Original Article
Failure of High-Dose Vitamin C (Ascorbic Acid) Therapy to Benefit Patients with Advanced Cancer — A Controlled Trial
N Engl J Med 1979; 301:687-690September 27, 1979DOI: 10.1056/NEJM197909273011303
- Abstract
- Abstract
One hundred and fifty patients with advanced cancer participated in a controlled double-blind study to evaluate the effects of high-dose vitamin C on symptoms and survival. Patients were divided randomly into a group that received vitamin C (10 g per day) and one that received a comparably flavored lactose placebo. Sixty evaluable patients received vitamin C and 63 received a placebo. Both groups were similar in age, sex, site of primary tumor, performance score, tumor grade and previous chemotherapy. The two groups showed no appreciable difference in changes in symptoms, performance status, appetite or weight. The median survival for all patients was about seven weeks, and the survival curves essentially overlapped. In this selected group of patients, we were unable to show a therapeutic benefit of high-dose vitamin C treatment. (N Engl J Med 301:687–690, 1979)
Article Activity
- Article
THE possible role of vitamin C in both the pathogenesis and therapy of malignant disease has been suggested by a variety of laboratory and clinical data. A deficiency of ascorbate has been reported in association with dissolution of the intercellular matrix, which might facilitate local infiltration and dissemination of neoplastic cells.1 Studies in laboratory animals have shown that ascorbate seems to concentrate in malignant tissue and thus depletes systemic reserves.2 3 4 Moreover, in patients with skin carcinoma, concentrations of vitamin C are higher in the tumor than in surrounding normal tissue.5 Lymphocytes, mediators of cellular immunity, contain relatively high amounts of ascorbate, and immune responsiveness has been enhanced by ascorbate administration in mice.6 Moreover, there have been some apparent regressions of adenomas after administration of ascorbate by mouth in persons with familial polyposis coli, a known premalignant condition.7
Several nonrandomized studies have suggested that high-dose vitamin C (10 g per day by mouth) might enhance survival and improve symptoms of patients with advanced cancer. Cameron and Campbell studied 50 such patients who had not received chemotherapy and reported five tumor regressions (10 per cent).8 These authors also reported that most patients experienced some subjective benefit.8 In a later report, 50 patients who had previously received irradiation and chemotherapy were combined with the first group, and the survival of all 100 patients was compared with that of 1000 historical control cases in the records at the Vale of Leven Hospital, Loch Lomondside, Scotland.9 For each ascorbate-treated patient, 10 controls were matched on the basis of age, sex, site and histologic features of the primary tumor. The mean survival of patients given ascorbate was 210 days, as compared with 50 for the selected controls. Since this was not a randomized study, doubt has been raised concerning the comparability of ascorbate-treated patients and the control population.10 Cameron and Pauling therefore revised the original study group to exclude 10 ascorbate-treated patients with unusual cancers; they substituted 10 other patients randomly selected from the records of ascorbate-treated patients at the Vale of Leven Hospital.11 In addition, a new group of 1000 controls was selected because data on some of the initial control patients were considered unreliable and incomplete. Most of the new controls, however, were drawn from the original control population. This revised and updated analysis showed that the mean survival of patients given vitamin C was greater than 293 days, as compared with 38 for the controls.
Since bias is possible in nonrandomized studies including selected controls, we conducted a randomized, controlled double-blind trial to evaluate the effect of vitamin C on symptoms and survival in patients with advanced and preterminal cancer.
Patients and Methods
All patients had histologically documented advanced cancer, and all were able to take medications by mouth. All were unsuitable for treatment with systemic chemotherapy, either because of progression of disease after previous efforts or because their general condition precluded cytotoxic regimens.
Relatively few pediatric patients met the eligibility criteria. No patients had leukemia. Patients were stratified on the basis of a performance score of 2 versus 3 or 4 on the Eastern Cooperative Oncology Group scale (in which a score of 0 indicates a fully active patient, whereas 4 indicates bedridden); patients with a score of 3 or 4 were grouped as one stratum. The patients were also classified on the basis of site of primary tumor (colon, stomach, lung, pancreas, breast and other) and then randomized to one of two groups: those given vitamin C (10 g per day by mouth in four divided doses, or a total of twenty 0.5-g capsules daily) and those given the same number of capsules containing a comparably flavored lactose placebo. Both drugs were given as identical capsules, dispensed in bottles of 1000, which were identified only by code number. The drug supply was renewed at six-week intervals as needed. Neither patient nor investigator knew which drug was being administered. Treatment was continued until death or until the patient was no longer able to take medications by mouth. At two-week intervals, patients reported the amount and frequency of the drug taken, the status of their symptoms and body weight.
