Intro on Glutamine
Glutamine is the most abundant, naturally occurring, non-essential amino acid in the human body. It is synthesized through enzymatic action of glutamine synthetase (GS) that combines glutamate and ammonia. It is synthesized through enzymatic action of glutamine synthetase (GS) that combines glutamate and ammonia. It serves as a vehicle for transporting ammonia in a nontoxic form from the peripheral tissues to visceral organs where it is cleared and excreted either as ammonium in urine or as urea through the liver. Is a precursor for protein, nucleotide, and nucleic acid synthesis and also regulates cellular pathways and related functions. Glutamine exists in a free circulating form in the blood and in storage forms mainly in skeletal muscles and in smaller amounts in other organs such as the lung and brain. (Ref.) Intracellular concentrations in muscle tissue, representing more than 50% of the body Glutamine pool. (Ref.)
Recently, I received questions on the use of Glutamine. The main question is what to do in case of cancer: “To use or not to use Glutamine?”
Some doctors are supporting the use of Glutamine (oral or intravenous) for cancer patients and others not. Indeed, since Glutamine can also fuel cancer cells there are reasons to be concern with its administration. So I will first go a bit through some scientific facts and than conclude what I think is best to do:
Relevance of Glutamine on short:
Glutamine is the most abundant free amino acid in human muscle and plasma and is utilized at high rates by rapidly dividing cells. This means that Glutamine represents an important fuel for the rapidly dividing tumor cells. Due to this fact, today there are various anti cancer treatment strategies that focuses on glutamine depletion to starve cancer.
Personally, I think that the best would be to stop tumor’s request for glutamine instead of depleting all body of the much needed glutamine. In another post (http://www.cancertreatmentsresearch.com/?p=569) I discussed a strategy on how I think this may be achieved. Ultimately, off course, the best way to reduce the glutamine demand is by killing the tumor.
If due to various reasons we cannot stop the tumor’s glutamine demand, we may focus on blood glutamine depletion. But this strategy is questionable, since Glutamine is highly relevant for a good activity of THE IMMUNE SYSTEM. This is because Glutamine is utilized at a high rate by cells of the immune system and is required to support optimal lymphocyte proliferation and production of cytokines by lymphocytes and macrophages. (Ref1, Ref2). As such, it is considered to be essential for proper immune function. On this line, I think that glutamine depletion is an interesting strategy to be applied on short term only and preferably together with other therapies so that pressure on cancer cells is applied from multiple angles. But, I would certainly not apply glutamine depletion techniques when patients are in a state of wasting, with a low immune system profile (that includes the use of Phenyl Butyrate).
If we can not stop tumor’s demand for glutamine (using techniques such as discussed on this page http://www.cancertreatmentsresearch.com/?p=569, or via short term combination therapies that may include glutamine depletion), Glutamine supplementation may be the next option to try to achieve immune reactivation, reversal of cancer-related wasting and maybe even tumor reduction:
- Reversal of cancer-related wasting using oral supplementation with a combination of beta-hydroxy-beta-methylbutyrate, arginine, and glutamine. http://www.ncbi.nlm.nih.gov/pubmed/11975938
- Glutamine: an obligatory parenteral nutrition substrate in critical care therapy. http://www.ncbi.nlm.nih.gov/pubmed/26495301
- Glutamine: A novel approach to chemotherapy-induced toxicity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385273/
Below, is a figure indicating the consequences of glutamine depletion for the organism (Ref.)
As discussed above, since Glutamine is an important fuel for rapidly dividing cells, it is expected that Glutamine supplementation may fuel cancer. In contrast to this, some may even argue that “glutamine can be administered to the tumor-bearing host over a long period of time without significantly stimulating tumor growth kinetics or metastasis” http://link.springer.com/article/10.1007/BF02303705.
The dilemma is what to do given that supplementation with Glutamine may on one hand feed cancer while on the other hand it may revert patient wasting and improve immune function.
I think the choice has to be made based on each case, any every chosen route comes with scientific-based hope and with risks.
For those patients where wasting and immune status is not an issue, I would not use supplemental Glutamine. However, for those patients in which the immune system is very low and the wasting is a serious issue, Glutamine (oral and/or intravenous) could make very much sense.
When using Glutamine note that:
- The amonia level needs to be checked. This is because glutamine is used as a fuel by fast dividing cells and amonia is a degradation product of glutamine.
- Can be administrated via the parenteral route, using approved and recommended doses up to 0.3–0.5 g/kg BW/day (Ref.)
- Glutamine is a precursor of glutathione which is a main mechanism for tumors to fight pro oxidant treatments. So it is best to avoid before, during and some days after pro oxidant therapies such as chemo, 3BP, radiation, etc.
There are various sources online for the oral version, i.e. http://www.iherb.com/Jarrow-Formulas-L-Glutamine-35-3-oz-1000-g-Powder/183
In IV form, 2g costs about 6 euro at German pharmacies – no prescription required.
