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Re: Re: Results of study in line with predictions
- Leonardo A. Noriega, Steve Hickey, Hilary Roberts (20 November 2008)
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Re: Results of study in line with predictions
- Sebastian J Padayatty, Bethesda, Maryland, 20892. USA (18 September 2008)
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Re: Results of study in line with predictions
- L. John Hoffer, Mark Levine, Wilson H Miller Jr (30 July 2008)
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Results of study in line with predictions
- Steve Hickey, Hilary Roberts (18 June 2008)
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Leonardo A. Noriega, Senior Lecturer Staffordshire University, Beaconside, Stafford, England, ST16 9DG, Steve Hickey, Hilary Roberts
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The comments by Hoffer and Padayatti do not provide a rational response to our objections to the Hoffer et al. paper.[1] Ascorbate alone, whether given orally or intravenously, is a weak anticancer agent. Evidence suggests that oral combinations with other redox active agents are more likely to provide an effective cancer treatment. We did not claim to have “known” in advance that the study would not provide optimal clinical benefit, as Hoffer suggests. We simply stated that their observations were consistent with our predictions. This main objection was not addressed in the responses. Hoffer claims their protocol was similar to Riordan’s, but that Riordan included “a variety of other agents”, and a “continuous infusion” with positive results. This is in line with our objection to the use of pulsed intravenous ascorbate as a single anticancer agent. Contrary to what Hoffer claims, our response did not suggest that ascorbate “has to enter cancer cells” in order to kill them. We said that its action depends on its concentration “within the tumor”, as we do not know of any chemical capable of acting at a distance. Potentially, ascorbate could kill or inhibit cancer cells in several ways. Hoffer et al. explicitly claim that ascorbate acts externally to the cancer cells: this extrapolation is based on inadequate evidence. Oxidized ascorbate may enter cancer cells and kill them; the authors’ claims ignore the literature on the absorption and cytotoxicity of dehydroascorbate in cell and animal studies.[2] We did point out that the infusion of ascorbate could not “enter and equilibrate” with the body cells, as the observed plasma concentrations were inconsistent with this hypothesis. In short, the infusion time was too short for equilibration and observed plasma concentrations. Also, the plasma levels would be far lower if equilibration had occurred, since the total tissue volume in the body is much greater than that of blood plasma. We have not “speculated” on ascorbate pharmacokinetics, as Padayatty claims. We have, however, demonstrated gross errors in the authors’ interpretation and provided a consistent model of the process, which agrees with the data. We have also shown that oral doses of ascorbate can achieve levels about 10 fold higher than the “saturated steady state” maximum, incorrectly claimed by Padayatti and others.[3] Padayatti’s claim, that the concentration of ascorbate needed for cytotoxicity is 5mM, is incorrect. For short exposures to ascorbate, his co-workers at the NIH have published data showing that “For five of the nine cancer cell lines, ascorbate concentrations causing a 50% decrease in cell survival (EC50 values) were less than 5 mM”.[4] Furthermore, reported results (Human Burkitt’s lymphoma) included 60% cell death at only 0.5 mM/L, and significant cytotoxicity at 0.3 mM/L. These results were for a one hour exposure. Cytotoxic plasma concentrations (at least 0.4-0.6 mM/L) are achievable with oral administration of ascorbate and these levels can be sustained indefinitely.[3] Furthermore, the amount of ascorbate needed to selectively kill cancer cells is far lower when synergistic substances, such as copper, iron, or vitamin K, are present. There is an extensive literature on this point.[5] Notably, cytotoxic levels of these combinations are easily achieved with oral administration. Padayatti repeats a claim that specialized white blood cells, which specifically accumulate ascorbate, can be used as a proxy for other cells that are not specialized in this way. This claim can be discredited using basic physics. The maximum body pool is reported to be 2g.[6][7] If Padayatti were correct, a back of the envelope calculation indicates that, for a large adult consuming the US RDA, the body pool of ascorbate would be far greater and in the approximate range 12-37g! Padayatti’s odd, if fashionable, demands for “proof” are unscientific. Science is a process of inductive accumulation of knowledge: proceeding by hypothesis, experiment, replication, and refutation. This process was described by Popper,[8] and rigorously formalized in algorithmic probability theory by Solomonoff[9] and others. Padayatti’s statements concerning “proof” therefore lack merit and can be disregarded. We restate our hypothesis that use of this intravenous ascorbate protocol will yield suboptimal results: the results in the Hoffer et al. paper are consistent with this proposition. Ascorbate is a weak but selective anticancer agent. When ascorbate is used in a redox therapy combination with synergistic substances, such as alpha-lipoic acid or copper, its cytotoxic action is greatly enhanced. Furthermore, the high plasma levels attained for short periods with intravenous ascorbate may be far less effective than sustained oral intakes. Unlike pulsed IV administration, oral intakes can sustain levels in the cytotoxic range indefinitely, providing a consistent selection pressure on tumor cells. Hoffer and Padayatti’s responses have little bearing on this issue. References
1. Hoffer L.J. Levine M. Assouline S. Melnychuk D. Paddayatty S.J. Rosadiuk K. Rousseau C. Robitaille L. Miller W.H. (2008) Phase I clinical trial of i.v. ascorbic acid in advanced Malignancy, Ann Oncol, 0: mdn377v4-377, June 14.
