The effect of ascorbic acid on cancer has been a subject of great controversy. This is a follow-up review of the 1979 article by Cameron, Pauling, and Leibovitz published in Cancer Research. In this updated version, the authors address general aspects of ascorbic acid and cancer that have been presented before, while reviewing, analyzing, and updating new existing literature on the subject. In addition, they present and discuss their own mechanistic hypothesis on the effect of ascorbic acid on the cancer cell. The objective of this review is to provide an updated scientific basis for the use of ascorbic acid, especially intravenously as adjuvant treatment in pharmacological nutritional oncology.
Levine M. New concepts in the biology and biochemistry of ascorbic acid. N Engl J Med. 1986;314:892-902.
2.
Food and Nutrition Board, National Research Council. Recommended Dietary Allowances. 10th ed.Washington, DC: National Academy Press; 1989.
3.
Guthrie H. Introductory Nutrition. 7th ed.St. Louis, Mo: Mosby College Publishing; 1989:381-382.
4.
Shils M. Modern nutrition in health and disease. In: Shils M, Olson J, Shike M, eds. Modern Nutrition in Health and Disease. 8th ed.Philadelphia, Pa: Lea and Febiger; 1994:444-445.
5.
Sies H, Stahl W, Sundquist A. Antioxidant functions of vitamins. Ann N Y Acad Sci. 1992;669:7-20.
6.
Leibovitz B, Mueller J. Carnitine. J Optimal Nutr. 1993;2:90-109.
7.
Block G. Vitamin C and cancer prevention: the epidemiologic evidence. Am J Clin Nutr. 1991;53:270s-282s.
8.
Komarova SV, Ataullakhanov FI, Globus RK. Bioenergetics and mitochondrial transmembrane potential during differentiation of cultured osteoblasts. Am J Physiol Cell Physiol. 2000;279:c1220-c1229.
9.
Szent-Gyorgyi A. Introduction to submolecular biology. J Biol Chem. 1960;90:385-385.
10.
Klenner FR. The treatment of polyomyelitis and other virus diseases with vitamin C. South Med Surg. 1949;3:7-12.
11.
McCormick WJ. Ascorbic acid as a chemotherapeutic agent. Arch Pediat. 1952;69:151-155.
12.
Padayatty SJ, Katz A, Wang Y, et al. Vitamin C as an antioxidant: evaluation of its role in disease prevention. J Am Coll Nutr. 2003;22:18-35.
13.
Tamayo C, Richardson MA. Vitamin C as a cancer treatment: state of the science and recommendation for research. Altern Ther. 2003;9:94-102.
14.
Cameron E, Pauling L, Leibovitz B. Ascorbic acid and cancer: a review. Cancer Res. 1979;39:663-681.
15.
Niki E. Action of ascorbic acid as a scavenger of active and stable oxygen radicals. Am J Clin Nutr. 1991;54:1119s-1124s.
16.
Frei B, England L, Ames B. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. 1989;86:6377-6381.
17.
van den Berg JJ, Kuypers FA, Roelofsen B, Op den Kamp JA. The cooperative action of vitamins E and C in the protection against peroxidation of parinaric acid in human erythrocyte membranes. Chem Phys Lipids. 1990;53:309-320.
18.
Chan A. Partners in defense: vitamin E and vitamin C. Can J Physiol Pharmacol. 1993;71:725-731.
19.
Levine M, Dhariwal K, Washko PW, et al. Ascorbic acid and in situ kinetics: a new approach to vitamin requirements. Am J Clin Nutr. 1991;54:1157s-1162s.
20.
Packer J, Slater T, Wilson R. Direct observation of a free radical interaction between vitamin E and vitamin C. Nature. 1979;278:737-738.
21.
Burton GW, Wronska U, Stone L. Biokinetics of dietary RRROC-tocopherol in the male guinea pig at three dietary levels of vitamin C does not spare vitamin E in vivo. Lipids. 1990;25:199-210.
22.
Mirvish S. Experimental evidence for inhibition of N-nitroso compound formation as a factor in a negative correlation between vitamin C consumption and the incidence of certain cancers. Cancer Res. 1974;54:1948s-1951s.
