The glutamine story: where are we now?

PURPOSE OF REVIEW: A recent editorial proclaimed, 'Glutamine, a life saving nutrient, but why?' This review will assess if recent data support glutamine as a life-saving nutrient in critical illness, and, if so, utilize new understanding of gene-nutrient interactions to address potential mechanisms by which glutamine may be 'life-saving'. RECENT FINDINGS: Updated meta-analysis data reveal that glutamine appears to exert a beneficial effect on mortality in critical illness. The questions remaining to be answered regard in what settings and via what method of administration does this phamaconutrient show optimal benefit? It is likely that examination of molecular mechanisms by which glutamine functions will lead to an understanding of how best to utilize glutamine as a pharmacologic agent. Recent laboratory data reveal that these mechanisms include tissue protection, attenuation of inflammation, improved tissue metabolic function, and attenuation of oxidant stress. SUMMARY: Glutamine may be potentially 'life-saving' in critical illness, particularly when administered in doses greater then 0.3 g/kg/day. Present data indicate that glutamine functions as a 'stress signaling molecule' following illness/injury and thus, needs to be given as a pharmacologic agent, rather then as nutritional replacement. Presently, multicenter clinical trials utilizing glutamine as a drug, independent of nutritional needs, are indicated.     

Glutamine and acute illness

This is a literature review over a time period of the past 2 years concerning glutamine in clinical nutrition. Emphasis is put upon studies of glutamine in clinical settings, but a brief overview of the large range of literature over the role of glutamine in various experimental settings is also included. The most interesting concept for the past 2 years is the suggestion to use plasma glutamine concentration at admission to the intensive care unit as a prognostic marker and as a possible indicator for indication of glutamine supplementation.     

Glutamine supplementation in catabolic patients

OBJECTIVE: To evaluate the safety and efficacy of parenteral and enteral glutamine supplementation in patients who are catabolic. DATA SOURCES: English-language clinical trials and review articles identified by MEDLINE searches (January 1970-December 1997) and from bibliographies of selected articles were considered for possible inclusion. Key words used in the search strategy were glutamine, critical illness, stress, catabolism, injury, enteral nutrition, and parenteral nutrition. STUDY SELECTION AND DATA EXTRACTION: Inclusion was restricted to pertinent studies that evaluated the safety of glutamine supplementation, as well as effects of glutamine on amino acid metabolism, immune function, and patient outcome. Data from 18 clinical trials and multiple review articles were compiled into a review format. DATA SYNTHESIS: Glutamine is an important metabolic fuel for intestinal enterocytes, lymphocytes and macrophages, and metabolic precursors such as purines and pyrimidines. Although originally considered a nonessential amino acid, experimental work suggests that glutamine is essential for maintaining intestinal function, immune response, and amino acid homeostasis during periods of severe stress. In the past decade, clinical trials conducted in metabolically stressed patients indicate that glutamine improves nitrogen balance, increases cellular proliferation, decreases the incidence of infection, and shortens hospital stay in some catabolic patients. CONCLUSIONS: Glutamine has been studied extensively over the past decade for its role during critical illness. Clinical trials conducted in humans demonstrate glutamine to be well tolerated without adverse consequences, even during times of stress. Although glutamine has shown promise in select groups of catabolic patients, additional studies are needed to define which patient populations derive the greatest benefit from supplemental glutamine and the mechanisms by which these effects are exerted.     

Glutamine: indicated in cancer care?

Glutamine is a nonessential amino acid contained in most dietary proteins and provides immune functions and fuel for the small intestine. For healthy people, dietary glutamine (from protein) usually is considered adequate. Results of research evaluating the potential benefits of glutamine during cancer therapy are encouraging but remain inconclusive. Some researchers have suggested recently that glutamine may, in fact, be a conditionally essential amino acid (Buchman, 2001). Decreases in glutamine levels after trauma or major burns, postoperatively, and in patients with diseases such as inflammatory bowel disease, AIDS, and cancer are widely recognized and acknowledged (Medina, 2001; Miller, 1999). The interpretation of data suggesting that glutamine supplementation is of benefit in almost any clinical situation is controversial. Additional research is needed to confirm the mechanism of action and efficacy of glutamine as adjuvant therapy in patients receiving cancer treatment.     

