ויטמין C - עוד בלוף?

מחקר מעבדתי שנערך ב NIH (מכון המחקר הלאומי של ארצות הברית) בוושינגטון קובע כי ויטמין C במינון גבוה הורס באופן סלקטיבי את תאי הסרטן על ידי יצירת רדיקלים חופשיים בתא הסרטני בלי שזה יוכל לסלק אותם. לעומת זאת לתאים נורמליים יש מנגנונים לנטרל חומרים אלה. ד"ר יוסף ברנר This Article Abstract Figures Only Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in PNAS Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My File Cabinet Download to citation manager Cited by other online articles Request Copyright Permission Google Scholar Articles by Chen, Q. Articles by Levine, M. Articles citing this Article PubMed PubMed Citation Articles by Chen, Q. Articles by Levine, M. MEDICAL SCIENCES Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues Qi Chen *, , Michael Graham Espey , Murali C. Krishna , James B. Mitchell , Christopher P. Corpe *, Garry R. Buettner , Emily Shacter , AND Mark Levine *, ¶ *Molecular AND Clinical Nutrition Section, National Institute of Diabetes AND Digestive AND Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; Radiation Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; Free Radical AND Radiation Biology Program, University of Iowa, Iowa City, IA 52242-1101; AND Laboratory of Biochemistry, Center for Drug Evaluation AND Research, Food AND Drug Administration, Bethesda, MD 20892 Communicated by J. E. Rall, National Institutes of Health, Bethesda, MD, August 2, 2005 (received for review June 1, 2005) Abstract Top Abstract Materials AND Methods Results Discussion References Human pharmacokinetics data indicate that i.v. ascorbic acid (ascorbate) in pharmacologic concentrations could have an unanticipated role in cancer treatment. Our goals here were to test whether ascorbate killed cancer cells selectively, AND if so, to determine mechanisms, using clinically relevant conditions. Cell death in 10 cancer AND 4 normal cell types was measured by using 1-h exposures. Normal cells were unaffected by 20 mM ascorbate, whereas 5 cancer lines had EC50 values of <4 mM, a concentration easily achievable i.v. Human lymphoma cells were studied in detail because of their sensitivity to ascorbate (EC50 of 0.5 mM) AND suitability for addressing mechanisms. Extracellular but not intracellular ascorbate mediated cell death, which occurred by apoptosis AND pyknosis/necrosis. Cell death was independent of metal chelators AND absolutely dependent on H2O2 formation. Cell death from H2O2 added to cells was identical to that found when H2O2 was generated by ascorbate treatment. H2O2 generation was dependent on ascorbate concentration, incubation time, AND the presence of 0.5-10% serum, AND displayed a linear relationship with ascorbate radical formation. Although ascorbate addition to medium generated H2O2, ascorbate addition to blood generated no detectable H2O2 AND only trace detectable ascorbate radical. Taken together, these data indicate that ascorbate at concentrations achieved only by i.v. administration may be a pro-drug for formation of H2O2, AND that blood can be a delivery system of the pro-drug to tissues. These findings give plausibility to i.v. ascorbic acid in cancer treatment, AND have unexpected implications for treatment of infections where H2O2 may be beneficial. cell death | ascorbate radical -------------------------------------------------------------------------------- Ascorbic acid (vitamin C, ascorbate) has a controversial history in cancer treatment (1). Observational reports described ascorbate, given in pharmacologic doses of 10 g daily, as effective in treating some cancers AND in improving patient well-being (2-4). Subsequently, the same dose had no effect on patient well-being AND survival in two double-blind placebo-controlled trials, AND ascorbate was discarded as a treatment modality (5, 6). Recent clinical evidence, however, indicates that the role of ascorbate in cancer treatment should be examined anew (7). The originally reported observational studies used i.v. AND oral ascorbate, but the subsequent double-blind placebo-controlled studies used only oral ascorbate. It was not recognized that the route of ascorbate administration might produce large differences in plasma concentrations. Recent pharmacokinetics studies in men AND women show that 10 g of ascorbate given i.v. is expected to produce plasma concentrations of nearly 6 mM, which are >25-fold higher than those concentrations from the same oral dose (7-9). As much as a 70-fold difference in plasma concentrations is expected between oral AND i.v. administration, depending on dose. Despite inconsistencies, some in vitro studies showed that ascorbate killed cancer cells, although mechanisms AND physiologic relevance were unclear (10-12). Complementary AND alternative medicine practitioners worldwide currently use ascorbate i.v. in some patients, in part because there is no apparent harm (13-15). Given its potential safety AND benefit, there is merit in investigating i.v. ascorbate as a possible novel cancer treatment modality. It is essential first to learn whether ascorbate acts as an anticancer agent in vitro, AND if so, by what mechanisms. Our goals were to address the following: Does ascorbate in pharmacologic concentrations kill cancer cells, but not normal cells, using conditions that mimic i.v. use AND a clinically relevant time course? Is action dependent on extracellular ascorbate, intracellular ascorbate, OR both? If effective, what are the mechanisms? Can ascorbate be delivered to tissues without harm? Are there implications for other diseases? We studied ascorbate at physiologic (0.1 mM) AND pharmacologic (0.3-20 mM) concentrations using 1-h incubations to mimic clinical i.v. use (7-9). The data showed that pharmacologic concentrations of ascorbate killed cancer but not normal cells, that cell death was dependent only on extracellular but not intracellular ascorbate, AND that killing was dependent on extracellular hydrogen peroxide (H2O2) formation with ascorbate radical as an intermediate. Ascorbate generated detectable levels of H2O2 in extracellular medium in the presence of trace serum protein but not in whole blood. The findings indicate that ascorbate at pharmacologic concentrations in blood may be a pro-drug for H2O2 delivery to tissues, with major therapeutic implications