A total of 150 patients were entered into the clinical trial. Patient and tumor characteristics for the 123 patients who took the study medication are listed in Tables 1Table 1
Patient Characteristics. and 2Table 2
Tumor Characteristics and Previous Treatment.. Twenty-seven patients elected not to participate after randomization, but before taking the first dose of vitamin C or placebo. These patients (12 assigned randomly to the placebo group and 15 to the vitamin C group) were considered unevaluable for comparative drug effects but were analyzed separately for survival. Their characteristics are shown in Table 3Table 3
Characteristics of 27 Patients Who Took No Study Drug..Chi-square tests of homogeneity were performed to compare the distributions of the following five pretreatment clinical characteristics between the two treatment groups: age, sex, site of primary tumor, initial performance score and previous treatment. Kaplan–Meier survival curves were plotted separately for the two treatment groups and tested for inequality by use of the Gehan-Wilcoxon and log-rank tests. A Cox covariate analysis was performed, using the survival data from the 123 treated patients.12
Results
Survival
The survival curves for the 123 patients treated with vitamin C and with placebo are shown in Figure 1Figure 1
High-Dose Vitamin C versus Placebo and Survival Results in Patients with Advanced Cancer.. There was no significant difference in survival between the two groups (log-rank test; P = 0.61). We were unable to show any survival benefit according to tumor site. Note that the two treatment groups are evenly balanced in age, sex, site of primary tumor, initial performance status and previous treatment (Tables 1 and 2).Cox covariate analysis showed that none of the six potentially prognostic factors was significantly associated with survival in the 123 treated patients. Only performance score was even marginally associated (P = 0.08) after taking into account the effects of the remaining factors.
The one long-term survivor in this study is a patient with metastatic islet-cell carcinoma, massive hepatomegaly and jaundice who had shown no response to many previous attempts at chemotherapy. After entering the study, he showed improvement in symptoms and some reduction in serum bilirubin. He was still alive 63 weeks after entering the study. This patient received the lactose placebo.
Symptom Reduction and Side Effects
Fifty-eight per cent of the patients given the placebo and 63 per cent of those given vitamin C claimed some improvement in symptoms during treatment. There were no statistically significant differences in symptoms between the two treatment groups (Table 4Table 4
Symptomatic Results and Side Effects.).Mild nausea and vomiting were the most frequent toxic reactions, affecting about 40 per cent of patients, but there were no statistically significant differences in the number of episodes between the two groups (Table 4). There was no noteworthy excess of heartburn or other upper-gastrointestinal-tract symptoms in patients given vitamin C, nor was there any documented occurrence of renal calculi.
Analysis of Untreated Patients
An interesting group of patients in this study are those who accepted randomization but subsequently elected not to participate. These patients, in a nonrandomized study, would be presumed to be included only in the nontreated historical controls (Table 3). These patients were excluded from the above analysis because they would not show evidence of the effect of vitamin C or placebo.
The 27 patients who did not receive treatment had a significantly worse (log-rank test; P = 0.017) survival than the 123 patients who did take the medication. The median survival in the untreated patients was 25 days, as compared with 51 for treated patients.
Discussion
We were unable to demonstrate any statistically significant benefit of high-dose vitamin C in selected patients with advanced cancer. It should be noted, however, that only nine of our 123 patients had not previously received chemotherapy or radiation therapy. It is therefore impossible to draw any conclusions about the possible effectiveness of vitamin C in previously untreated patients. In Cameron and Campbell's report of a 10 per cent regression rate in 50 patients with widely disseminated cancer, none had received definitive prior treatment and presumably were more immunocompetent than our patients. Since vitamin C may have an impact on host resistance to cancer,13 we recognize that earlier immunosuppressive treatment might have obscured any benefit provided by this agent. Nevertheless, the nonrandomized study9 that showed a fourfold enhancement of survival with vitamin C included patients who had received conventional cancer treatment (i.e., cytotoxic agents and radiation therapy). This improvement could not be substantiated by our study.