Management of perioperative nutrition support

PURPOSE OF REVIEW: Perioperative nutrition has been extensively studied, but numerous questions remain unanswered. This review focuses on new developments in nutrient delivery in the immediate perioperative period. Issues specifically addressed include which patients are most likely to benefit from perioperative nutritional supplementation, and the optimal route, timing, and quantity of nutrient delivery. RECENT FINDINGS: Visceral proteins, particularly albumin, play an important role in nutritional and perioperative risk assessment. Although the recommendation to use the enteral route for delivery of nutrition whenever possible is clear, the cautious introduction of enteral feeds in the labile group of patients with circulatory failure is essential. Preoperative use of immune-modulating enteral formulas, preoperative carbohydrate loading, and the concept of early enteral feeding are important developments. Supplementary arginine, glutamine, and omega-3 fats play a potential role in nutritional management, as does 'permissive' hypocaloric feeding. SUMMARY: The particulars of nutritional support for perioperative and critically ill patients remain controversial. Recent studies addressing specific issues in this diverse discipline perhaps raise more questions than are answered. However, each new contribution to the literature brings us closer to an understanding of optimal nutritional management in the metabolically stressed patient.     

Oxidative stress in lymphocytes,neutrophils, and serum of oral cavity cancer patients: modulatory array of <Emphasis Type="SmallCaps">l</Emphasis>-glutamine

Objectives Our aim was to assess the oxidative stress and ameliorative effect of l-glutamine in serum, neutrophils, and lymphocytes of oral cancer patients by measuring the levels of malondialdehyde (MDA) and antioxidants. Materials and methods This study has been conducted on serum and specific blood cells in adult, male oral cancer patients (stage III-6, stage IV-42) and normal subjects of an equal number of age and sex-matched disease-free healthy subjects. The levels of lipid peroxidation and antioxidant enzymes were assayed using spectrophotometric methods. Results MDA levels were elevated, and antioxidant enzyme status was decreased significantly in all groups of cancer patients simultaneously, but after supplementation of “glutammune” (66.66% l-glutamine), oxidative stress has been alleviated to some extent; especially, it has repaired the glutathione cascade system. Conclusion We conclude that oxidative stress is due to the enhanced lipid peroxidation and decrease in antioxidant enzymes, and it can be restored with dietary supplementation of l-glutamine related drug.     

Systematic review of natural agents for the management of oral mucositis in cancer patients

Purpose

The aim of this study was to review the available literature and define clinical practice guidelines for the use of natural agents for the prevention and treatment of oral mucositis.

Methods

A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible.

Results

A total of 49 papers across 15 interventions were examined. A new suggestion was developed in favor of systemic zinc supplements administered orally in the prevention of oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation (Level III evidence). A recommendation was made against the use of intravenous glutamine for the prevention of oral mucositis in patients receiving high-dose chemotherapy prior to hematopoietic stem cell transplant (Level II evidence). No guideline was possible for any other agent, due to inadequate and/or conflicting evidence.

Conclusions

Of the various natural agents reviewed here, the available evidence supported a guideline only for two agents: a suggestion in favor of zinc and a recommendation against glutamine, in the treatment settings listed above. Well-designed studies of other natural agents are warranted.     

Nutrition Management

Whether it is used as a primary, adjunct or palliative intervention, radiation therapy can have a deleterious effect on nutritional status. Routine and systematic screening for malnutrition with early and appropriate nutrition intervention can improve tolerance to therapy, reduce morbidity, increase nutrient intake and improve quality of life in patients undergoing radiation therapy. Medical nutrition therapy (MNT) integrates pharmacological intervention and dietary modification to manage symptoms that may affect nutrient intake. Fewer hospitalisations, a decrease in complications, reduction in weight loss, a greater sense of wellbeing and improved quality of life are additional benefits of nutrition support. For patients in whom toxicity is expected to substantially hinder oral intake for more than 1 week, more aggressive nutrition support may be indicated. The prophylactic placement of gastrointestinal feeding tubes has been shown to significantly reduce weight loss and the number of admissions for the complications of mucositis and dehydration in patients receiving radiation therapy. While controversy still exists regarding the use of antioxidants during cancer treatment, results of some studies suggest that supplementation with individual micronutrients and phytochemicals such as n-3 fatty acids, genistein or glutamine may not only help to reduce adverse effects but also act synergistically to enhance the effectiveness of radiation therapy in the cancer patient. Although these diet-derived agents have shown promising results in animal studies, further studies, particularly randomised, placebo-controlled, phase III clinical trials, are needed to define the role of dietary supplementation during cancer therapy.     

