Glutamine and Cancer Cachexia

  • Barrie P. Bode
  • Craig Fischer
  • Steven Abcouwer
  • Masafumi Wasa
  • Wiley W. Souba
Part of the Medical Intelligence Unit book series (MIU.LANDES)


The observation that cancer cachexia is associated with specific metabolic abnormalities has stimulated several investigators to attempt to correct these deficiencies with the hopes that it would nutritionally benefit the patient with malignant disease. Initial enthusiasm for this approach emerged about 25 years ago when total parenteral nutrition was first introduced into clinical medicine. The provision of exogenous macronutrients to the depleted cancer patient often resulted in weight gain and improved tolerance to anti-neoplastic therapies. More recently, the use of specific nutrients to reverse or combat cancer cachexia has become the focus of study. The amino acid which has received the most attention in this regard has been glutamine and this interest has grown for several reasons. Glutamine is absent from most commercially available TPN formulations. Although glutamine is the most abundant amino acid in the body, a marked glutamine depletion is observed in the host with cancer and a correction of this deficit using glutamine-enriched feedings may translate into functional improvements. Glutamine has been shown to be a regulator of muscle protein synthesis, suggesting that the net muscle catabolism that is observed in cancer patients may be related to altered glutamine metabolism. Furthermore, glutamine is a principal fuel for most rapidly proliferating cancers.


Amino Acid Metabolism Cancer Cachexia Glutamine Concentration Glutamine Metabolism Glutaminase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Krebs HA. Metabolism of amino acids. IV. The synthesis of glutamine form glutamic acid and ammonia and the enzymatic hydrolysis of glutamine in animal tissues. Biochem J 1935; 33: 1951–1969.Google Scholar
  2. 2.
    Rose WC. The nutritive significance of the amino acids. Physiol Rev 1938; 18: 109–136.Google Scholar
  3. 3.
    Lacey J, and Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr Rev 1990; 48: 297–313.PubMedCrossRefGoogle Scholar
  4. 4.
    Scheltinga MR, Young LS, Benfell K et al. Glutamine-enriched intravenous feedings attenuate extracellular fluid expansion after standard stress. Ann Surg 1991; 214: 385–395.PubMedCrossRefGoogle Scholar
  5. 5.
    Ziegler TR, Young LS, Benfell K et al. Glutamine-supplemented parenteral nutrition improves nitrogen retention and reduces hospital mortality versus standard parenteral nutrition following bone marrow transplantation:a randomized, double-blind trial. Ann Int Med 1992; 116: 821–828.PubMedGoogle Scholar
  6. 6.
    Souba WW. Interorgan ammonia metabolism in health and disease:a surgeon’s view. J Parent Ent Nutr 1987; 11: 569–579.CrossRefGoogle Scholar
  7. 7.
    Windmueller HG. Glutamine utilization by the small intestine. Adv Enzymol 1982; 53: 202–231.Google Scholar
  8. 8.
    Welbourne TC, Childress D, Givens G. Renal regulation of interorgan glutamine flow in metabolic acidosis. Am J Physiol 1986; 251: R858 - R866.Google Scholar
  9. 9.
    Plumley DA, Austgen TR, Salloum RM et al. The role of the lungs in maintaining amino acid homeostasis. JPEN 1990; 14 (6): 569–573.CrossRefGoogle Scholar
  10. 10.
    Bergstrom J, Furst P, Noree LO et al. Intracellular free amino acid concentration in human muscle tissue. J Appl Physiol 1974; 36: 693–699.PubMedGoogle Scholar
  11. 11.
    Brand K, Feld W, von Hintzenstern J et al. Metabolism of glutamine in lymphocytes. Metabolism (suppl) 1989; 38 (8): 29–33.CrossRefGoogle Scholar
  12. 12.
    Bennegard K, Lindmark L, Eden E et al. Flux of amino acids across the leg in weight-losing cancer patients. Cancer Res 1984: 44: 386–393.PubMedGoogle Scholar
  13. 13.
