לד"ר ברנר- גלוטמין במהלך טיפולים כימותרפיים

אני מודע לעובדה כי בספרך אתה מזהיר חולי סרטן מלקיחה של החומצה האמינית גלוטמין. ברשותך אשתף אותך ואת הקוראים בעובדות שונות לגבי השימוש של L-Glutamine במהלך טיפולים רעילים בחולי סרטן. אין ויכוח לגבי החשיבות של גלוטמין במניעה של מצבים קטבוליים, במצבי HIgh STRESS, בחולי טראומה, במצבי ניתוחים ובחולים קשים. גלוטמין משפרת מצבי הסננה במעיים ואטרופיה של רירית המעיים, מונעת ספסיס ואולי מונעת אפילו מצבי כשל מערכתיים. בתקופת טיפולים רעילים היא גם מונעת מוקוסיטיס, סטומטיטיס ותופעות נזק נוספות של הטיפולים הרעילים. מונעת וגם מצליחה להביא ל- reversal של קצ'קסיה במצבי מחלה מתקדמים. אכן, אני מודע לכך כי יש מעט חששות לגבי לקיחת גלוטמין ע"י חולי סרטן, וזאת משום שקיימת השערה כי הגלוטמין יכולה לגרום לשגשוג גידולים סרטניים. ואכן נכון הוא כי מחקרי in vitro מצביעים על תלות בגלוטמין וצמיחה וחלוקה מואצת של תאים כתוצאה מהוספת גלוטמין. Kang YJ, Feng Y, Hatcher EL. Glutathione stimulates A549 cell proliferation in glutamine-deficient culture: the effect of glutamate supplementation. J Cell Physiol 1994;161:589-596. Kang YJ. Buthionine sulfoximine spares intracellular glutamate: a possible mechanism for cell growth stimulation. Cell Mol Biol Res 1993;39:675-684. Ollenschlager G, Simmel A, Roth E. Availability of glutamine from peptides AND acetylglutamine for human tumor-cell cultures. Metabolism 1989;38:S40-S42. Moyer MP, Armstrong A, Aust JB, et al. Effects of gastrin, glutamine AND somatostatin on the in vitro growth of normal AND malignant human gastric mucosal cells. Arch Surg 1986;121:285-288 עם זאת, חשוב לזכור כי הנ"ל לא הוכח במחקרי in vivo: Bartlett DL, Charland S, Torosian MH. Effect of glutamine on tumor AND host growth. Ann Surg Oncol 1995;2:71-76. Austgen TR, Dudrick PS, Sitren H, et al. The effects of glutamine-enriched total parenteral nutrition on tumor growth AND host tissues. Ann Surg 1992;215:107-113. Klimberg VS, Souba WW, Salloum RM, et al. Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. J Surg Res 1990;48:319-323. האמת היא כי מחקר בחיות הוכיח את ההיפך הגמור, כלומר, במחקר זה צמיחת התאים הסרטניים קטנה ב- 40% ובמקביל נצפה גידול של 30% בתאי ההרג (NK CELLS). המחקר: 54. Fahr MJ, Kornbluth J, Blossom S, et al. Harry M. Vars Research Award. Glutamine enhances immunoregulation of tumor growth. JPEN J Parenter Enteral Nutr 1994;18:471-476. במחקר בחולדות עם פיברוסרקומה Klimberg et al מצאו כי הוספה של גלוטמין בתזונה תוך מיעית הגדילה את רמות הגלוטמין בשרירים בכ -60% וזאת מבלי שהמריצה את צמיחת הגידול, ומבלי שהעלתה את ניצולת הגלוטמין ע"י הגידול. המחקר: Klimberg VS, Souba WW, Salloum RM, et al. Glutamine-enriched diets support muscle glutamine metabolism without stimulating tumor growth. J Surg Res 1990;48:319-323. יותר מכך, מינונים גבוהים של החומצה האמינית גלוטמין (15-40 מ"ג ביום) מביאים לתוצאות סינרגיות עם תרופות כימותרפיות. תאים סרטניים מכילים רמות של גלוטטיון הגבוהות בהרבה (לעיתים פי 12) מרמות הגלוטטיון בתאים בריאים, עובדה המקשה לתרופות הכימותרפיות וגורמת לגידול לפתח עמידות אליהן. גלוטמין המסונתזת בגופנו לחומצה גלוטמית מצליחה, כשהיא נלקחת במינונים גבוהים, להוריד את רמות הגלוטטיון הגבוהות של גלוטטיון בתאים הסרטניים ובכך למנוע עמידות שלהם לכימותרפיה וכן להפוך את הגידול לפגיע יותר למתקפה הכימותרפית. המחקרים: 1: Free Radic Biol Med. 2000 Nov 1;29(9):913-23. Related Articles, Books, LinkOut Mitochondrial glutathione depletion by glutamine in growing tumor cells. Carretero J, Obrador E, Pellicer JA, Pascual A, Estrela JM. Departamento de Fisiologia, Universidad de Valencia, Valencia, Spain. The effect of L-glutamine (Gln) on mitochondrial glutathione (mtGSH) levels in tumor cells was studied in vivo in Ehrlich ascites tumor (EAT)-bearing mice. Tumor growth was similar in mice fed a Gln-enriched diet (GED; where 30% of the total dietary nitrogen was from Gln) OR a nutritionally complete elemental diet (SD). As compared with non-tumor-bearing mice, tumor growth caused a decrease of blood Gln levels in mice fed an SD but not in those fed a GED. Tumor cells in mice fed a GED showed higher glutaminase AND lower Gln synthetase activities than did cells isolated from