Influence of glutamine and glycyl-glutamine on in vitro lymphocyte proliferation in children with solid tumors

It is reported that the proliferative response of lymphocytes is lowered in patients with solid tumors. Glutamine is a major nutrient for rapidly proliferating cells. Unlike glutamine itself, the dipeptide glycyl-glutamine as a source for glutamine is stable in aqueous solutions ex vivo. In order to evaluate the possible therapeutic role of glutamine in lymphocyte proliferation, we investigated its influence on lymphocytes of children with solid tumors before and after chemotherapy. Lymphocytes were collected from 21 children and adolescents suffering from solid tumors (before and after chemotherapy) and from healthy controls. Glutamine and glycyl-glutamine, respectively, were added to cell cultures at concentrations between zero and 1.0 mmol/l. ConA or SAC served as T- or B-cell mitogens, respectively. The lymphocyte proliferation in the healthy control group was similar in degree to lymphocyte proliferation seen in the patients with solid tumors, regardless of the mitogen used. No difference in the degree of lymphocyte proliferation before or after chemotherapy was seen with either source of glutamine. Specific subgroups of malignancies showed trends that differed from the overall findings, but these differences were not found to be statistically significant. Routine supplementation with glutamine in children with solid tumors to enhance lymphocyte function is not supported by the data gained from in vitro proliferation tests.     

The role of choline in prostate cancer

Choline is an essential nutrient that is necessary for cell membrane synthesis and phospholipid metabolism and functions as an important methyl donor. Multiple roles for choline in cancer development have been suggested. Choline can affect DNA methylation and lead to a disruption of DNA repair. It can also modify cell signaling that is mediated by intermediary phospholipid metabolites, and it can support the synthesis of cell membranes and thus support cell proliferation. A higher intake or status of choline in plasma and tissues has been related to higher cancer risks. Prostate cancer shows elevated levels of choline uptake and levels of certain choline metabolites. Choline metabolites can be used as potential prognostic biomarkers for the management of prostate cancer patients. Targeting certain enzymes, which are related to choline metabolism, provides promising therapeutic opportunities for tumor growth arrest. This review summarizes the potential role of choline metabolism in cancer, especially in prostate cancer.     

Oral glutamine for the prevention of oral mucositis associated with high-dose paclitaxel and melphalan for autologous bone marrow transplantation

OBJECTIVE: To determine the effect of glutamine suspension on mucositis associated with the administration of high-dose preparative regimens for bone marrow transplantation. METHODS: We performed a retrospective analysis of 21 consecutive patients receiving high-dose paclitaxel and melphalan as the preparative regimen for autologous peripheral blood stem-cell transplantation for metastatic breast cancer between January 1997 and December 1997. Glutamine suspension was given as swish-and-swallow administration every four hours around the clock starting day-7, for a total dose of 24 g/d. RESULTS: The group given oral glutamine suspension demonstrated significantly fewer days of mucositis and a lower maximum grade of mucositis. The treatment group also had fewer days of parenteral morphine for pain relief. The group that did not receive glutamine required an average of 5.22 days of patient-controlled analgesia (PCA) morphine; the glutamine group did not require PCA morphine. The total days of narcotic pain relief were decreased in the glutamine group; however, this did not reach statistical significance. Qualitatively, the patients in the glutamine group had less oral ulceration and bleeding, and were able to tolerate liquids sooner than those in the nonglutamine group. Patients tolerated the glutamine suspension well. CONCLUSIONS: This study showed that around-the-clock administration of oral glutamine may decrease both the severity and duration of mucositis associated with high-dose bone marrow transplant preparative regimens. The decrease in severity and duration of mucositis translated into reduced parenteral narcotic use. A prospective, randomized, controlled trial is needed to determine future applications of glutamine in the support of patients undergoing high-dose chemotherapy.     