23.
González MJ, Mora E, Riordan NH, Riordan HD, Mojica P. Rethinking vitamin C and cancer: an update on nutritional oncology. Cancer Prev Int. 1998;3:215-224.
24.
Yamamoto K, Takahashi M, Niki E. Role of iron and ascorbic acid in the oxidation of methyl linoleate micelles. Chem Lett. 1987;1:49-52.
25.
Rowly DA, Halliwell B. Superoxide-dependents and ascorbatedependent formation of hydroxy radicals in the presence of copper salts: a physiologically significant reaction?Arch Biochem Biophys. 1983;225:279-284.
26.
Ramp WK, Thorton PA. The effects of ascorbic acid on the glycolytic and respiratory metabolism of embryonic chick tibias. Calcif Tissue Res. 1968;2:77-82.
27.
Beetens JR, Hermen AG. Ascorbic acid and prostaglandin formation. Int J Vitam Nutr Res. 1983;24(suppl):131s-144s.
28.
Mikino Y, Sakagami H, Takeda M. Induction of cell death by ascorbic acid derivatives in human renal carcinoma and glioblastoma cell lines. Anticancer Res. 1999;19:3125-3132.
29.
Nakamura Y, Yamafuji K. Antitumor activities of oxidized products of ascorbic acid. Sci Bull Fac Kyushu Univ. 1968;23:119-125.
30.
Yamafuji K, Nakamura Y, Omura H, Soeda T, Gyotoku K. Antitumor potency of ascorbic, dehydroascorbic or 2, 3-diketogulonic acid and their action on deoxyribonucleic acid. Z Krebsforsh Klin Onkol Cancer Res Clin Oncol. 1971;76:1-7.
31.
Omura H, Tomita Y, Yasuhiko N. Antitumor potentiality of some ascorbate derivaties. J Fac Agr Kyushu Univ. 1974;18:181-189.
32.
Tomita Y, Eto M, Lio M. Antitumor potency of 3-methyl-3,4-dihydroxytetrone. Sci Bull Fac Agr Kyushu Univ. 1974;28:131-137.
33.
Poydock ME, Reikert D, Rice J, Aleandri L. Inhibiting effect of dehydroascorbic acid on cell division in ascites tumors in mice. Exp Cell Biol. 1982;50:34-38.
34.
Leung PY, Miyashita K, Young M, Tsao CS. Cytotoxic effect of ascorbate and its derivative on cultured malignant and nonmalignant cell lines. Anticancer Res. 1993;13:47-80.
35.
Avakawa N, Nemoto S, Suzuki E, Otsuka M. Role of hydrogen peroxide in the inhibitory effect of ascorbate on cell growth. J Nutr Sci Vitaminol. 1994;40:219-227.
36.
Peterkofsky B, Prather W. Cytotoxicity of ascorbate and other reducing agents towards cultured fibroblasts as a result of hydrogen peroxide formation. J Cell Physiol. 1971;90:61-70.
37.
Yve B, Niedra JT, Baum JL. Effects of ascorbic acid on cultured rabbit endothelial cells. Invest Opthal Mol Vis Sci. 1980;19:1471-1476.
38.
Jampel HD. Ascorbic acid is cytotoxic to dividing human Tenon’s capsule fibroblasts. Arch Opthal Mol. 1990;108:1323-1325.
39.
Tsao CS, Dunhan WB, Leung PY. In vivo antineoplastic activity of ascorbic acid for human mammary tumor. In Vivo. 1988;2:147-150.
40.
Tsao CS, Dunhan WB, Leung PY. Effect of ascorbic acid and its derivatives on the growth of human mammary tumor xenografts in mice. Cancer J. 1989;5:53-59.
41.
Poydock ME. Effect of combined ascorbic acid and B12 on survival of mice implanted with Ehrlich carcinoma and L1210 leukemia. Am J Clin Nutr. 1982;54:1261s-1265s.
42.
Edgar JA. Dehydroascorbic acid and cell division. Nature. 1970;227:24-26.
43.
Bram S, Froussard P, Guichard M, et al. Vitamin C preferential toxicity for malignant melanoma cells. Nature. 1980;284:629-631.