Conflict of Interest:None declared |
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Sebastian J Padayatty, Physician National Institutes of Health, Bethesda, Maryland, 20892. USA
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Dr. Hickey has raised interesting points and speculated on many aspects of vitamin C pharmacokinetics and potential therapeutic effects. Unfortunately, there is no experimental data available in peer reviewed journals that support or refute these hypotheses. Therefore we can only extrapolate from existing evidence, but such extrapolations may or may not be borne out by future experiments. The recent trial (1) was a phase one study that provided data on pharmacokinetics and safety of intravenously administered vitamin C in cancer patients. The study was not deigned to test efficacy, which requires a larger trial with treatment and control groups. It is possible that some but not all cancer cells are killed by millimolar concentrations of vitamin C, and resistant cells may preferentially multiply in the presence of toxic concentrations of vitamin C. Whether continuous or intermittent administration of IV vitamin C will forestall this is unknown. Recent evidence shows that the anticancer effects of vitamin C are mediated by extracelluar vitamin C, and correlate with hydrogen peroxide generated in the extracellular space but not in the intra vascular compartment (2). Such actions are only seen when vitamin C concentrations are above 5mM, a concentration that can be achieved by intravenous but not oral administration of vitamin C (3). Hence the use of high dose intravenous vitamin C in the experimental treatment of cancer. It is possible that if high plasma vitamin C concentrations are maintained, some or all tissues will accumulate significant amounts of vitamin C. Many tissues normally have millimolar concentrations of vitamin C even when plasma vitamin C concentrations are only about 50µMol/L. When plasma and tissue vitamin C concentrations are compared, it is clear that the avidity with which tissues accumulate vitamin C peaks before plasma concentrations reach steady state for physiological amounts of vitamin C ordinarily found in diet; perhaps about 300 mg/day. Further increases in consumption had only a small effect on vitamin C concentrations in circulating white cells, used as proxy for other cells (4). This is in keeping with the properties of the predominant tissue transporter for vitamin C - Sodium Vitamin C Transporter 2. Nevertheless, very high plasma vitamin C concentrations may further increase intracellular vitamin C concentrations, but this has not been properly studied. Human and laboratory studies show that high plasma vitamin C concentrations can be achieved by intravenous administration; vitamin C produces hydrogen peroxide in the extracellular space and is toxic to cancer cells in vitro. Whether high dose intravenous vitamin C treatment will improve clinical outcome in patients with cancer or other diseases is not known. Science may be driven by hypothesis but it is experimental evidence that defines it and separates it from other forms of knowledge. Medicine advances when the underlying science is strengthened with proof of efficacy. The use of vitamin C for treatment of diseases other than its deficiency state is unproven and remains contentious. It is necessary to prove its efficacy by well conducted clinical studies before advocacy of vitamin C treatment for any condition other than scurvy. References 1. Hoffer LJ, Levine M, Assouline S, et al. Phase I clinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008;25:25. 2. Chen Q, Espey MG, Krishna MC, et al. Pharamacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissuse. Proc Natl Acad Sci USA 2005;102:13604-9. 3. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med 2004;140:533-7. 4. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A 2001;98:9842-6. Conflict of Interest:None declared |
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L. John Hoffer, Professor of Medicine, McGill University Lady Davis Institute for Medical Research, 3755 Cote Ste Catherine, Montreal, Quebec, H3T 1E2, Canad, Mark Levine, Wilson H Miller Jr