    Yamamoto H, Aikawa T, Matsutaka H et al. Relative uptake of plasma amino acids by fetal and tumor tissues. Metabolism 1974; 23: 1017–1022.PubMedCrossRefGoogle Scholar
  14. 14.
    Wu C, Bauer JM. A study of free amino acids and of glutamine synthesis in tumor-bearing rats. Cancer Research 1960; 20: 848–857.PubMedGoogle Scholar
  15. 15.
    Rivera S, Azcon-Bieto J, Lopez-Soriano FL et al. Amino acid metabolism in tumor-bearing mice. Biochem J 1988; 249; 443–449.PubMedGoogle Scholar
  16. 16.
    Quesada AR, Medina MA, Marquez H et al. Contribution by host tissues to circulating glutamine in mice inoculated with Ehrlich ascites tumor cells. Cancer Res 1988; 48: 1551–1553.PubMedGoogle Scholar
  17. 17.
    Chen MK, Salloum RM, Austgen TR et al. Tumor regulation of hepatic glutamine metabolism. J Parent Ent Nutr 1991; 15: 159–164.CrossRefGoogle Scholar
  18. 18.
    Souba WW, Strebel FR, Bull JM et al. Interorgan metabolism in the tumor-bearing rat. J Surg Res 1988; 44: 720–726.PubMedCrossRefGoogle Scholar
  19. 19.
    Stovroff M, Fraker DL, Norton JA. Cachectin levels in the serum of tumor-bearing rats. Arch Surg 1989; 124: 94.PubMedCrossRefGoogle Scholar
  20. 20.
    Chen MK, Austgen TR, Klimberg VS et al. Tumor glutamine use exceeds intestinal glutamine use in cachectic tumor-bearing rats. Surg Forum 1990; 41: 12–14.Google Scholar
  21. 21.
    Espat NJ, and Souba WW. Influence of fasting on glutamine transport in rat liver. JPEN 17: 493–500, 1993.CrossRefGoogle Scholar
  22. 22.
    Chen MK, Espat NJ, Bland KI et al. Influence of progressive tumor growth on glutamine metabolism in skeletal muscle and kidney. Ann Surg 217: 655–667, 1993.PubMedCrossRefGoogle Scholar
  23. 23.
    Rennie MJ, MacLennan PA, Hundal HS et al. Skeletal muscle glutamine transport, intramuscular glutamine concentration, and muscle protein turnover. Metabolism (Suppl) 1989; 38 (8): 47–51.CrossRefGoogle Scholar
  24. 24.
    Salloum RM, Sitren HS, Bland KI et al. Selective inhibition of intestinal glutaminase activity in the tumor-bearing rat. Surgical Forum 1991; 50: 115–117.Google Scholar
  25. 25.
    Penn RL, Maca RD, Berg RD. Increased translocation of bacteria from the gastrointestinal tracts of tumor-bearing mice. Infection and Immunity 1985; 47: 793–798.PubMedGoogle Scholar
  26. 26.
    Salloum RM, Copeland EM, Bland KI et al. Selective stimulation of brush border glutamine transport in the tumor-bearing rat. J Surg Res 1992; 50: 391–397.CrossRefGoogle Scholar
  27. 27.
    Pacitti AJ, Chen MK, Bland KI et al. Mechanisms of accelerated hepatic glutamine efflux in the tumor-bearing rat. Surgical Oncology 1992; 1: 173–182.PubMedCrossRefGoogle Scholar
  28. 28.
    Warren RS, Jeevanandam M, Brennan MF. Comparison of hepatic protein synthesis in vivo versus in vitro in the tumor-bearing rat. J Surg Res 1987; 42: 43–50.PubMedCrossRefGoogle Scholar
  29. 29.
    Warren RS, Jeevanandam M, Brennan MF. Protein synthesis in the tumor-influenced hepatocyte. Surgery 1985; 98 (2): 275–282.PubMedGoogle Scholar
  30. 30.