44.
Riordan NH, Riordan HD, Meng XL, Li Y, Jackson JA. Intravenous ascorbate as a tumor cytotoxic chemotherapeutic agent. Med Hypotheses. 1995;44:207-213.
45.
Sakagami H, Satoh K. Pro-oxidant action of two antioxidants: ascorbic acid and gallic acid. Anticancer Res. 1997;17:221-224.
46.
Muñoz E, Blazquez MV, Ortiz C, Gómez-Díaz C, Navas P. Role of ascorbate in the activation of NF.B by tumour necrosis factor- • in T-cells. Biochem J. 1997;325:23-28.
47.
Halliwell B. Vitamin C: antioxidant or pro-oxidant in vivo?Free Radic Res. 1996;25:439-454.
48.
Alcain FJ, Buron MI. Ascorbate on cell growth and differentiation. J Bioenerg Biomembr. 1996;26:393-398.
49.
Asano K, Satoh K, Hosaka M, et al. Production of hydrogen peroxide in cancerous tissue by intravenous administration of sodium 5,6 benzylidene-L-ascorbate. Anticancer Res. 1999;19:229-236.
50.
Jonas SK, Riley PA, Willson RL. Hydrogen peroxide cytotoxicity. Biochem J. 1989;264:651-655.
51.
ClementMV, Ramalingam J, Long LH, Halliwell B. The in vitro cytotoxicity of ascorbate depends on the culture medium used to perform the assay and involves hydrogen peroxide. Antiox Redox Signal. 2001;3:157-163.
52.
Sakagami H, Satoh K, Kochi M. Comparative study of the antitumor action between sodium 5,6 benzylidene-L-ascorbate and sodium ascorbate. Anticancer Res. 1997;17:4401-4452.
53.
González MJ, Schemel RA, Gray JI, Dugan LJR, Sheffield LG, Welsch CW. Effect of dietary fat growth of MCF-7 and MDAMB231 human breast carcinomas in athymic nude mice: relationship between carcinoma growth and lipid peroxidation products level. Carcinogenesis. 1991;12:1231-1235.
54.
González MJ. Lipid peroxidation and tumor growth: an inverse relationship. Med Hypotheses. 1992;38:106-110.
55.
González MJ, Riordan NH. The paradoxical role of lipid peroxidation on carcinogenesis and tumor growth. Med Hypotheses. 1996;46:503-504.
56.
Gutteridge JMC, Richmond R, Halliwell B. Oxygen freeradicals and lipid peroxidation: inhibition by the protein caeruloplasmin. FEBS Lett. 1980;112:269-272.
57.
Szent-Gyorgyi A. The living state and cancer. Physiol Chem Physics. 1980;12:99-110.
58.
Schwarz JL. The dual roles of nutrients as antioxidants and pro-oxidants: their effects on tumor cell growth. J Nutr. 1996; 126:1221S-1227S.
59.
Sigal A, King CG. The relationship of vitamin C to glucose tolerance in the guinea pig. J Biol Chem. 1936;166:489-492.
60.
Landauver W, Sopher D. Succinate, glycerophosphate and ascorbate as sources of cellular energy as antiteratogens. J Embryol Exp Morph. 1970;24:187-202.
61.
Cathcart RF. A unique function for ascorbate. Med Hypotheses. 1991;35:32-37.
62.
Li Y, Cobb CE, Hill KE, Burk RF, May JM. Mitochondrial uptake and recycling of ascorbic acid. Arch Biochem Biophys. 2001;387:143-153.
63.
González MJ, Schemmel RA, Dugan L Jr, Gray JI, Welsch CW. Dietary fish oil inhibits human breast carcinoma growth: a function of increased lipid peroxidation. Lipids. 1993;28:827-832.
64.
Sakagami H, Satoh K, Hakeda Y, Kumegawa M. Apoptosisinducing activity of vitamin Cand vitamin K. Cell Mol Biol. 2000; 46:129-143.
65.
Iwasaka K, Koyama N, Nogaki A, et al. Role of hydrogen peroxide in cytotoxicity induction by ascorbates and other redox compounds. Anticancer Res. 1998;18:4333-4337.