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Hickey makes several statements that require comment. He claims to have known even before we carried out our study that pulsed intravenous ascorbic acid cannot be useful in cancer therapy because it induces biological resistance. But induced resistance follows initial activity. Our clinical trial established robust safety parameters and practical dosing guidelines, but did not yield promising evidence of efficacy as the sole anti-cancer treatment in a small series of unselected patients with advanced, multiply pre-treated malignancies. Of note, only 6 patients in our series received the highest ascorbate dose. Our protocol was closely similar to one developed by Riordan (1,2), except that Riordan administered intravenous ascorbic acid 2 or 3 times weekly whereas we administered it 3 times weekly; another difference is that Riordan commonly combined ascorbic acid with a variety of other agents. Riordan carried out a phase I clinical trial of the kind advocated by Hickey, administering ascorbic acid by continuous infusion to 24 patients with advanced cancer and achieving plasma ascorbic acid concentrations of approximately 1.1 mmol/L (3). One patient had stable disease and continued treatment for 4 years. Hickey is correct that induced resistance is an important phenomenon in cancer therapy. Cameron and Campbell described remarkable clinical remissions in apparent response to intravenous and oral ascorbic acid, only to be followed months later by a dramatic resurgence of the original disease (4). Hickey incorrectly claims that ascorbic acid has to enter cancer cells to kill them. Pharmacologic ascorbic acid induces hydrogen peroxide formation in the extracellular space without entering the cells (5-7); extracellular hydrogen peroxide diffuses into susceptible cells and kills them (6). It is of interest that some malignant cells have been reported to accumulate ascorbic acid to higher concentrations than normal cells (8- 14), and it is a reasonable hypothesis that very high intracellular ascorbate concentrations could potentiate the toxicity of hydrogen peroxide entering from the extracellular space (15,16). Hickey incorrectly states that our study shows that pulsed intravenous ascorbic acid does not enter the cells. When a very large dose of ascorbic acid is infused, a positive body balance of as little as 5% (which is within the measurement error) would considerably increase intracellular ascorbate concentrations, especially those of target tissues. A detailed pharmacokinetic analysis is currently underway to examine the possibility that high-dose intravenous ascorbic acid increases intracellular ascorbate stores. References 1. Riordan NH, Riordan HD, Casciari JJ. Clinical and experimental experiences with intravenous vitamin C. J Orthomolecular Med 2000;15:201- 13. 2. Riordan HD, Hunninghake RB, Riordan NH et al. Intravenous ascorbic acid: protocol for its application and use. P R Health Sci J 2003;22:287-90. 3. Riordan HD, Casciari JJ, Gonzalez MJ et al. A pilot clinical study of continuous intravenous ascorbate in terminal cancer patients. P R Health Sci J 2005;24:269-76. 4. 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. 5. Koh WS, Lee SJ, Lee H et al. Differential effects and transport kinetics of ascorbate derivatives in leukemic cell lines. Anticancer Res 1998;18:2487-93. 6. Chen Q, Espey MG, Krishna MC et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci USA 2005;102:13604-9. 7. Chen Q, Espey MG, Sun AY et al. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc Natl Acad Sci USA 2007;104:8749-54. 8. Kakar SC, Wilson CWM. Ascorbic acid values in malignant disease. Proc Nutr Soc 1975;35:9A-10A. 9. Anthony HM, Schorah CJ. Severe hypovitaminosis C in lung-cancer patients: the utilization of vitamin C in surgical repair and lymphocyte- related host resistance. Br J Cancer 1982;46:354-67. 10. Farber CM, Kanengiser S, Stahl R, Liebes L, Silber R. A specific high-performance liquid chromatography assay for dehydroascorbic acid shows an increased content in CLL lymphocytes. Anal Biochem 1983;134:355- 60. 11. 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;43:1169-73. 12. Casciari JJ, Riordan HD, Miranda-Massari JR, Gonzalez MJ. Effects of high dose ascorbate administration on L-10 tumor growth in guinea pigs. P R Health Sci J 2005;24:145-50. 13. Piyathilake CJ, Bell WC, Johanning GL, Cornwell PE, Heimburger DC, Grizzle WE. The accumulation of ascorbic acid by squamous cell carcinomas of the lung and larynx is associated with global methylation of DNA. Cancer 2000;89:171-6. 14. May JM, Li L, Hayslett K, Qu ZC. Ascorbate transport and recycling by SH-SY5Y neuroblastoma cells: response to glutamate toxicity. Neurochem Res 2006;31:785-94. 15. Riviere J, Ravanat JL, Wagner JR. Ascorbate and H2O2 induced oxidative DNA damage in Jurkat cells. Free Rad Biol Med 2006;40:2071-9. 16. Duarte TL, Jones GD. Vitamin C modulation of H2O2-induced damage and iron homeostasis in human cells. Free Rad Biol Med 2007;43:1165-75. Conflict of Interest:None declared |