There is evidence that vitamin C maintains immunocompetence. Although patients with advanced cancer who have previously been treated with irradiation or chemotherapy are indeed immunosuppressed, they are not totally incapable of mounting an immune response. In two previous studies of patients with advanced cancer who were selected on the basis of essentially the same criteria used in this study, we found that 80 per cent were capable of responding to recall skin tests (O'Connell MJ, O'Fallon JR, Ritts RE, et al: unpublished data), and 56 per cent responded to dinitrochlorobenzene.14 One might expect, therefore, that vitamin C would exert some restorative influence in patients whose immune apparatus has been compromised by earlier treatment efforts. If such an effect did occur in our patients, it was not seen in their clinical improvement.
We cannot recommend the use of high-dose vitamin C in patients with advanced cancer who have previously received irradiation or chemotherapy.
Supported in part by a contract (CM 02066) with the National Institutes of Health.
We are indebted to Mrs. H. Golenzer, Mrs. T. Hu and Mrs. R. Rogers for their support and cooperation.
Source Information
From the Division of Medical Oncology and the Cancer Statistics Unit, Mayo Clinic, Rochester, MN 55901, where reprint requests should be addressed to Dr. Creagan.
- References
References
1
Cameron
Web of Science | Medline2
Boyland
Web of Science | Medline3
Sure 4
Watson
Web of Science5
Moriarty
CrossRef | Web of Science | Medline6
Siegel
CrossRef | Medline7
DeCosse
Web of Science | Medline8
Cameron
CrossRef | Web of Science | Medline9
Cameron
CrossRef | Web of Science | Medline10
Comroe
CrossRef | Web of Science | Medline11
Cameron
CrossRef | Web of Science | Medline12
Cox 13
Cameron
CrossRef | Web of Science | Medline14
Moertel
Web of Science | Medline
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12
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13
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14
S. Schneider, P. Bachmann, P. Latino-Martel, M. Simon, M. -P. Vasson, L. Zelek. (2011) Nutrition. Oncologie
15
J. S. McLay, D. Stewart, J. George, C. Rore, S. D. Heys. (2011) Complementary and alternative medicines use by Scottish women with breast cancer. What, why and the potential for drug interactions?. European Journal of Clinical Pharmacology
16
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17
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18
Ping Chen, Jennifer Stone, Garrett Sullivan, Jeanne A. Drisko, Qi Chen. (2011) Anti-cancer effect of pharmacologic ascorbate and its interaction with supplementary parenteral glutathione in preclinical cancer models. Free Radical Biology and Medicine 51:3, 681-687
19
Jack Challem. (2011) Current Controversies in Nutrition: The Blind Leading the Blind: Common Problems with the Nature of Clinical Trials. Alternative and Complementary Therapies 17:5, 279-283
20
Michael Graham Espey, Ping Chen, Brian Chalmers, Jeanne Drisko, Andrew Y. Sun, Mark Levine, Qi Chen. (2011) Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer. Free Radical Biology and Medicine 50:11, 1610-1619
21
Joseph J. Cullen, Douglas R. Spitz, Garry R. Buettner. (2011) Comment on “Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer,” i.e., all we are saying is, give C a chance. Free Radical Biology and Medicine 50:12, 1726-1727
22
Jayne Hutchinson, Victoria J Burley, Darren C Greenwood, James D Thomas, Janet E Cade. (2011) High-dose vitamin C supplement use is associated with self-reported histories of breast cancer and other illnesses in the UK Women’s Cohort Study. Public Health Nutrition 14:05, 768-777
23