    Kilberg, MS, Handlogten, ME and Christensen, HN. Characteristics of an amino acid transport system in rat liver for glutamine, asparagine, histidine and closely related analogs. J Biol Chem 255: 4011–4019 (1980).PubMedGoogle Scholar
  31. 31.
    Pacitti AJ, Inuoe Y, Souba WW. Characterization of Na+-independent glutamine transport in rat liver. Am J Physiol 265:G90 - G98, 1993.Google Scholar
  32. 32.
    Dudrick PS, Bland KI, Copeland EM et al. Hepatocyte glutamine transport in advanced malignant disease. Surg Forum 1992; 43: 13–15.Google Scholar
  33. 33.
    Dudrick PS, Inuoe Y, Espat NJ et al. Na’-dependent glutamine transport in the liver of tumor-bearing rats. Surgical Oncology 2: 205–215, 1993.PubMedCrossRefGoogle Scholar
  34. 34.
    Fafournoux P, Demigne C, Remesy C et al. Bidirectional transport of glutamine across the cell membrane in rat liver. Biochem J 216: 401–408, 1983.PubMedGoogle Scholar
  35. 35.
    Haussinger, D. Nitrogen metabolism in liver: structural and functional organization and physiological relevance. Biochem J 267: 281–290 (1990).PubMedGoogle Scholar
  36. 36.
    Burger HJ, Gebhardt R, Mayer C et al. Different capacities for amino acid transport in periportal and perivenous hepatocytes isolated by digitonin/collagenase perfusion. Hepatology 9: 22–26, 1989.PubMedCrossRefGoogle Scholar
  37. 37.
    Norton JA, Moley JF, Green MV et al. Parabiotic transfer of cancer cachexia/anorexia in male rats. Cancer Res 1985; 45: 5547–5552.PubMedGoogle Scholar
  38. 38.
    Langstein HN, Norton JA. Mechanisms of cancer cachexia. In: Nutrition and Cancer. DW Nixon, ed. Hematology Clinics of North America 1991; 5(1):103–123.Google Scholar
  39. 39.
    Pacitti AJ, Inuoe Y, Souba WW. Tumor necrosis factor stimulates amino acid transport in plasma membrane vesicles from rat liver. J Clin Invest 1993; 91: 474–483.PubMedCrossRefGoogle Scholar
  40. 40.
    Eagle H. Nutritional needs of mammalian cells in tissue culture. Science 1935; 122: 501–504.CrossRefGoogle Scholar
  41. 41.
    Reitzer LJ, Wice BM, Kennell D. Evidence that glutamine not sugar, is the major energy source for cultured HeLa cells. J Biol Chem 1979; 254: 2669–2775.PubMedGoogle Scholar
  42. 42.
    Kovacevic Z, Morris HP. The role of glutamine in the oxidative metabolism of malignant cells. Cancer Res 1972; 32: 326–335.PubMedGoogle Scholar
  43. 43.
    Linder-Horowitz M, Knox WE, Morris HO. Glutaminase activities and growth rates of rat hepatomas. Cancer Research 1969; 29: 1195–1199.PubMedGoogle Scholar
  44. 44.
    Knox WE, Horowitz ML, Friedell GH. The proportionality of glutaminase content to growth rate and morphology of rat neoplasms. Cancer Res 1969; 29: 669–675.PubMedGoogle Scholar
  45. 45.
    Sauer LA, Stayman JW, Dauchy RT. Amino acid, glucose, and lactic acid utilization in vivo by rat tumors. Cancer Res 1986; 46: 3469–3475.PubMedGoogle Scholar
  46. 46.
    Sauer LA, Dauchy RT. Ketone body, glucose, lactic acid, and amino acid utilization by tumors in vivo in fatsed rats. Cancer Res 1983; 43: 3497–3503.PubMedGoogle Scholar
  47. 47.
    Newsholme EA, Newsholme P, Curi R et al. A role for muscle in the immune system and its importance in surgery, trauma, sepsis, and burns. Nutrition 1988; 4: 261–268.Google Scholar
  48. 48.