mice fed an SD. Cytosolic glutamate concentration was 2-fold higher in tumor cells from mice fed a GED ( approximately 4 mM) than in those fed an SD. This increase in glutamate content inhibited GSH uptake by tumor mitochondria AND led to a selective depletion of mitochondrial GSH (mtGSH) content (not found in mitochondria of normal cells such as lymphocytes OR hepatocytes) to approximately 57% of the level found in tumor mitochondria of mice fed an SD. In tumor cells of mice fed a GED, 6-diazo-5-norleucine- OR L-glutamate-gamma-hydrazine-induced inhibition of glutaminase activity decreased cytosolic glutamate content AND restored GSH uptake by mitochondria to the rate found in EAT cells of mice fed an SD. The partial loss of mtGSH elicited by Gln did not affect generation of reactive oxygen intermediates (ROIs) OR mitochondrial functions (e.g., intracellular peroxide levels, O(2)(-)(*) generation, mitochondrial membrane potential, mitochondrial size, adenosine triphosphate AND adenosine diphosphate contents, AND oxygen consumption were found similar in tumor cells isolated from mice fed an SD OR a GED); however, mitochondrial production ROIs upon TNF-alpha stimulation was increased. Our results demonstrate that glutamate derived from glutamine promotes an inhibition of GSH transport into mitochondria, which may render tumor cells more susceptible to oxidative stress-induced mediators. PMID: 11063916 [PubMed - indexed for MEDLINE] ******************************************************************************************* 1: Breast Cancer Res Treat. 2004 Dec;88(3):247-56. Related Articles, Books, LinkOut Effect of dietary glutamine on tumor glutathione levels AND apoptosis-related proteins in DMBA-induced breast cancer of rats. Todorova VK, Harms SA, Kaufmann Y, Luo S, Luo KQ, Babb K, Klimberg VS. Division of Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. Glutamine (GLN) is a non-essential amino acid that is present in nearly every biochemical pathway AND is the major intraorgan nitrogen carrier. GLN via glutamate, is one of the precursors for the synthesis of glutathione (GSH), the major endogenous antioxidant in mammalian cells, which protects them from oxidative injury AND cell death. Cancer cells have higher GSH levels than the surrounding normal cells, which attributes to a higher rate of cell proliferation AND resistance to chemotherapy. Therefore, selective tumor depletion of GSH presents a promising strategy in cancer treatment. Experimental studies have associated decreased GSH levels with inhibition of proliferation AND stimulation of apoptosis. Previous results of our laboratory have provided evidence that dietary GLN diminished tumor development in implantable as well as 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer AND elevated GSH in the host tissues. In this study we examined the effects of GLN on GSH levels in DMBA-induced mammary tumors AND correlated the results with protein AND mRNA expression of apoptosis-related proteins Bcl-2, Bax AND caspase-3 in tumor cells. The results have shown that GLN supplementation caused a significant decrease in the tumor GSH levels AND the ratio GSH/oxidized GSH (GSSG), accompanied by up-regulation of Bax AND caspase-3, AND down-regulation of Bcl-2. These findings suggest that dietary GLN supplementation suppresses mammary carcinogenesis by activation of apoptosis in tumor cells AND this probably is a result of GSH down-regulation. PMID: 15609127 [PubMed - indexed for MEDLINE] ******************************************************************************************* A critical role of glutathione in determining apoptosis sensitivity AND resistance in leukemia cells. Friesen C, Kiess Y, Debatin KM. University Children's Hospital, Prittwitzstr.43, D-89075 Ulm, Germany. In chemosensitive leukemias AND solid tumors, anticancer drugs have been shown to induce apoptosis. Deficiencies in the apoptotic pathways may lead to chemoresistance. Here we report that glutathione (GSH) plays a critical role in activation of apoptosis