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Steve Hickey, Academic FCET, Staffordshire University, Stafford, England, ST16 9DG, Hilary Roberts
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The results of Hoffer et al., on the use of pulsed intravenous ascorbate in cancer, are consistent with the phenomenon of biological resistance. We have previously predicted that this approach will be suboptimal.[1] Tumours comprise a population of genetically varied cells, competing for growth. Pulsed doses of IV ascorbate generate an intermittent selection pressure on the cancer cells: each dose may kill a proportion of the cells most susceptible to the treatment. Between treatments, remaining cells face reduced competition, during which time they multiply. Thus, over time, susceptible cells die out and the hardy remainders become more virulent. The benefits of killing susceptible cells are compensated by the more rapid malignant growth of resistant cells. The process is analogous to the development of bacterial resistance to antibiotics.[1] Laboratory studies of ascorbate’s anticancer activity employ short periods, often of the order of one hour. Such studies may greatly underestimate the response to sustained exposure.[1] Hoffer et al. found that, based on a 20% extracellular volume, plasma concentration could be determined from the dose alone. This suggests that during the short infusion period the plasma ascorbate did not have time to enter and equilibrate with other tissues (such as the tumour). If it did, the plasma concentration would be much lower than they predicted, due to redistribution into other body compartments. Anti-tumour activity depends on the concentration of redox active molecules, such as ascorbate, within the tumour. The peak plasma level is irrelevant if the vitamin C is excreted before it reaches the tumour. We would expect, from Hoffer et al's results, that sustained plasma ascorbate levels would be required to increase consistently the concentration in the tumour. Pulsed IV doses, as described by Hoffer et al., would not suffice. Because of the short excretion half-life of high dose ascorbate, widely separated doses are predicted to have minimal biological effects.[2] Oral doses of vitamin C can produce a sustained plasma level.[2][3] Furthermore, contrary to widespread misconceptions about the pharmacokinetics of ascorbate, cytotoxic levels of plasma ascorbate can be sustained with oral doses.[4] Ascorbate levels in excess of 400 microM/l can be sustained with liposomal formulations.[4][5] An often-overlooked point is that Vitamin C alone is a relatively weak anticancer agent. Its activity can be greatly enhanced by the addition of alpha-lipoic acid, vitamin K3, or certain forms of selenium. The redox model of anticancer activity involves generating an oxidative response within the tumour. This may be achieved more effectively with combinations of nutrients.[1] To conclude, we have predicted in previous publications that pulsed intravenous ascorbate will select for resistant cells, reducing the effectiveness of the treatment. By contrast, sustained levels can be achieved with appropriate oral regimes. Patients are interested in inexpensive oral therapy, which allows them to retain a degree of control. By contrast, some physicians may prefer the more economically advantageous intravenous ascorbate therapy, as they retain control and appear “holistic”. Furthermore, IV vitamin C fits with the current paradigm of cytotoxic chemotherapy, rather than attempting the optimal orthomolecular approach to therapy. The paper by Hoffer et al. confirms our prediction that the pulsed intravenous approach, using ascorbate alone, is inappropriate and is likely to be ineffective. References 1. Hickey S. Roberts H. (2005) Cancer: Nutrition and Survival, Lulu press. 2. Hickey S. Roberts H. Cathcart R.F. (2005) Dynamic flow, JOM, 20(4), 237-244. 3. Duconge J, Miranda-Massari JR, Gonzalez MJ, Jackson JA, Warnock W, Riordan NH. (2008) Pharmacokinetics of vitamin C: insights into the oral and intravenous administration of ascorbate, P R Health Sci J, 27(1), 7-19. 4. Hickey S. Roberts H. Miller N.J. (2008) Pharmacokinetics of oral ascorbate liposomes, JNEM, in press. 5. Hickey S. Saul A. (2008) Vitamin C: The Real Story, Basic Health Books. Conflict of Interest:None declared |
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