Dibenzophenanthridines as inhibitors of glutaminase C and cancer cell proliferation

One hallmark of cancer cells is their adaptation to rely upon an altered metabolic scheme that includes changes in the glycolytic pathway, known as the Warburg effect, and elevated glutamine metabolism. Glutaminase, a mitochondrial enzyme, plays a key role in the metabolism of glutamine in cancer cells, and its inhibition could significantly impact malignant transformation. The small molecule 968, a dibenzophenanthridine, was recently shown to inhibit recombinantly expressed glutaminase C, to block the proliferation and anchorage-independent colony formation of human cancer cells in culture, and to inhibit tumor formation in mouse xenograft models. Here, we examine the structure-activity relationship that leads to 968-based inhibition of glutaminase and cancer cell proliferation, focusing upon a "hot-spot" ring previously identified as critical to 968 activity. We find that the hot-spot ring must be substituted with a large, nonplanar functionality (e.g., a t-butyl group) to bestow activity to the series, leading us to a model whereby the molecule binds glutaminase at a previously undescribed allosteric site. We conduct docking studies to locate potential 968-binding sites and proceed to test a specific set of docking solutions via site-directed mutagenesis. We verify the results from our initial assay of 968 and its analogues by cellular studies using MDA-MB-231 breast cancer cells.     

Outpatient transfusion practice and factors leading to inpatient transfusion in a pediatric hematology/oncology program.

Oral mucositis continues to be a common and debilitating side effect of the conditioning regimens that use high-dose chemotherapy with or without radiation for pediatric bone marrow transplantation. Limited interventions have demonstrated success in preventing or treating it. Administration of glutamine, which is a nitrogen-rich amino acid found in the body, has emerged as a possible method of preventing oral mucositis in patients undergoing bone marrow transplantation. Numerous studies have looked at the effects of oral glutamine supplementation during bone marrow transplant. The purpose of this article is to describe glutamine and how it functions, review the literature regarding the use of oral glutamine in the prevention of oral mucositis in bone marrow transplantion, discuss the administration concerns related to the pediatric setting, and stress the importance of the nurse's role at the bedside. Nurses working in pediatric bone marrow transplant play a key role in the assessment of oral mucositis, administration of oral glutamine, and education of the patient and family.     

靶向谷氨酰胺代谢治疗癌症及其肿瘤微环境中的作用及其研究进展

谷氨酰胺(Glutamine),作为人体中最丰富的自由氨基酸,对多种生理过程起着至关重要的作用。这些作用包括提供细胞能量、支持免疫系统功能、维持肠道健康,以及在氮运输中扮演关键角色。在正常的生理条件下,肌肉组织是谷氨酰胺的主要合成和释放场所,它被释放到血液中,以供肠道和免疫系统等其他组织使用。然而,在疾病状态下,尤其是肿瘤情况中,谷氨酰胺的代谢和功能发生显著变化,这已成为研究焦点。本综述主要讨论肿瘤细胞中谷氨酰胺参与的代谢步骤及谷氨酰胺阻断在肿瘤微环境中的作用。     

Translation initiation in cancer: a novel target for therapy

Translation initiation is regulated in response to nutrient availability and mitogenic stimulation and is coupled with cell cycle progression and cell growth. Several alterations in translational control occur in cancer. Variant mRNA sequences can alter the translational efficiency of individual mRNA molecules, which in turn play a role in cancer biology. Changes in the expression or availability of components of the translational machinery and in the activation of translation through signal transduction pathways can lead to more global changes, such as an increase in the overall rate of protein synthesis and translational activation of the mRNA molecules involved in cell growth and proliferation. We review the basic principles of translational control, the alterations encountered in cancer, and selected therapies targeting translation initiation to help elucidate new therapeutic avenues.     

Intestinal permeability and systemic infections in critically ill patients: effect of glutamine

OBJECTIVE: This article provides a critical review of the evidence indicating that an increase in intestinal permeability is associated with the installation of bacteremia, sepsis, and the multiple organ failure syndrome and that glutamine in pharmacologic doses reduces the acute increase of intestinal permeability and the infection frequency in critically ill patients. DATA SOURCE: All studies published until December 2004 about intestinal permeability, bacterial translocation, and glutamine were located by search of PubMed and Web of Science. The reference lists of review articles and primary publications were also examined to identify references not detected in the computer search. STUDY SELECTION: Clinical and experimental studies investigating the correlation between intestinal permeability, bacterial translocation, and frequency of infections, associated or not with the effect of glutamine administration. DATA EXTRACTION: Information regarding patient population, experimental design, glutamine doses and routes of administration, nutritional therapy prescribed, methods used to assess intestinal permeability, metabolic variables, and the frequency of infections were obtained from the primary literature. DATA SYNTHESIS: Intestinal permeability is increased in critically ill patients. The results have not always been consistent, but the studies whose results support the association between intestinal permeability and systemic infections have had better design and more appropriate controls. The administration of glutamine by the intravenous or oral route and at the doses recommended before or immediately after surgery, burns, or the administration of parenteral nutrition has a protective effect that prevents or reduces the intensity of the increase in intestinal permeability. Glutamine reduces the frequency of systemic infections and may also reduce the translocation of intestinal bacteria and toxins, but this has not been demonstrated. CONCLUSIONS: Glutamine administration improves the prognosis of critically ill patients presumably by maintaining the physiologic intestinal barrier and by reducing the frequency of infections.     

Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond

Tumor cells have an increased demand for nutrients; this demand is met by increased availability of nutrients through vasculogenesis and by enhanced cellular entry of nutrients through upregulation of specific transporters. This review focuses on three groups of nutrient transporters relevant to cancer: glucose transporters, lactate transporters, and amino acid transporters. Tumor cells enhance glucose uptake via induction of GLUT1 and SGLT1, and coordinate the increased entry of glucose with increased glycolysis. Since enhanced glycolysis in cancer is associated with lactate production, tumor cells must find a way to eliminate lactic acid to prevent cellular acidification. This is achieved by the upregulation of MCT4, a H+-coupled lactate transporter. In addition, the Na+-coupled lactate transporter SMCT1 is silenced in cancer. SMCT1 also transports butyrate and pyruvate, which are inhibitors of histone deacetylases. The silencing of SMCT1 occurs in cancers of a variety of tissues. Re-expression of SMCT1 in cancer cell lines leads to growth arrest and apoptosis in the presence of butyrate or pyruvate, suggesting that the transporter may function as a tumor suppressor. Tumor cells meet their amino acid demands by inducing xCT/4F2hc, LAT1/4F2hc, ASCT2, and ATB0,+. xCT/4F2hc is related primarily to glutathione status, protection against oxidative stress, and cell cycle progression, whereas the other three transporters are related to amino acid nutrition. Pharmacologic blockade of LAT1/4F2hc, xCT/4F2hc, or ATB0,+ leads to inhibition of cancer cell growth. Since tumor cells selectively regulate these nutrient transporters to support their rapid growth, these transporters have potential as drug targets for cancer therapy.     

Amino acid uptake and release by colorectal cancer in man

Little information is available regarding the amino acid exchange by human tumors. To characterize this exchange in vivo, 21 patients with resectable colorectal carcinomas were studied during curative operations. Concerning the amino acid uptake and release by peripheral tissues, 20 non-cancer patients served as controls. Both groups of subjects were well-nourished, as indicated by anthropometric and biochemical variables. In the cancer patients, we cannulated a peripheral artery and vein as well as a central tumor-draining vein and the portal vein. Plasma concentrations and concentration differences were determined in mumol/l and in percentages of the total amino acid amounts. Peripheral glutamate uptake per liter plasma was reduced in the cancer patients (p = 0.02). In these patients, the central tumor-draining vein contained less glutamine (p = 0.002) and more glutamate (p = 0.002) than the peripheral vein. Glutamine uptake by the tumor occurred more often than glutamine release, while glutamate had a negative balance across the tumor in all but three cases. The qualitative differences between the peripheral tissues and the tumors with respect to glutamine and glutamate exchange reached high levels of significance (p = 0.002 for both of the amino acids). In addition, the tumors released more glycine, ornithine, and tyrosine than the periphery. As to glutamine and glutamate metabolism, there was a significant difference between the tumors and the portal-drained organs (p greater than or equal to 0.05). The discussion of the results emphasizes the contributions made by the periphery and the tumor to the plasma amino pattern. The role of glutamine as a potential high importance energy source for neoplastic tissues is delineated.     

Circulating tumor cells: Advances in isolation and analysis,and challenges for clinical applications

Circulating tumor cells (CTCs) are rare cancer cells released from tumors into the bloodstream that are thought to have a key role in cancer metastasis. The presence of CTCs has been associated with worse prognosis in several major cancer types, including breast, prostate and colorectal cancer. There is considerable interest in CTC research and technologies for their potential use as cancer biomarkers that may enhance cancer diagnosis and prognosis, facilitate drug development, and improve the treatment of cancer patients. This review provides an update on recent progress in CTC isolation and molecular characterization technologies. Furthermore, the review covers significant advances and limitations in the clinical applications of CTC-based assays for cancer prognosis, response to anti-cancer therapies, and exploratory studies in biomarkers predictive of sensitivity and resistance to cancer therapies.