pathways by CD95 (APO-1/Fas) OR anticancer drugs. Upon treatment with anticancer drugs OR CD95 triggering, CD95-resistant OR Bcl-x(L) overexpressing CEM cells were deficient in activation of apoptosis pathways. CD95-resistant AND Bcl-x(L) overexpressing CEM cells exhibited higher intracellular GSH levels in comparison to parental cells. Downregulation of GSH by L-buthionine-(S,R)-sulfoxime (BSO), a specific inhibitor of glutathione synthesis, reversed deficiencies in activation of apoptosis pathways by anticancer drugs OR CD95. Interestingly, downregulation of GSH by BSO increased CD95 DISC formation in type I cells. In hybrids of CD95-resistant cells with sensitive cells AND hybrids of overexpressing Bcl-x(L) cells with sensitive cells, the phenotype of apoptosis resistance was dominant. Also, in these hybrids, downregulation of GSH reversed CD95- AND chemoresistance. We conclude that dominant apoptosis resistance depends, at least in part, on intracellular GSH levels, which may affect apoptosis signaling at different compartments, for example, the death receptor OR mitochondria. PMID: 15105835 [PubMed - indexed for MEDLINE] ******************************************************************************************* Mitochondrial glutathione: importance AND transport. Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A. Department of Medicine, Hospital Clinic i Provincial AND Instituto Investigaciones Biomedicas August Pi i Sunyer, Consejo Superior Investigaciones Cientificas, Barcelona, Spain. Accumulating evidence pointing to mitochondria as critical participants in the control of apoptotic AND necrotic cell death AND in the development of specific disease states has led to a renaissance on the study of these organelles. Because mitochondria are the major consumers of molecular oxygen within cells, they stand as one of the most important generators of reactive oxygen species AND therefore constitute potential targets of therapeutic intervention in pathologic states in which oxidative stress originates from these organelles. In this regard, mitochondria are specific targets of ethanol intoxication, thereby leading to reported morphologic AND functional alterations of mitochondria. Because mitochondria are also indispensable for the maintenance of cell functions, their dysfunction induced by ethanol may be a key event in the development of alcoholic liver disease. Indeed, chronic ethanol feeding in experimental animals has been reported to cause a selective deficiency in the availability of reduced glutathione (GSH) in mitochondria due to the impaired functioning of the specific mitochondrial carrier that translocates GSH from cytosol into the mitochondrial matrix. Such a selective depletion sensitizes hepatocytes from chronic ethanol-fed animals to the oxidative effects of cytokines, e.g., tumor necrosis factor (TNF). Restoration of mitochondrial GSH by the in vivo administration of S-adenosyl-L-methionine OR the in vitro use of GSH ethyl ester prevents the susceptibility of hepatocytes to TNF. Although the nature of this specific carrier has not yet been uncovered, the elucidation of the mechanisms whereby ethanol leads to its impaired activity may provide important clues as to its function AND mechanism of action, which in turn may be useful toward the definitive characterization AND identification of this important carrier. ******************************************************************************************* 1: Free Radic Biol Med. 2001 Sep 1;31(5):642-50. Related Articles, Books, LinkOut Glutamine potentiates TNF-alpha-induced tumor cytotoxicity. Obrador E, Carretero J, Esteve JM, Pellicer JA, Pascual A, Petschen I, Estrela JM. Departamento de Fisiologia, Universidad de Valencia, Valencia, Spain L-glutamine (Gln) sensitizes tumor cells to tumor necrosis factor (TNF)-alpha-induced cytotoxicity. The type AND mechanism of cell death induced by TNF-alpha was studied in Ehrlich ascites tumor (EAT)-bearing mice fed a Gln-enriched diet (GED; where 30% of the total dietary nitrogen