Vitamin C whether intravenous or oral is one of the most prevalent types of alternative and complimentary cancer therapies. Yet, this nutrient is still considered “controversial” by mainstream oncology. Since two time Nobel Prize winner (in chemistry and peace) Dr. Linus Pauling advocated its use in cancer starting in the late 1970’s, evidence to its efficacy has been quietly and steadily mounting. In this article, we review the history of this nutrient in cancer, the controversy, and discuss current findings.
Vitamin C is Important
Almost all animals and plants synthesize their own vitamin C except humans and a small number of other animals, including, apes, guinea pigs, the red-vented bulbul, a fruit-eating bat and a species of trout. Pure L-ascorbic acid (vitamin C) was first prepared in 1928 by Albert Szent-Gyorgyi and in 1932 it was shown that this substance was vitamin C. In 1954 and 1959 Dr. W. J. McCormick, a Canadian physician, hypothesized that cancer is a collagen disease, secondary to a vitamin C deficiency. His theory was based on the fact that collagen is the “mortar” that binds cells together and if cells stick together, tumors would have a more difficult time breaking away and metastasizing. This concept was expanded upon when, in 1966, Dr. Ewan Cameron wrote a book entitled “Hyaluronidase and Cancer.” In it he pointed out that the ground substance or “intercellular cement” that binds cells of normal tissues contains various molecules that strengthen it including glycosaminoglycans and fibrils of collagen. Dr. Cameron discussed how tumors can produce enzymes that breakdown these molecules (i.e. hyaluronidase and collagenase).
Linus Pauling, Ph.D. (chemistry) had been interested in vitamin C for many years and had written previously how people required large amounts of vitamin C (1). Working with Dr. Cameron, Dr. Pauling pointed out that Vitamin C could: A) stimulate normal cells to produce increased amounts of a hyaluronidase inhibitor and; B) increase the number of collagen fibrils made (2). Based on these theories, Drs. Pauling and Cameron embarked on a number of studies to test the efficacy of vitamin C in cancer patients.
Early Pauling and Cameron Studies
In 1976, Drs. Pauling and Cameron reported the survival times of 100 terminal cancer patients who were given supplemental ascorbate (10 grams/daily intravenously) and those of a control group of 1,000 patients of similar status treated by the same clinicians in the same hospital (Vale of Leven Hospital in Scotland) who had been managed identically except for the ascorbate. The 1,000 controls were matched by sex, age, primary tumor type, and clinical status. By August 10, 1976 all 1,000 of the controls had died while 18 of the 100 ascorbate-treated patients were still living. As of September 15, 1979, five ascorbate treated patients were still alive and “living normal lives.” The 100 acorbate-treated patients lived, on the average, 300 days longer than their matched controls with better quality of life (measured from the time all patients were considered “untreatable”).
A second study was performed in 1978 with 100 new ascorbate-treated patients and 1,000 matched controls (about half of the controls were in the original set) (3). This analysis broke out the improved survival times by cancer type. As presented in the graph below, for each type of cancer there was an improvement in survival. (In fact, with the exception of rectum and ovary cancer, the other cancers actually had longer survival in the ascorbate group than indicated in the graph because survivors were still alive when this data was collected and published.)
Mayo Clinic Studies
Pauling’s and Cameron’s studies were not considered the gold standard in clinical studies. The gold standard was and remains the randomized, prospective, double-blind study in which half the patients are randomized to one arm of a study, half to another arm and neither the patient nor the doctor knows who is getting what.
To test whether ascorbate was effective, Dr. Charles Moertel and his colleagues at the Mayo Clinic conducted two randomized placebo controlled studies (published in 1979 and 1985) of patients each with advanced cancer (4). Patients randomized to the treatment group were given 10 grams of oral ascorbate, and neither study showed significant benefit. (In the first study, median survival was improved two weeks with the ascorbate group.) Because Moertel’s studies were taken as definitive, ascorbate treatment was considered useless. There were however, at least three significant differences between the Mayo Clinic’s “definitive” studies and those of Drs. Pauling and Cameron.
