PC, Brissot P, Powell LW, Edwards CQ, Cook JD, Kowdley KV. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med. 1998;129:932-9.
24)Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids: a report of the Panel on Dietary Antioxidants and Related Compounds, Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine. Washington, D.C: National Academy Press. 2000:156–161.
25) Verrax J, Calderon PB. The controversial place of vitamin C in cancer treatment. Biochem. Pharmacol. 2008;76:1644–52.
26)Institute of Medicine. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press, 2000.
27)Bael TE, Peterson BL, Gollob JA. Phase II trial of arsenic trioxide and ascorbic acid with temozolomide in patients with metastatic melanoma with or without central nervous system metastases. Melanoma Res. 2008;18:147-51.
28) Joseph J. Cullen. Clinical Trial of High-dose Vitamin C for Advanced Pancreatic Cancer (PACMAN-II). U.S. National Institutes of Health, Clinicaltrials.gov. NCT01515046.
29) Daniel A Monti. Research Study of IV Vitamin C in Combination With Irinotecan vs Irinotecan Alone for Advanced Colorectal CA. U.S. National Institutes of Health, Clinicaltrials.gov. NCT01550510.
30)Frömberg A, Gutsch D, Schulze D, et al.: Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemother Pharmacol 67 (5): 1157-66, 2011.
31) Chen P, Stone J, Sullivan G, Drisko JA, Chen Q. Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radic Biol Med. 2011;51:681-7.
32) Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner GR, Shacter E, Levine M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005;102:13604-9.
33)Verrax J, Calderon PB. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic Biol Med. 2009;47:32-40.
34)Ong PS, Chan SY, Ho PC. Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death: oxidative stress-independent and -dependent cytotoxic potentiation. Int J Oncol. 2011;38:1731-9.
35)Martinotti S, Ranzato E, Burlando B. In vitro screening of synergistic ascorbate-drug combinations for the treatment of malignant mesothelioma. Toxicol In Vitro. 2011;25:1568-74.
36) Espey MG, Chen P, Chalmers B, Drisko J, Sun AY, Levine M, Chen Q. Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radic Biol Med. 2011;50:1610-9.
37) Herst PM, Broadley KW, Harper JL, McConnell MJ.Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic Biol Med. 2012;52:1486-93.
38) Heaney ML, Gardner JR, Karasavvas N, Golde DW, Scheinberg DA, Smith EA, O'Connor OA. Vitamin C antagonizes the cytotoxic effects of antineoplastic drugs. Cancer Res. 2008;68:8031-8.
39) Creagan ET, Moertel CG, O'Fallon JR, Schutt AJ, O'Connell MJ, Rubin J, Frytak S. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial. N Engl J Med. 1979;301:687-90.
40) Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM. High-dose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med. 1985;312:137-41.
41) Padayatty SJ, Sun H, Wang Y, Riordan HD, Hewitt SM, Katz A, Wesley RA, Levine M. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140:533-7.
42) Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, Rousseau C, Robitaille L, Miller WH Jr. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol. 2008;19:1969-74.
43) Ma Y, Chapman J, Levine M, Polireddy K, Drisko J, Chen Q. High-dose parenteral ascorbate enhanced chemosensitivity of ovarian cancer and reduced toxicity of chemotherapy. Sci Transl Med. 2014;6:222ra18.
44) Vitamin C: MedlinePlus Medical Encyclopedia. U.S National Library of Medicine.
45) Natural food-Fruit Vitamin C Content. The Natural Food Hub. Retrieved March 7, 2007.
Was this article helpful?
Your feedback helps us improve our content.
Reader comments
Share your comment
Your name and comment are published only after administrator approval. Your email address is never shown to visitors.
Be the first to comment.