was from Gln). A high rate of Gln oxidation promotes a selective depletion of mitochondrial glutathione (mtGSH) content to approximately 58% of the level found in tumor mitochondria of mice fed a nutritionally complete elemental diet (standard diet, SD). The mechanism of mtGSH depletion involves a glutamate-induced inhibition of GSH transport from the cytosol into mitochondria. The increase in reactive oxygen intermediates (ROIs) production induced by TNF-alpha further depletes mtGSH to approximately 35% of control values, which associates with a decrease in the mitochondrial transmembrane potential (MMP), AND elicits mitochondrial membrane permeabilization AND release of cytochrome c. Mitochondrial membrane permeabilization was also found in intact tumor cells cultured with a Gln-enriched medium under conditions of buthionine sulfoximine (BSO)-induced selective GSH synthesis inhibition. Enforced expression of the bcl-2 gene in tumor cells could not avoid the glutamine- AND TNF-alpha-induced cell death under conditions of mtGSH depletion. However, addition of GSH ester, which delivers free intracellular GSH AND increases mtGSH levels, preserved cell viability. These findings show that glutamine oxidation AND TNF-alpha, by causing a change in the glutathione redox status within tumor mitochondria, activates the molecular mechanism of apoptotic cell death. PMID: 11522449 [PubMed - indexed for MEDLINE] ******************************************************************************************* Bcl-2 AND Mn-SOD antisense oligodeoxynucleotides AND a glutamine-enriched diet facilitate elimination of highly resistant B16 melanoma cells by tumor necrosis factor-alpha AND chemotherapy. Benlloch M, Mena S, Ferrer P, Obrador E, Asensi M, Pellicer JA, Carretero J, Ortega A, Estrela JM. Department of Physiology, University of Valencia, 17 Av. Blasco Ibanez, 46010 Valencia, Spain. Mitochondrial glutathione (mtGSH) depletion increases sensitivity of Bcl-2-overexpressing B16 melanoma (B16M)-F10 cells (high metastatic potential) to tumor necrosis factor-alpha (TNF-alpha)-induced oxidative stress AND death in vitro. In vivo, mtGSH depletion in B16M-F10 cells was achieved by feeding mice (where the B16M-F10 grew as a solid tumor in the footpad) with an L-glutamine (L-Gln)-enriched diet, which promoted in the tumor cells an increase in glutaminase activity, accumulation of cytosolic L-glutamate, AND competitive inhibition of GSH transport into mitochondria. L-Gln-adapted B16M-F10 cells, isolated using anti-Met-72 monoclonal antibodies AND flow cytometry-coupled cell sorting, were injected into the portal vein to produce hepatic metastases. In l-Gln-adapted invasive (iB16M-Gln+) cells, isolated from the liver by the same methodology AND treated with TNF-alpha AND an antisense Bcl-2 oligodeoxynucleotide, viability decreased to approximately 12%. iB16M-Gln+ cell death associated with increased generation of O2*- AND H2O2, opening of the mitochondrial permeability transition pore complex, AND release of proapoptotic molecular signals. Activation of cell death mechanisms was prevented by GSH ester-induced mtGSH replenishment. The oxidative stress-resistant survivors showed an adaptive response that includes overexpression of manganese-containing superoxide dismutase (Mn-SOD) AND catalase activities. By treating iB16M-Gln+ cells with a double anti- antisense therapy (Bcl-2 AND SOD2 antisense oligodeoxynucleotides) AND TNF-alpha, metastatic cell survival decreased to approximately 1%. Chemotherapy (taxol plus daunorubicin) easily removed this minimum percentage of survivors. This contribution identifies critical molecules that can be sequentially targeted to facilitate elimination of highly resistant metastatic cells. PMID: 16263711 [PubMed - indexed for MEDLINE] ******************************************************************************************* בברכה, גובי www.cure-cancer-naturally.com

האבחנות שיש לי עם מטופלים מחזקות את שכתבתי על מינונים גבוהים של גלוטמין. בברכה, גובי www.cure-cancer-naturally.com