Difference #1
The overwhelming majority (52 of 60 or 87%) of the patients in the first Mayo study had received chemotherapy before the study began. In contrast, only 4% of the patients in Pauling and Cameron study had received chemo. Pauling wrote, “It is known that cytotoxic chemotherapy damages the immune system and might prevent the vitamin C from being effective, inasmuch as it functions mainly by potentiating this system.(5)”
This is a valid critique. A Pubmed search for vitamin C reveals a large number of peer reviewed medical and scientific journal articles that demonstrate that vitamin C scavenges free radicals when it acts as an antioxidant (6), helps neutralize carcinogenic chemicals such as nitrosamine and nitrites (7), enhances lymphocyte function and mobilization of phagocytes (8), improves natural killer cell activities (9), modulates cell growth and differentiation (10), and enhances IgA, IgG and IgM antibody levels (11). Several of these mechanisms are directly related to the body’s immune system and to cancer resistance. Cytotoxic (cell-killing) chemotherapy is notorious for seriously compromising the patient’s immune system by killing the cells that mediate immunity. (In the 1985 Mayo clinic study, this difference was removed as none of the Mayo patients were administered prior chemotherapy.)
Difference #2
A commentary published by doctors from the National Institute of Health (NIH) in 2000 pointed out that there was a second significant difference in study design that may have accounted for the different results in the Mayo Clinic studies (12). The authors explained that intravenous (IV) administration (used by Pauling and Cameron) was superior to oral administration (used by Moertel) in respect to bioavailability of the vitamin. The NIH authors said, “Clinical data show that when ascorbate is given orally, fasting plasma concentrations are tightly controlled at <100 µM. As doses exceed 200 mg, absorption decreases, urine excretion increases, and ascorbate bioavailability is reduced. In contrast, when 1.25 grams of ascorbate are administered intravenously, concentrations as high as 1 mM (1,000 µM) are achieved…It is now clear that intravenous administration of ascorbate can yield very high plasma levels, while oral treatment does not.” The NIH authors concluded that, “Moertel’s results were not comparable to those of Cameron, as ascorbate was given orally and not intravenously. In retrospect, the route of administration may have been key.(13)” This observation was repeated in another peer reviewed paper published in 2004 which stated “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. (14)” Vitamin C pharmacokinetics: implications for oral and intravenous use.
Difference #3
And yet a third difference with the Mayo Clinic study was that vitamin C administration was discontinued immediately after a patient could no longer take oral medications or there was progression of the disease. Apparently, in the Pauling and Cameron studies the IV doses continued regardless of the patient’s changing status. Vitamin C was provided during the life of the patient. However, in Moertel’s studies, because it was administered orally, vitamin C was discontinued in a large number of patients whenever there was a sign of worsening. According to writer Ralph Moss, “Because of the odd departure from Cameron’s protocol, patients in the treatment arm of the experiment (in Moertel’s second study) received vitamin C for a median time of only 10 weeks. None of the Mayo patients died while receiving it. Their deaths occurred after the vitamin had been taken away from them.(15)”
Obviously if the Mayo Clinic studies were designed to test the outcomes of Drs. Pauling and Cameron then they should have replicated their methodology of administration (as long as it was scientifically reliable and clinically appropriate). Why didn’t Moertel’s group administer the vitamin intravenously throughout the life of the patient? We don’t know. Any one of these discrepancies should have been sufficient for a complete reevaluation, but as is so often the case, the cancer establishment had successfully “proved” that a mere vitamin was of no value in cancer and the case was closed. Or was it?
In the intervening 20 years since Moertel’s last study two trends have continued: 1) patients are being administered IV vitamin C in various cancer clinics around the world and many are showing benefit; 2) the overall plausibility of ascorbic acid administered intravenously as a cancer therapy is being better understood by recent insights into clinical pharmacokinetics and its in vitro cancer-specific cytotoxicity.
Clinical Examples
A reading of Drs. Cameron and Pauling’s book “Cancer and Vitamin C” provides 26 case histories of patients with various cancers who received a benefit from vitamin C including: brain, breast, prostate, bladder, lung, stomach, ovarian cancer, leukemia and mesothelioma. But, since Cameron and Pauling have been considered advocates of vitamin C, here is another source. Three case examples come from a peer reviewed article whose authors come from the National Cancer Institute, the National Institutes of Health, and other universities. In a March 2006 article entitled “Intravenously administered vitamin C as cancer therapy: three cases” the authors examined clinical details of three cases in accordance with National Cancer Institute (NCI) Best Case Series guidelines (16). Tumor pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment.