    Lowy DR and Willumse BM. Function and regulation of ras. Ann Rev Biochem 1993; 62: 851–891.PubMedCrossRefGoogle Scholar
  49. 49.
    Levine AJ. The tumor suppressor genes. Ann Rev Biochem 1993; 62: 623–651.PubMedCrossRefGoogle Scholar
  50. 50.
    Souba WW. Glutamine and cancer. Ann Surg 1993; 218: 715–728.PubMedCrossRefGoogle Scholar
  51. 51.
    Medina MA, Sanchez-Jimenez F, Marquez J, Rodriguez A, Nunez de Castro I. Relevance of glutamine metabolism to tumor cell growth. Mol Cell Biochem 1992; 113: 1–15.PubMedCrossRefGoogle Scholar
  52. 52.
    Hundal H, Rennie M, Watt P. Characteristics of glutamine transport in perfused skeletal muscle. J Physiol (London) 1987; 393: 283–305.Google Scholar
  53. 53.
    Meijer AJ, Lamers W, Chamuleau A. Nitrogen metabolism and ornithine cycle function. Physiol Rev 1990; 70: 701–748.PubMedGoogle Scholar
  54. 54.
    Bode BP, Mailliard ME, Tamarappoo BJ, Kilberg MS. Regulation of hepatic glutamine transport. J Parent Enteral Nutr (Suppl) 1989; 48S - 52S.Google Scholar
  55. 55.
    Haussinger D, Soboll S, Meijer A, Gerok W, Tager J, Sies H. Role of plasma membrane transport in hepatic glutamine metabolism. Eur J Biochem 1985; 152: 597–603.PubMedCrossRefGoogle Scholar
  56. 56.
    Bode BP, Kaminski DL, Souba WW, Li AP. Glutamine transport in isolated human hepatocytes and transformed liver cells. Hepatology 1995; 21:(2)511–520.PubMedGoogle Scholar
  57. 57.
    Spolarics Z, Lang CH, Bagby GJ, Spitzer JJ. Glutamine and fatty acid oxidation are the main sources of energy for Kupffer and endothelial cells. Am J Physiol 1991; 24: G185 - G190.Google Scholar
  58. 58.
    Matsuno T, Goto I. Glutaminase and glutamine synthetase activities in human cirrhotic liver and hepatocellular carcinoma. Cancer Res 1992; 52: 1192–1194.PubMedGoogle Scholar
  59. 59.
    Mares-Perlman JA, Shrago E. Energy substrate utilization in freshly isolated Morris hepatoma 7777 cells. Cancer Res 1988; 48: 602–608.PubMedGoogle Scholar
  60. 60.
    Sebolt JS, Weber, G. Negative correlation of L-glutamine concentration with proliferation rate in rat hepatomas. Life Sci 1984; 34: 301–306.PubMedCrossRefGoogle Scholar
  61. 61.
    Watford M. Hepatic glutaminase expression:relationship to kidney-type glutaminase and to the urea cycle. FASEB J 1993; 7: 1468–1474.PubMedGoogle Scholar
  62. 62.
    Morris HP. Studies on the development, biochemistry, and biology of experimental hepatomas. Adv Cancer Res 1965; 9: 227–302.PubMedCrossRefGoogle Scholar
  63. 63.
    Linder-Horowitz M, Knox WE. A phosphate-activated glutaminase in rat liver different from that in kidney and other tissues. Enzymol Biol Clin 1968; 9: 241–255.Google Scholar
  64. 64.
    Bode BP, Souba WW. Modulation of cellular proliferation alters glutamine transport and metabolism in human hepatoma cells. Ann Surg 1994; 220: 411–424.PubMedCrossRefGoogle Scholar
  65. 65.
    Shapiro RA, Farrell L, Srinivasan M, Curthoys NP. Isolation, characterization, and in vivo expression of a cDNA that encodes the kidney isozyme of mitochondrial glutaminase. J Biol Chem 1991; 266: 18792–18796.PubMedGoogle Scholar
  66. 66.