Anja Frömberg, Daniela Gutsch, Daniel Schulze, Claudia Vollbracht, Gabriele Weiss, Frank Czubayko, Achim Aigner. (2011) Ascorbate exerts anti-proliferative effects through cell cycle inhibition and sensitizes tumor cells towards cytostatic drugs. Cancer Chemotherapy and Pharmacology 67:5, 1157-1166
24
Rupa R. Sawant, Onkar Vaze, Gerard G. M. D’Souza, Karen Rockwell, Vladimir P. Torchilin. (2011) Palmitoyl Ascorbate-Loaded Polymeric Micelles: Cancer Cell Targeting and Cytotoxicity. Pharmaceutical Research 28:2, 301-308
25
M. F. Ullah, H. Y. Khan, H. Zubair, U. Shamim, S. M. Hadi. (2011) The antioxidant ascorbic acid mobilizes nuclear copper leading to a prooxidant breakage of cellular DNA: implications for chemotherapeutic action against cancer. Cancer Chemotherapy and Pharmacology 67:1, 103-110
26
J. Hübner, C. Stoll. (2011) Komplementärtherapie in der Palliativmedizin. Der Internist 52:1, 36-42
27
Elia Ranzato, Stefano Biffo, Bruno Burlando. (2011) Selective Ascorbate Toxicity in Malignant Mesothelioma. American Journal of Respiratory Cell and Molecular Biology 44:1, 108-117
28
Alessandro Corti, Alessandro F. Casini, Alfonso Pompella. (2010) Cellular pathways for transport and efflux of ascorbate and dehydroascorbate. Archives of Biochemistry and Biophysics 500:2, 107-115
29
P. P. Singh, Anu Chandra, Farzana Mahdi, Ajanta Roy, Praveen Sharma. (2010) Reconvene and Reconnect the Antioxidant Hypothesis in Human Health and Disease. Indian Journal of Clinical Biochemistry 25:3, 225-243
30
Yukitoshi Takemura, Motohiko Satoh, Kiyotoshi Satoh, Hironobu Hamada, Yoshitaka Sekido, Shunichiro Kubota. (2010) High dose of ascorbic acid induces cell death in mesothelioma cells. Biochemical and Biophysical Research Communications 394:2, 249-253
31
M. Babar, M. M. M. Abdel-Latif, N. Ravi, A. Murphy, P. J. Byrne, D. Kelleher, J. V. Reynolds. (2010) Pilot translational study of dietary vitamin C supplementation in Barrett's esophagus. Diseases of the Esophagus 23:3, 271-276
32
Giuseppe Garcea, David P. Berry. Randomized Controlled Trials. In: Pharmaceutical Sciences Encyclopedia. John Wiley & Sons, Inc., 2010.
33
U. Gröber, J. Hübner, P. Holzhauer. (2010) Vitamin C in der komplementären Onkologie. Der Onkologe 16:3, 309-313
34
Simon Nagel, Nick P. Talbot, Jasmin Mecinović, Thomas G. Smith, Alastair M. Buchan, Christopher J. Schofield. (2010) Therapeutic Manipulation of the HIF Hydroxylases. Antioxidants & Redox Signaling 12:4, 481-501
35
E. van Tonder, M. G. Herselman, J. Visser. (2009) The prevalence of dietary-related complementary and alternative therapies and their perceived usefulness among cancer patients. Journal of Human Nutrition and Dietetics 22:6, 528-535
36
Ehab H. Sarsour, Maneesh G. Kumar, Leena Chaudhuri, Amanda L. Kalen, Prabhat C. Goswami. (2009) Redox Control of the Cell Cycle in Health and Disease. Antioxidants & Redox Signaling 11:12, 2985-3011
37
J Mandl, A Szarka, G Bánhegyi. (2009) Vitamin C: update on physiology and pharmacology. British Journal of Pharmacology 157:7, 1097-1110
38
Julien Verrax, Pedro Buc Calderon. (2009) Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radical Biology and Medicine 47:1, 32-40
39
Mark Levine, Michael Graham Espey, Qi Chen. (2009) Losing and finding a way at C: New promise for pharmacologic ascorbate in cancer treatment. Free Radical Biology and Medicine 47:1, 27-29
40
Wang-Jae Lee. (2009) The Prospects of Vitamin C in Cancer Therapy. Immune Network 9:5, 147
41
T. Kremser, A. Evans, A. Moore, K. Luxford, S. Begbie, A. Bensoussan, R. Marigliani, H. Zorbas. (2008) Use of complementary therapies by Australian women with breast cancer. The Breast 17:4, 387-394
42
Mary L. Hardy. (2008) Dietary Supplement Use in Cancer Care: Help or Harm. Hematology/Oncology Clinics of North America 22:4, 581-617
43
James M. Metz, Heather Jones. Complementary and Alternative Medicine. In: Abeloff's Clinical Oncology. Elsevier, 2008:545-561.