Case #1
The first case involved the regression of pulmonary metastatic renal cancer in a patient who had received high-dose intravenous vitamin C therapy and no orthodox cancer therapies. The patient declined conventional cancer treatment and instead chose to receive high-dose vitamin C administered intravenously at a dosage of 65 g twice per week starting in October 1996 and continuing for 10 months. She also used other alternative therapies, including: thymus protein extract, N-acetylcysteine, niacinamide and whole thyroid extract. In June 1997 chest radiography results were normal except for one remaining abnormality in the left lung field, possibly a pulmonary scar. The patient died at the end of 2002 from lung cancer. She was a long-standing cigarette smoker.
Case #2
The second case involved a 49-year-old man with a primary bladder tumor with multiple satellite tumors extending 2–3 cm around it. The following is an excerpt from the article: “The patient declined systemic or intravesical chemotherapy or radiotherapy and instead chose intravenous vitamin C treatment. He received 30 g of vitamin C twice per week for 3 months, followed by 30 g once every 1–2 months for 4 years, interspersed with periods of 1–2 months during which he had more frequent infusions. Histopathologic review at the NIH revealed a grade 3/3 papillary transitional cell carcinoma invading the muscularis propria. Now, 9 years after diagnosis, the patient is in good health with no symptoms of recurrence or metastasis. The patient used the following supplements: botanical extract, chondroitin sulfate, chromium picolinate, flax oil, glucosamine sulfate, α-lipoic acid, Lactobacillus acidophilus and L. rhamnosus and selenium.”
Case #3
The third case involved a 66-year-old woman who was diagnosed in January 1995 with a diffuse large B-cell lymphoma. The following is an excerpt from the article: “The patient’s oncologist recommended local radiation therapy and chemotherapy. Although she agreed to a 5-week course of local radiation therapy, the patient refused chemotherapy, electing instead to receive vitamin C intravenously. She received 15 g of vitamin C twice per week for about 2 months, 15 g once to twice per week for about 7 months, and then 15 g once every 2–3 months for about 1 year.In late April 1995 a new left cervical lymph node was detected, and histopathologic review identified a biopsy specimen as identical to the original tumor. The patient once again refused chemotherapy and continued her program of intravenous vitamin C injections…Intravenous vitamin C therapy continued through late December 1996, at which time the patient was in normal health and had no clinical sign of lymphoma. The patient remains in normal health 10 years after the diagnosis of diffuse large B-cell lymphoma, never having received chemotherapy. The patient used additional products: β-carotene, bioflavonoids, chondroitin sulfate, coenzyme Q10, dehydroepiandrosterone, a multiple vitamin supplement, N-acetylcysteine, a botanical supplement and bismuth tablets…Patients with untreated stage III diffuse B-cell lymphoma have a dismal prognosis. This case, like the preceding one, is unusual in that the patient refused chemotherapy, which might have produced a long-term remission. It appears, nonetheless, that a cure occurred in connection with intravenous vitamin C infusions.”
Although these case histories by themselves are insufficient to prove that vitamin C is an effective treatment for cancer, in the words of the authors, these histories “increase the clinical plausibility of the notion that vitamin C administered intravenously might have effects on cancer under certain circumstances.(17)”
Clinical Pharmacokinetics and In Vitro Cancer-Specific Cytotoxicity
The number of peer reviewed journal articles continues to grow that describe the clinical pharmacokinetics and in vitro cancer-specific cytotoxicity of vitamin C. For example, an article published in the Annals of Internal Medicine set out the pharmacokinetics of intravenous vitamin C (18); another article in the journal Nature discussed how vitamin C preferentially killed melanoma cells (19); and there have been several articles in Anticancer Research(20), and Oncology (21) that described how ascorbate killed various other cancer cell lines in vitro.
Vitamin C and Collagen
You may recall that Drs. Cameron and Pauling pointed out that Vitamin C could increase the number of collagen fibrils made. In the last 20 years biochemists have described the molecular basis of scurvy and in doing so have helped us understand how vitamin C and collagen are related. Apparently vitamin C plays a role in collagen metabolism by acting as a cofactor in the enzymatic reactions involved in the hydroxylation of praline and lysine. Without this hydroxylation, proper aligned stable helices of the alpha chains are not formed, so the procollagen that is formed is unstable and degraded (22).