    Smith EM Watford M. Molecular cloning of a cDNA for rat hepatic glutaminase:sequence similarity to kidney-type glutaminase. J Biol Chem 1990; 265: 10631–10636.PubMedGoogle Scholar
  67. 67.
    Weber G, Liu MS, Natsumeda Y, Faderan MA. Salvage capacity of hepatoma 3924A and action ‘of dipyridamole. Adv Enz Reg 1983; 21: 53–69.CrossRefGoogle Scholar
  68. 68.
    Prajda N, Katunuma N, Morris HP, Weber G. Imbalance of purine metabolism in hepatomas of different growth rates as expressed in behavior of glutamine-phosphoribosylpyrophosphate amidotransferase. Cancer Res 1975; 35: 3061–3068.PubMedGoogle Scholar
  69. 69.
    Boritzki TJ, Jackson RC, Morris HP, Weber, G. Guanosine-5’-phosphate synthetase and guanosine-5’-phosphate kinase in rat hepatomas and kidney tumors. Biochim Biophys Acta 1981; 658: 102–110.PubMedCrossRefGoogle Scholar
  70. 70.
    Elliot WL, Weber G. Proliferation-linked increase in phosphoribosylformylglycinamidine synthetase activity. Cancer Res 1988; 44: 2430–2434.Google Scholar
  71. 71.
    Reardon MA, Weber G. Increased synthesis of carbamoyl phosphate synthase II in hepatoma 3924A. Cancer Res 1986; 46: 3673–3676.PubMedGoogle Scholar
  72. 72.
    Hirayama C, Suyama K, Horie Y, Tanimoto K, Kato S. Plasma amino acid patterns in hepatocellular carcinoma. Biochem Med Metabol Biol 1987; 38: 127–133.CrossRefGoogle Scholar
  73. 73.
    Weber G, Prajda N, Lui MS, Denton JE, Takashi A, Sebolt J, Zhen YS, Burt ME, Faderan MA, Reardon MA. Multi-enzyme-targeted chemotherapy by acivicin and actinomycin. Adv Enz Reg 1982; 20: 75–96.CrossRefGoogle Scholar
  74. 74.
    Ahluwalia GS, Grem JL, Hao Z, Cooney DA. Metabolism and action of amino acid analog anti-cancer agents. Pharmac Ther 1990; 46: 243–271.CrossRefGoogle Scholar
  75. 75.
    Baskerville A, Hambleton P, Benbough JE. Pathologic features of glutaminase toxicity. Br J Exp Pathol 1980; 61: 132–138.PubMedGoogle Scholar
  76. 76.
    Kisner DL, Catane R, Muggia FM. The rediscovery of DON (6-Diazo-5oxo-L-norleucine). Recent Results Cancer Res 1980; 74: 258–263.PubMedCrossRefGoogle Scholar
  77. 77.
    Ovejera AA, Houchens DP, Catane R et al. Efficacy of 6-Diazo-5-oxo-Lnorleucine and N-[N-g-glutamyl-6-diazo-5-oxo-norleucinyl]-6-diazo-5-oxonorleucine against experimental tumors in conventional nude mice. Cancer Res 1979; 39: 3220–3224.PubMedGoogle Scholar
  78. 78.
    Chance WT, Cao L, Fischer JE. Response of tumor and host to hyperalimentation and antiglutamine treatments. JPEN 14(2):122–128.Google Scholar
  79. 79.
    Chance WT, Cao L, Fischer JE. Insulin and acivicin improve host nutrition and prevent tumor growth during total parenteral nutrition. Ann Surg 1988; 208 (4): 524–531.PubMedCrossRefGoogle Scholar
  80. 80.
    Kaibara A, Yoshida S, Mizote H et al. Effect of glutamine supplementation on host protein metabolism and tumor growth in rats. JPEN (suppl) abstract. Jan-Feb 1994.Google Scholar
  81. 81.
    Austgen TR, Dudrick PS, Sitren HS et al. The effects of glutamine-enriched total parenteral nutrition on tumor growth and host tissues. Ann Surg 1992; 215 (2): 107–113.PubMedCrossRefGoogle Scholar
  82. 82.