44
Neena Philips, Thomas Keller, Carol Holmes. (2007) Reciprocal effects of ascorbate on cancer cell growth and the expression of matrix metalloproteinases and transforming growth factor-β. Cancer Letters 256:1, 49-55
45
Jose Viña, Mari-Carmen Gomez-Cabrera, Consuelo Borras. (2007) Fostering antioxidant defences: up-regulation of antioxidant genes or antioxidant supplementation?. British Journal of Nutrition 98:S1,
46
Q. Chen, M. G. Espey, A. Y. Sun, J.-H. Lee, M. C. Krishna, E. Shacter, P. L. Choyke, C. Pooput, K. L. Kirk, G. R. Buettner, M. Levine. (2007) Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proceedings of the National Academy of Sciences 104:21, 8749-8754
47
Robert Thomas, Mabel Blades, Madeleine Williams. (2007) Can dietary intervention alter prostate cancer progression?. Nutrition & Food Science 37:1, 24-36
48
Kevin T. Fitzgerald, Alvin C. Bronstein, Aryn A. Flood. (2006) “Over-The-Counter” Drug Toxicities in Companion Animals. Clinical Techniques in Small Animal Practice 21:4, 215-226
49
Ian D. Coulter, Mary L. Hardy, Sally C. Morton, Lara G. Hilton, Wenli Tu, Di Valentine, Paul G. Shekelle. (2006) Antioxidants Vitamin C and Vitamin E for the Prevention and Treatment of Cancer. Journal of General Internal Medicine 21:7, 735-744
50
Jacqueline Filshie, Carolyn N.J. Rubens. (2006) Complementary and Alternative Medicine. Anesthesiology Clinics of North America 24:1, 81-111
51
Lawrence B. Berk. (2006) Primer on Integrative Oncology. Hematology/Oncology Clinics of North America 20:1, 213-231
52
Showket Hussain Bhat, Asfar Sohail Azmi, Sarmad Hanif, S.M. Hadi. (2006) Ascorbic acid mobilizes endogenous copper in human peripheral lymphocytes leading to oxidative DNA breakage: A putative mechanism for anticancer properties. The International Journal of Biochemistry & Cell Biology 38:12, 2074-2081
53
Mark A. Moyad. (2005) Prescription versus herbal medications for prostate cancer prevention: Why history cannot be allowed to repeat itself in your clinical practice. Current Prostate Reports 3:4, 160-168
54
Robert Thomas, Mabel Blades, Madeleine Williams, Sara Godward. (2005) Dietary advice combined with a salicylate, mineral and vitamin supplement (CV247) has some tumour static properties: a phase II study. Nutrition & Food Science 35:6, 436-451
55
Barrie R Cassileth, Andrew J Vickers. (2003) Complementary and alternative therapies. Urologic Clinics of North America 30:2, 369-376
56
Jeanne A Drisko, Julia Chapman, Verda J Hunter. (2003) The use of antioxidant therapies during chemotherapy. Gynecologic Oncology 88:3, 434-439
57
Tomoyuki Oe, Ian Blair, Seon Hwa Lee. Vitamin C and Cancer. In: Antioxidants. AOCS Publishing, 2003.