May Prolong Life
Vitamin C has many roles that may be associated with fighting cancer including: acting as an anti-oxidant and scavenging free radicals, supporting the various immune cells, modulating cell growth and differentiation, helping to synthesize carnitine which is essential for the transport of fat to mitochondria, and possibly even strengthening collagen. Perhaps Drs. Pauling and his colleagues were right that vitamin C is a benefit to cancer patients so we will conclude with their words, “Vitamin C is not a miraculous cure for cancer, but…it significantly prolongs the life of the cancer patient…We believe that supplemental ascorbate can be of real help to all cancer patients and of quite dramatic benefit to a fortunate few.(23)”
End Notes
1 See for example: Pauling L., “Evolution and the need for ascorbic acid” Proc Natl Acad Sci 1970 Dec;67(4):1643-8. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=283405&blobtype=pdf And see Pauling L., “The significance of the evidence about ascorbic acid and the common cold” Proc Natl Acad Sci 1971 Nov;68(11):2678-81 Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=389499&blobtype=pdf 2 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979; see also original research – Cameron E, Pauling L. “Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer” Proc Natl Acad Sci 1976 Oct;73(10):3685-9. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=431183&blobtype=pdf
3 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979; see also original research – 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 1978 Sep;75(9):4538-42. Available at: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=336151&blobtype=pdf
4 Moertel CG, et al., “Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. A controlled trial” N Engl J Med. 1979 Sep 27;301(13):687-90. Moertel CG, et al., “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 Jan 17;312(3):137-41.
5 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979, pp. 142-3.
6 See for example: Duarte TL, Lunec J. “When is an antioxidant not an antioxidant? A review of novel actions and reactions of vitamin C.” Free Radic Res. 2005 Jul;39(7):671-86.
7 See for example: Tannenbaum SR, et al., “Inhibition of nitrosamine formation by ascorbic acid.” Am J Clin Nutr. 1991 Jan;53(1 Suppl):247S-250S.
8 See for example: Hernanz A, et al., “Effect of age, culture medium and lymphocyte presence on ascorbate content of peritoneal macrophages from mice and guinea pigs during phagocytosis” Int Arch Allergy Appl Immunol. 1990;91(2):166-70.
9 See for example: Heuser G and Vojdani A.. “Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C” Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312.
10 See for example: Mitsumoto Y, et al., A long-lasting vitamin C derivative, ascorbic acid 2-phosphate, increases myogenin gene expression and promotes differentiation in L6 muscle cells.Biochem Biophys Res Commun. 1994 Feb 28;199(1):394-402.
11 See for example: Mitsuzumi H, et al., “Requirement of cytokines for augmentation of the antigen-specific antibody responses by ascorbate in cultured murine T-cell-depleted splenocytes.” Jpn J Pharmacol. 1998 Oct;78(2):169-79.
12 Padayatty SJ, and Levine M. “Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.” J Am Coll Nutr. 2000 Aug;19(4):423-5. Available here: http://www.jacn.org/cgi/reprint/19/4/423
13 Padayatty SJ, and Levine M. “Reevaluation of ascorbate in cancer treatment: emerging evidence, open minds and serendipity.” J Am Coll Nutr. 2000 Aug;19(4):423-5. See p. 423. Available here: http://www.jacn.org/cgi/reprint/19/4/423
14 Padayatty SJ,et al., Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. Available here: http://www.annals.org/cgi/reprint/140/7/533.pdf
15 Ralph W. Moss, The Cancer Industry 1989 p. 224.
16 Padayatty SJ, et al., “Intravenously administered vitamin C as cancer therapy: three cases.” CMAJ. 2006 Mar 28;174(7):937-42. Available here: http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1405876&blobtype=pdf
17 Padayatty SJ, et al., “Intravenously administered vitamin C as cancer therapy: three cases.” CMAJ. 2006 Mar 28;174(7):937-42. See p. 940.
18 Padayatty SJ,et al., Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004 Apr 6;140(7):533-7. Available here: http://www.annals.org/cgi/reprint/140/7/533.pdf
19 Bram S, et al., “Vitamin C preferential toxicity for malignant melanoma cells” Nature 1980;284:629-31.
20 Leung PY, et al., “Cytotoxic effect of ascorbate and its derivatives on cultured malignant and nonmalignant cell lines” Anticancer Res1993;13:475-80.
21 Benade L, et al., Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. Oncology 1969;23:33-43.
22 See for example: Davidson, V and Sittman D, The National Medical Series for Independent Study – Biochemistry 3rd Edition 1994, p. 316.
23 Ewan Cameron and Linus Pauling, “Cancer and Vitamin C” 1979 p. 130.