66.
Davies KJA. The broad spectrum of responses to oxidants in proliferating cells: a new paradigm for oxidative stress. Life Sci. 1999;48:41-47.
67.
Dasgupta A, Zdunek T. In vitro lipid peroxidation of human serum catalyzed by cupric ion: antioxidant rather than pro-oxidant role of ascorbate. Life Sci. 1992;50:875-882.
68.
Sakagami H, Satoh K, Sugaya K, et al. Effect of the type of serum in the medium on sodium ascorbate-induced toxicity. Anticancer Res. 1996;16:1937-1942.
69.
Sakagami H, Satoh K, Taguchi S, Takeda M. Inhibition of cytotoxic activity of ascorbate by human cancer patient sera. Anticancer Res. 1997;17:425-428.
70.
González MJ. Fish oil, lipid peroxidation and mammary tumor growth. J Am Coll Nutr. 1995;14:325-335.
71.
Sestili P, Brandi G, Brambilla L, Cattabeni F, Cantoni O. Hydrogen peroxide mediates the killing of U937 tumor cells elicited by pharmacologically attainable concentrations of ascorbic acid cell death prevention by extracellular catalase from cultured erythrocytes of fibroblasts. J Pharmacol Exp Ther. 1996; 277:1719-1725.
72.
Iyanagi T, Yamazaki I, Anan KF. One electron oxidationreduction properties of ascorbic acid. Biochem Acta. 1985;806:255-261.
73.
Venugopal M, Jamison JM, Gilloteaux J, et al. Synergistic antitumor activity of vitamins C and K 3 on human urologic tumor cell lines. Life Sci. 1996;59:1389-1400.
74.
Satoh K, Kadofuku T, Sakagami H. Copper but not iron, enhances apoptosis-inducing activity of antioxidants. Anticancer Res. 1997;17:2487-2490.
75.
González MJ, Miranda-Massari JR, Mora EM, et al. Orthomolecular oncology: a mechanistic view of intravenous ascorbate’s chemotherapeutic activity. PR Health Sci J. 2002;21: 39-41.
76.
González MJ, Mora EM, Miranda-Massari JR, Matta J, Riordan HD, Riordan NH. Inhibition of human breast carcinoma cell proliferation by ascorbate and copper. PR Health Sci J. 2002;21:21-30.
77.
Nelson SR, Pazdernik TL, Samson FE. Copper plus ascorbate inactivates lactate dehydrogenase: are oxygen radicals involved?Proc West Pharmacol Soc. 1992;35:37-41.
78.
Powers HJ, Gibson AT, Bates CJ, Primhak RA, Beresford J. Does vitamin C intake influence the rate of tyrosine catabolism in premature babies?Ann Nutr Metab. 1994;38:166-173.
79.
Palumbo A, Misuraca G, D’Ischia M, Prota G. Effect of metal ions on the kinetics of tyrosine oxidation catalysed by tyrosinase. Biochem J. 1985;288:647-651.
80.
Sun Y, Oberley LW, Oberley TD, Elwell JH, Sierra-Rivera E. Lowered antioxidant enzymes in spontaneously transformed embryonic mouse liver cells in culture. Carcinogenesis. 1993;14:1437-1446.
81.
Benade L, Howard T, Burk D. Synergistic killing of Ehrlich ascites carcinoma cells by ascorbate and 3-amino-1,2,4,-triazole. Oncology. 1969;23:33-43.
82.
Punnonen K, Ahotupa M, Asaishi K, Hyoty M, Kudo R, Punnonen R. Antioxidant enzyme activities and oxidative stress in human breast cancer. J Cancer Res Clin Oncol. 1994; 120: 374-377.
83.
Jaruga P, Olinste R. Activity of antioxidant enzymes in cancer diseases. Postepy Hig Med Dosw. 1994;48:443-455.
84.
Sun Y, Colburn NH, Oberley LW. Depression of catalase gene expression after immortalization and transformation of mouse liver cells. Carcinogenesis. 1993;14:1505-1510.
85.