58
Richard L Nahin. (2002) Use of the best case series to evaluate complementary and alternative therapies for cancer: A systematic review. Seminars in Oncology 29:6, 552-562
59
Mary Ann Richardson, Stephen E Straus. (2002) Complementary and alternative medicine: Opportunities and challenges for cancer management and research. Seminars in Oncology 29:6, 531-545
60
Jeffrey D White. (2002) Complementary and alternative medicine research: A National Cancer Institute perspective. Seminars in Oncology 29:6, 546-551
61
Jeffrey D. White. (2002) The National Cancer Institute's Perspective and Agenda for Promoting Awareness and Research on Alternative Therapies for Cancer. The Journal of Alternative and Complementary Medicine 8:5, 545-550
62
K.N Prasad, W.C Cole, B Kumar, K Che Prasad. (2002) Pros and cons of antioxidant use during radiation therapy. Cancer Treatment Reviews 28:2, 79-91
63
Mark A Moyad. (2002) The placebo effect and randomized trials: analysis of alternative medicine. Urologic Clinics of North America 29:1, 135-155
64
James Enstrom. Epidemiological and Clinical Aspects of Ascorbate and Cancer. In: Handbook of Antioxidants. CRC Press, 2001.
65
Andrew J Vickers, Barrie R Cassileth. (2001) Unconventional therapies for cancer and cancer-related symptoms. The Lancet Oncology 2:4, 226-232
66
Barbara Eldridge, Cheryl L. Rock, Paula Davis McCallum. Nutrition and the Patient with Cancer. In: Nutrition in the Prevention and Treatment of Disease. Elsevier, 2001:397-412.
67
Sebastian J Padayatty, Mark Levine. (2000) Reevaluation of Ascorbate in Cancer Treatment: Emerging Evidence, Open Minds and Serendipity. Journal of the American College of Nutrition 19:4, 423-425
68
Chandrika J. Piyathilake, Walter C. Bell, Gary L. Johanning, Phillip E. Cornwell, Douglas C. Heimburger, William E. Grizzle. (2000) The accumulation of ascorbic acid by squamous cell carcinomas of the lung and larynx is associated with global methylation of DNA. Cancer 89:1, 171-176
69
James M. Metz. (2000) ?Alternative medicine? and the cancer patient: An overview. Medical and Pediatric Oncology 34:1, 20-26
70
Kedar N. Prasad, Arun Kumar, Vinod Kochupillai, William C. Cole. (1999) High Doses of Multiple Antioxidant Vitamins: Essential Ingredients in Improving the Efficacy of Standard Cancer Therapy. Journal of the American College of Nutrition 18:1, 13-25
71
SWY Chan, PC Reade. (1998) The role of ascorbic acid in oral cancer and carcinogenesis. Oral Diseases 4:2, 120-129
72
Sheila Weitzman. (1998) Alternative nutritional cancer therapies. International Journal of Cancer 78:S11, 69-72
73
Cheryl L. Rock, Vicky Newman, Shirley W. Flatt, Susan Faerber, Fred A. Wright, John P. Pierce. (1997) Nutrient intakes from foods and dietary supplements in women at risk for breast cancer recurrence. Nutrition and Cancer 29:2, 133-139
74
Alessandro Laviano, Michael M. Meguid. (1996) Nutritional issues in cancer management. Nutrition 12:5, 358-371
75
Evelleen Richards Phd. (1994) The Politics of Therapeutic Evaluation: The Vitamin C and Cancer Controversy. Journal of Nutritional and Environmental Medicine 4:2, 215-246
76
Joel Schwartz, Gerald Shklar, Diane Trickler. (1993) Vitamin C enhances the development of carcinomas in the hamster buccal pouch experimental model. Oral Surgery, Oral Medicine, Oral Pathology 76:6, 718-722
77
MASSIMO L.A. CASELLA, ANDREW CLIFFORD, JOHN R. WHITAKER. (1992) EFFECT OF ASCORBATE AND COPPER ON RAT SERUM ALBUMIN. Journal of Food Biochemistry 16:3, 193-206
78
Carl G. Kardinal, Charles L. Loprinzi, Daniel J. Schaid, A. Curtis Hass, Ann M. Dose, Laureen M. Athmann, James A. Mailliard, Greg W. McCormack, James B. Gerstner, Mark F. Schray. (1990) A controlled trial of cyproheptadine in cancer patients with anorexia and/or cachexia. Cancer 65:12, 2657-2662