Glutamine: A novel approach to chemotherapy-induced toxicity http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385273/
Treatment of cancer is associated with short- and long-term side-effects. Cancer produces a state of glutamine deficiency, which is further aggravated by toxic effects of chemotherapeutic agents leading to increased tolerance of tumor to chemotherapy as well as reduced tolerance of normal tissues to the side-effects of chemotherapy. This article reviews the possible role of glutamine supplementation in reducing the serious adverse events in patients treated with anticancer drugs. The literature related to the possible role of glutamine in humans with cancer and the supportive evidence from animal studies was reviewed. Searches were made and the literature was retrieved using PUBMED, MEDLINE, COCHRANE LIBRARY, CENAHL and EMBASE, with a greater emphasis on the recent advances and clinical trials. Glutamine supplementation was found to protect against radiation-induced mucositis, anthracycline-induced cardiotoxicity and paclitaxel-related myalgias/arthralgias. Glutamine may prevent neurotoxicity of paclitaxel, cisplatin, oxaplatin bortezomib and lenolidamide, and is beneficial in the reduction of the dose-limiting gastrointestinal toxic effects of irinotecan and 5-FU-induced mucositis and stomatitis. Dietary glutamine reduces the severity of the immunosuppressive effect induced by methotrexate and improves the immune status of rats recovering from chemotherapy. In patients with acute myeloid leukemia requiring parenteral nutrition, glycyl-glutamine supplementation could hasten neutrophil recovery after intensive myelosuppressive chemotherapy. Current data supports the usefulness of glutamine supplementation in reducing complications of chemotherapy; however, paucity of clinical trials weakens the clear interpretation of these findings.
Glutamine, exercise and immune function. Links and possible mechanisms. http://www.ncbi.nlm.nih.gov/pubmed/9802174
Glutamine is the most abundant free amino acid in human muscle and plasma and is utilised at high rates by rapidly dividing cells, including leucocytes, to provide energy and optimal conditions for nucleotide biosynthesis. As such, it is considered to be essential for proper immune function. During various catabolic states including surgical trauma, infection, starvation and prolonged exercise, glutamine homeostasis is placed under stress. Falls in the plasma glutamine level (normal range 500 to 750 mumol/L after an overnight fast) have been reported following endurance events and prolonged exercise. These levels remain unchanged or temporarily elevated after short term, high intensity exercise. Plasma glutamine has also been reported to fall in patients with untreated diabetes mellitus, in diet-induced metabolic acidosis and in the recovery period following high intensity intermittent exercise. Common factors among all these stress states are rises in the plasma concentrations of cortisol and glucagon and an increased tissue requirement for glutamine for gluconeogenesis. It is suggested that increased gluconeogenesis and associated increases in hepatic, gut and renal glutamine uptake account for the depletion of plasma glutamine in catabolic stress states, including prolonged exercise. The short term effects of exercise on the plasma glutamine level may be cumulative, since heavy training has been shown to result in low plasma glutamine levels (< 500 mumol/L) requiring long periods of recovery. Furthermore, athletes experiencing discomfort from the overtraining syndrome exhibit lower resting levels of plasma glutamine than active healthy controls. Therefore, physical activity directly affects the availability of glutamine to the leucocytes and thus may influence immune function. The utility of plasma glutamine level as a marker of overtraining has recently been highlighted, but a consensus has not yet been reached concerning the best method of determining the level. Since injury, infection, nutritional status and acute exercise can all influence plasma glutamine level, these factors must be controlled and/or taken into consideration if plasma glutamine is to prove a useful marker of impending overtraining.
Why is L-glutamine metabolism important to cells of the immune system in health, postinjury, surgery or infection? http://www.ncbi.nlm.nih.gov/pubmed/11533304
Glutamine is normally considered to be a nonessential amino acid. However, recent studies have provided evidence that glutamine may become “conditionally essential” during inflammatory conditions such as infection and injury. It is now well documented that under appropriate conditions, glutamine is essential for cell proliferation, that it can act as a respiratory fuel and that it can enhance the function of stimulated immune cells. Studies thus far have determined the effect of extracellular glutamine concentration on lymphocyte proliferation and cytokine production, macrophage phagocytic plus secretory activities and neutrophil bacterial killing. Other cells of the immune system remain to be studied. The high rate of glutamine utilization and its importance to the function of lymphocytes, macrophages and neutrophils have raised the question “why glutamine?” because these cells have access to a variety of metabolic fuels both in vivo and in vitro. I have attempted to answer this question in this article. Additionally, knowledge of the rate of utilization and the pathway of metabolism of glutamine by cells of the immune system raises some intriguing questions concerning therapeutic manipulation of utilization of this amino acid such that the proliferative, phagocytic and secretory capacities of cells of the defense system may be beneficially altered. Evidence to support the hypothesis that glutamine is beneficially immunomodulatory in animal models of infection and trauma, as well as trauma in humans, is provided.
Glutamine: an obligatory parenteral nutrition substrate in critical care therapy. http://www.ncbi.nlm.nih.gov/pubmed/26495301
Critical illness is characterized by glutamine depletion owing to increased metabolic demand. Glutamine is essential to maintain intestinal integrity and function, sustain immunologic response, and maintain antioxidative balance. Insufficient endogenous availability of glutamine may impair outcome in critically ill patients. Consequently, glutamine has been considered to be a conditionally essential amino acid and a necessary component to complete any parenteral nutrition regimen. Recently, this scientifically sound recommendation has been questioned, primarily based on controversial findings from a large multicentre study published in 2013 that evoked considerable uncertainty among clinicians. The present review was conceived to clarify the most important questions surrounding glutamine supplementation in critical care. This was achieved by addressing the role of glutamine in the pathophysiology of critical illness, summarizing recent clinical studies in patients receiving parenteral nutrition with intravenous glutamine, and describing practical concepts for providing parenteral glutamine in critical care.
Effect of glutamine on tumor and host growth http://link.springer.com/article/10.1007/BF02303705
These findings confirm the trophic effect of glutamine on small intestinal mucosa and suggest that glutamine can be administered to the tumor-bearing host over a long period of time without significantly stimulating tumor growth kinetics or metastasis.
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