Bozzi A, Mavelli I, Mondovi B, Strom R, Rotilio G. Differential sensitivity of tumor cells to externally generated hydrogen peroxide: role of glutathione and related enzymes. Cancer Biochem Biophys. 1979;3:135-141.
86.
Noto V, Taper HS, Jiang YH, Janssens J, Bonte J, De Loeker W. Effects of sodium ascorbate (vitamin C) and 2-methyl-1,4 naphthoquinone (vitamin K 3) treatment of human tumor cell growth in vitro. Cancer. 1989;63:901-906.
87.
Gilloteaux J, Jamison JM, Arnold D, et al. Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C— vitamin K 3 on human bladder carcinoma T-24 cells. Scanning. 1998;20:564-575.
88.
Gilloteaux J, Jamison JM, Ervin E, Arnold D, Summers JL. Scanning electron microscopy and transmission electron microscopy aspects of the synergistic antitumor activity of vitamin C/vitamin K 3 combinations against human T-24 bladder carcinoma: another kind of cell death. Scanning. 1998;20:208-209.
89.
Gilloteaux J, Jamison JM, Arnold D, Taper HS, Summers JL. Ultrastructural aspects of autoschizis: a new cancer cell death induced by the synergistic action of ascorbate/menadione on human bladder carcinoma cells. Ultrastructural Pathol. 2001;25:183-192.
90.
Grad JM, Bahlis NJ, Reis I, Oshiro MM, Dalton WS, Boise LH. Ascorbic acid enhances arsenic trioxide-induced cytotoxicity in multiple myeloma cells. Blood. 2001;98:805-813.
Riordan HD, Jackson JA, Schultz M. Case study: high-dose intravenous vitamin C in the treatment of a patient with adenocarcinoma of the kidney. J Orthomolec Med. 1990;5:5-7.
93.
Jackson JA, Riordan HD, Hunninghake RE, Riordan NH. High dose intravenous vitamin C and long time survival of a patient with cancer of the head of the pancreas. J Orthomolec Med. 1995;10:87-88.
94.
Riordan NH, Riordan HD, Casciari JJ. Clinical and experimental experiences with intravenous vitamin C. J Orthomolec Med. 2000;15:201-213.
95.
Casciari JJ, Riordan NH, Schmidt TL, Meng XL, Jackson JA, Riordan HD. Cytotoxicity of ascorbate, lipoic acid and other antioxidants in hollow fiber in vitro tumours. Br J Cancer. 2001;84:1544-1550.
96.
Lykkesfeldt J, Hagen TM, Vinarsky V, Ames BN. Age associated decline in ascorbic acid concentration, recycling and biosynthesis in rat hepatocytes-reversal with (R)-•-lipoic acid supplementation. FASEB J. 1998;12:1183-1189.
97.
Tsao CS, Miyashita K. Effects of high intake of ascorbic acid on plasma levels of amino acids. IRCS Med Sci. 1984;12:1052-1053.
98.
Tsao CS, Miyashita K. Effects of large intake of ascorbic acid on the urinary excretion of amino acids and related compounds. IRCS Med Sci. 1985;13:855-856.
99.
Basu TK. Possible role of vitamin Cin cancer therapy. In Hanck A, Ritzel G., eds. Vitamin C: Recent Advances and Aspects in Virus Disease, Cancer and in Lipid Metabolism. Bern, Switzerland: Hans Huber; 1979:95-102.
100.
Bensch KG, Fleming JE, Lohman W. The role of ascorbic acid in senile cataracts. Proc Natl Acad Sci USA. 1985;82:7193-7196.
101.
Garland D, Zigler JS, Kinoshita J. Structural changes in bovine lens crystallins induced by ascorbate, metal and oxygen. Arch Biochem Biophysics. 1986;251:771-776.
102.
Moss RW. Questioning Chemotherapy. New York, NY: Equinox Press; 1995.
103.
Wang Y, Russo TA, Kwon O, Chanok S, Rumsey SC, Levine M. Ascorbate recycling in human neutrophils: induction by bacteria. Proc Natl Acad Sci U S A. 1997;94:13816-13819.
104.