79
H. Langemann, J. Torhorst, A. Kabiersch, W. Krenger, C. G. Honegger. (1989) Quantitative determination of water- and lipid-soluble antioxidants in neoplastic and non-neoplastic human breast tissue. International Journal of Cancer 43:6, 1169-1173
80
Joseph Gold. (1987) Hydrazine sulfate: A current perspective. Nutrition and Cancer 9:2-3, 59-66
81
Sidney S. Mirvish. (1986) Effects of vitamins C and E on N-nitroso compound formation, carcinogenesis, and cancer. Cancer 58:S8, 1842-1850
82
(1986) Vitamin C Is a Versatile Tool for Teaching Introductory Biology Courses. The American Biology Teacher 48:7, 401-405
83
Regine Kahl. (1986) The dual role of antioxidants in the modification of chemical carcinogenesis. Environmental Carcinogenesis Reviews 4:1, 47-92
84
Wittes , Robert E. , . (1985) Vitamin C and Cancer. New England Journal of Medicine 312:3, 178-179
Full Text85
Moertel , Charles G. , Fleming , Thomas R. , Creagan , Edward T. , Rubin , Joseph , O'Connell , Michael J. , Ames , Matthew M. , . (1985) High-Dose Vitamin C versus Placebo in the Treatment of Patients with Advanced Cancer Who Have Had No Prior Chemotherapy. New England Journal of Medicine 312:3, 137-141
Full Text86
Toni Huwyler, Andreas Hirt, Andreas Morell. (1985) Effect of ascorbic acid on human natural killer cells. Immunology Letters 10:3-4, 173-176
87
Victor Herbert. (1985) Faddism and quackery in cancer nutrition
. Nutrition and Cancer 6:3, 196-20688
Raymond J. Shamberger. (1984) Genetic toxicology of ascorbic acid. Mutation Research/Reviews in Genetic Toxicology 133:2, 135-159
89
J.M. Smit, N.H. Mulder, D.Th. Sleijfer, J.G. Bouman, W. Veeger, H. Schraffordt Koops. (1983) The effect of continuous enteral tube feeding on various nutritional parameters in patients with disseminated malignant melanoma during intensive chemotherapy. Clinical Nutrition 1:4, 335-341
90
Michael A. Dubick, Robert B. Rucker. (1983) Dietary supplements and health aids
A critical evaluation part 1
91
Paul M. Newberne, Voranunt Suphakarn. (1983) Nutrition and cancer: A review, with emphasis on the role of vitamins C and E and selenium
. Nutrition and Cancer 5:2, 107-11992
(1982) Laetrile. New England Journal of Medicine 307:2, 118-120
Full Text93
B THIERS. (1982) Chemotherapy of malignant melanoma. Journal of the American Academy of Dermatology 6:3, 412-416
94
Jerald Silverman, Abraham Rivenson, Bandaru Reddy. (1982) Effect of sodium ascorbate on transplantable murine tumors. Nutrition and Cancer 4:3, 192-197
95
C. J. Schorah. (1981) The level of vitamin C reserves required in man: towards a solution to the controversy. Proceedings of the Nutrition Society 40:02, 147-154
96
Joseph Gold. (1981) Anabolic profiles in late‐stage cancer patients responsive to hydrazine sulfate. Nutrition and Cancer 3:1, 13-19
97
F. W. J. Gribnau. (1980) Alternatieve geneeswijzen: enkele overwegingen en meningen van een klinisch farmacoloog. Pharmaceutisch Weekblad Scientific Edition 2:1, 1167-1174
98
Pertti J. Arkko, Birgit L. Arkko, Onni Kari-Koskinen, Pentti J. Taskinen. (1980) A survey of unproven cancer remedies and their users in an outpatient clinic for cancer therapy in Finland. Social Science & Medicine. Medical Psychology and Medical Sociology 14:6, 511-514
99
Stanley Bram, Patrick Froussard, Marcelle Guichard, Claude Jasmin, Yvette Augery, Françoise Sinoussi-Barre, Wayne Wray. (1980) Vitamin C preferential toxicity for malignant melanoma cells. Nature 284:5757, 629-631
100
(1980) Vitamin C Therapy of Advanced Cancer. New England Journal of Medicine 302:12, 694-695
Full Text101
(1980) Vitamin C for Cancer. New England Journal of Medicine 302:5, 298-300
Full Text102
(1979) Vitamin C Therapy of Advanced Cancer. New England Journal of Medicine 301:25, 1399-1399
Full Text