Spielholz C, Golde DW, Houghton AN, Nualart F, Vera JC. Increased transport of dehydroascorbic acid without changes in sodium dependent ascorbate transport in human melanoma cells. Cancer Res. 1997;57:2529-2537.
105.
Warburg O. On the origin of cancer cells. Science. 1956;123: 309-314.
106.
Younes M, Lechago LV, Somoano JR, Mosharaf M, Lechago J. Nude expression of the human erythrocyte glucose transporter Glut-1 in human cancers. Cancer Res. 1996;56:1164-1167.
107.
Alcain FJ, Buron I, Rodríguez-Aguilera JC, Villalba JM, Navas P. Ascorbate free radical stimulates the growth of a human promyelocytic leukemia cell line. Cancer Res. 1990;50:5887-5891.
108.
Arnold RS, Shi J, Murad E, et al. Hydrogen peroxide mediates the cell growth and transformation caused by the mitogenic oxidase Nox1. Proc Natl Acad Sci U S A. 2001;98:5550-5555.
109.
Djuric Z, Everett CK, Luongo DA. Toxicity, single-strand breaks and 5-hydroxymethyl-2-deoxyuridine formation in human breast epithelial cells treated with hydrogen peroxide. Free Radic Biol Med. 1993;14:541-547.
110.
González MJ, López D, Argüelles M, Riordan NH. Antioxidants and pro-oxidants: a commentary about their discrepant role in carcinogenesis. Age. 1996;19:17-18.
111.
González MJ, Riordan NH, Matos MI, Argüelles M. Antioxidants and cancer: a brief discussion on controversies, contradictions and paradoxes. J Orthomolec Med. 1997;12:145-148.
112.
Allen RG, Venkatraj VS. Oxidants and antioxidants in development and differentiation. J Nutr. 1992;22:631-635.
113.
Lee JY, Chang MY, Park CH, et al. Ascorbate induced differentiation of embryonic cortical precursors into neurons and astrocytes. J Neurosci Res. 2003;73:156-165.
114.
Kang JH, Shi YM, Zheng RL. Effects of ascorbic acid in human hepatoma cell proliferation and redifferentiation. Acta Pharmacol Sin. 1999;20:1019-1024.
115.
John AP. Dysfunctional mitochondria, not oxygen insufficiency, cause cancer cells to produce inordinate amounts of lactic acid: the impact of this on the treatment of cancer. Med Hypotheses. 2000;57:429-431.
116.
Ingebretsen OC, Normann PT. Transport of ascorbate into guinea pig liver mitochondria. Biochem Biophys Acta. 1982;684: 21-26.
117.
McCormick WJ. Cancer: a collagen disease, secondary to a nutritional deficiency?Arch Pediatr. 1959;76:166-171.
118.
Dresden MH, Heilman SA, Schmidt JD. Collagenolytic enzymes in human neoplasms. Cancer Res. 1972;32:993-996.
119.
Cameron E, Pauling L. Ascorbic acid and the glycosaminoglycan: an orthomolecular approach to cancer and other diseases. Oncology. 1973;27:181-192.
120.
Yoneda M, Shimizu S, Nishi Y, Yamagata M, Suzuki S, Kimata K. Hyaluronic acid dependent change in the extracellular matrix of mouse dermal fibroblasts that is conducive to cell proliferation. J Cell Sci. 1998;90:275-286.
121.
Kennedy JF. Chemical and biochemical aspects of the glycosaminoglycans and proteoglycans in health and disease. Adv Clin Chem. 1976;18:1-101.
122.
Ringsdorf WM JR, Cheraskin E. Vitamin C and human wound healing. Oral Surg. 1982;53:231-236.
123.
Lewin S. Vitamin C: Its Molecular Biology and Medical Potential. New York, NY: Academic Press; 1976.
124.
Goetzl EJ, Wasserman SI, Gigli I, Austen KF. Enhancement of random migration and chemotactic response of human leukocytes by ascorbic acid. J Clin Invest. 1974;53:813-818.
125.
Siegel BV. Enhancement of interferon production by poly (r1), poly (rC) in mouse cell cultures by ascorbic acid. Nature. 1975;254:531-532.
126.
Dahl H, Degre M. The effect of ascorbic acid on production of human interferon and the antiviral activity in vitro. Acta Pathol Scand Sect B. 1976;84:280-284.
127.
Mirvish SS, Wallcave L, Eagen M, Shubik P. Ascorbate-nitrate reaction: possible means of blocking the formation of carcinogenic N-nitroso compounds. Science. 1972;177:65-68.
128.
El Attar TMA, Lin HS. Effect of vitamin C on prostaglandin synthesis by fibroblasts and squamous carcinoma cells. Prostaglandins Leukot Essent Fatty Acids. 1992;47:253-257.
129.
Reddy VG, Khanna D, Singh N. Vitamin C augments chemotherapeutic response of cervical carcinoma beta cells by stabilizing p53. Biochem Biophys Res Comm. 2001;282:409-415.
130.
Barness LA. Safety consideration with high ascorbic acid dosage. Ann N Y Acad Sci. 1974;258:253-258.
131.
Carthcart RF. Vitamin C, titrating to bowel tolerance, anascorbemia and acute induced scurvy. Med Hypotheses. 1981; 7:1359-1376.
132.
Carthcart RF. The method of determining proper doses of vitamin C for the treatment of diseases by titrating to bowel intolerance. Australas Nurses J. 1981;9:9-13.
133.
Rees DC, Kelsey H, Richards JDM. Acute hemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. Br Med J. 1993;306:841-842.
134.
González MJ. Ascorbic acid and selenium interaction: its relevance in carcinogenesis. J Orthomolec Med. 1990;5:67-69.
135.
Heinz-Schmidt K, Hagmaier V, Hornig DH, Vuilleumier JP, Rutishauser G. Urinary oxalate excretion after large intakes of ascorbic acid in man. Am J Clin Nutr. 1981;34:305-311.
136.
Sutton JL, Basu TK, Dickerson JWT. Effect of large doses of ascorbic acid in man on some nitrogenous components of urine. Human Nutr. 1983;37A:136-140.
137.
Erden F, Hacisalihoglu A, Kocer Z, Simsek B, Nebioglu S. Effects of vitamin C intake on whole blood plasma, leukocyte and urine ascorbic acid and urine oxalic acid levels. Acta Vitaminol Enzymol. 1985;7:123-130.
138.
Tsao CS, Leung PY. Urinary ascorbic acid levels following the withdrawal of large doses of ascorbic acid in guinea pigs. J Nutr. 1988;118:895-900.
139.
Gerster H. No contribution of ascorbic acid to renal calcium oxalate stones. Ann Nutr Metab. 1997;41:269-282.
140.
Wandzilak TR, D’Andre SD, Davis PA, Williams HE. Effect of high dose vitamin C on urinary oxalate levels. J Urol. 1994;151: 834-837.
141.
Klenner FR. Observations on the dose and administration of ascorbic acid when employed beyond the range of a vitamin in human pathology. J Appl Nutr. 1971;23:61-88.
142.
Cathcart RF. Vitamin C: the non-toxic, non-rate-limited antioxidant free radical scavenger. Med Hypotheses. 1985;18:61-77.
143.
Campbell A, Jack T. Acute reactions to mega ascorbic acid therapy in malignant disease. Scott Med J. 1979;24:151-153.
144.
Schwartz J, Shklar G, Trickler D. Vitamin Cenhances the development of carcinoma in the hamster buccal pouch experimental model. Oral Surg Oral Med Oral Pathol. 1993;76:718-722.
145.
Shklar G, Schwartz J, Trickler D, Cheverie SR. The effectiveness of a mixture of beta carotene, alpha tocopherol, glutathione and ascorbic acid for cancer prevention. Nutr Cancer. 1993;20:145-151.
146.
Cohen M, Bhagavan HN. Ascorbic acid and gastrointestinal cancer. J Am Coll Nutr. 1995;14:565-578.
147.
Park CH. Vitamin C and leukemia and preleukemia cell growth. Prog Clin Biol Res. 1988;259:321-330.
148.
Koh WS, Lee SJ, Lee H, et al. Differential effects and transport kinetics of ascorbate derivatives in leukemic cell lines. Anticancer Res. 1998;18:2487-2493.
149.
Prasad KN, Kumar R. Effect of individual and multiple antioxidant vitamins on growth and morphology of human nontumorigenic and tumorigenic parotid acinar cell in cultures. Nutr Cancer. 1996;26:11-19.
150.
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. 1976;73:3685-3689.
151.
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. 1978;75:4538-4542.
152.
Creagan ET, Moertel CG, O’Fallon JR, et al. Failure of highdose vitamin C (ascorbic acid) to benefit patients with advanced cancer: a controlled trial. N Engl J Med. 1979;301:687-690.
153.
Moertel CG, Fleming TR, Creagan ET, Rubin J, O’Connell MJ, Aves MM. High-dose vitamin Cversus placebo in the treatment of patients with advanced cancer who had no prior chemotherapy. N Engl J Med. 1985;312:137-141.
154.
Richards E. The politics of therapeutic evaluation: the vitamin C and cancer controversy. J Nutr Med. 1994;4:215-246.
155.
Blanchard J, Tozer TN, Rowland M. Pharmacokinetic perspective on megadoses of ascorbic acid. Am J Clin Nutr. 1997;66:1165-1171.
156.
Agus DB, Vera JC, Golde DW. Stand allocation: a mechanism by which tumors obtain vitamin C. Cancer Res. 1999;59:4555-4558.
157.
Langemann H, Torhorst J, Kabiersch A, Krenger W, Honegger CG. Quantitative determination of water -and lipid-soluble antioxidants in neoplastic and non-neoplastic human breast tissue. Int J Cancer. 1989;43:1169-1173.
158.
Nagy B, Mucs i I, Molnar J, Varga A, Thurzo L. Chemosensitizing effect of vitamin C in combination with 5-FU. In Vitro. 2003;17:289-292.
159.
Prasad KN, Cole WC, Kumar B, Prasad KC. Pros and cons of antioxidant use during radiation therapy. Cancer Treat Rev. 2002;28:79-91.
160.
Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003;22:118-123.
161.
Lamson DW, Brignall MS. Antioxidants in cancer therapy: their actions and interactions with oncologic therapies. Alt Med Rev. 1999;4:304-329.
162.
Lamson DW, Brignall MS. Antioxidants in cancer therapy II: quick reference guide. Altern Med Rev. 2000;5:152-163.
163.
Lamson DW, Brignall MS. Antioxidants in cancer III. Altern Med Rev. 2000;5:196-208.
164.
Prasad KN, Kumar A, Kochupillai V, Cole WC. High doses of multiple antioxidant vitamins: essential ingredients in improving the efficacy of standard cancer therapy. J Am Coll Nutr. 1999;18:13-25.
165.
Moss RW. Antioxidants Against Cancer. New York, NY: Equinox Press; 2000.
166.
Weijl NI, Hopman GD, Wipkink-Bakker A, et al. Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients. Ann Oncol. 1998;9:1331-1337.
167.
Clemens MR, Muller-Ladner CI, Gey KF. Vitamins during high dose chemo and radio therapy. Z Ermahrungwiss. 1992;31:110-120.
168.
Schreurs WH, Odink J, Egger RJ, Wedel M, Brunning PF. The influence of radiotherapy and chemotherapy on the vitamin status of cancer patients. Int J Vitam Nutr Res. 1985;55:425-432.
169.
Murata A, Murata A, Morishige F, Yamaguchi H. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitam Nutr Suppl. 1982;23:103-113.
170.
Ringsdorf WM. Vitamin C supplementation and relief from pain. J Ala Dent Assoc. 1969;68:47-50.
171.
Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. Ugeskr Laeger. 2003;165:2563-2566.
172.
Luo G, Xie ZZ, Liu FY, Zhang GB. Effect of vitamin C on mitochondrial function and ATP content in hypoxic rats. Zhongguo Yao Li Xue Bao. 1998;19:351-355.
173.
Riordan HD, Hunnighake RB, Riordan NR, et al. Intravenous ascorbic acid: protocol for its application and use. PR Health Sci J. 2003;22:287-290.