    Burke D, Alverdy JC, Aoys E et al. Glutamine supplemented TPN improves gut immune function. Arch Surg 1989; 124: 1396–1399.PubMedCrossRefGoogle Scholar
  83. 83.
    Alverdy JC, Aoys E, Weiss-Carrington P et al. The effect of glutamineenriched TPN on gut immune cellularity. J Surg Res 1992; 52: 34–38.PubMedCrossRefGoogle Scholar
  84. 84.
    Fox AD, Kripke SA, DePaula J et al. Effect of a glutamine supplemented enteral diet on methotrexate-induced enterocolitis. J Parent Ent Nutr 1988; 12: 325–331.CrossRefGoogle Scholar
  85. 85.
    Jacobs DO, Evans, DA, O’Dwyer ST et al. Disparate effects of 5-fluorouracil on the ileum and colon of enterally fed rats with protection by dietary glutamine. Surg Forum 1987; 38: 45–47.Google Scholar
  86. 86.
    O’Dwyer ST, Scott T, Smith JR et al. 5-fluorouracil toxicity on small intestinal mucosa but not white blood cells is decreased by glutamine (abstract). Clin Res 1987; 35: 369a.Google Scholar
  87. 87.
    Klimberg VS, Nwodeki E, Hutchins LF et al. Glutamine facilitates chemotherapy while reducing toxicity. J Parent Ent Nutr (suppl) 1992; 16: 83S - 87S.CrossRefGoogle Scholar
  88. 88.
    Alverdy JC. Effect of glutamine-supplemented diets on immunology of the gut. J Parent Ent Nutr (suppl) 14: 109S - 113S.Google Scholar
  89. 89.
    Klimberg VS, Salloum RM, Kasper M et al. Oral glutamine accelerates healing of the small intestine and improves outcome following whole abdominal radiation. Arch Surg 1990; 125: 1040–1045.PubMedCrossRefGoogle Scholar
  90. 90.
    Klimberg VS, Souba WW, Dolson DJ et al. Prophylactic glutamine protects the intestinal mucosa from radiation injury. Cancer 1990; 66: 62–68.PubMedCrossRefGoogle Scholar
  91. 91.
    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.PubMedCrossRefGoogle Scholar
  92. 92.
    Klimberg VS, Pappas AA, Nwodeki E et al. Effect of oral glutamine on tumor concentrations of methotrexate. Arch Surg 1992; 127: 1317–1320.PubMedCrossRefGoogle Scholar
  93. 93.
    Taudou G, Wiart J, Panijel J. Influence of amino acid deficiency and tRNA aminoacylation on DNA polymerase activity during the secondary immune response in vitro. Molecular Immunology 1983; 20: 255–262.PubMedCrossRefGoogle Scholar
  94. 94.
    Lowe DL, Benfell K, Smith RJ et al. Glutamine-enriched total parenteral nutrition is safe in normal humans. Surg Forum 1989; 40: 9–11.Google Scholar
  95. 95.
    Ziegler TR, Benfell K, Smith RJ et al. Safety and metabolic effects of L-glutamine administration in humans. JPEN supp 1990; 14 (4): 137S - 146S.CrossRefGoogle Scholar
  96. 96.
    Lochs H, Hubl W. Metabolic basis for selecting glutamine-containing substrates for parenteral nutrition. JPEN Suppl 1990; 14 (4): 114S - 117S.CrossRefGoogle Scholar
  97. 97.
    Furst P, Albers S, Stehle P. Glutamine-containing dipeptides in parenteral nutrition. JPEN (suppl) 1989; 14 (4): 1185–124S.Google Scholar
  98. 98.
    Adibi SA. Intravenous use of glutamine in peptide form:clinical applications of old and new observations. Metabolism (suppl) 1989; 38: 89–92.CrossRefGoogle Scholar
  99. 99.
    Van der Hulst RR, van Kreel BK, von Meyerfeldt MF et al. Glutamine and the preservation of gut integrity. Lancet 1979; 341: 1363–1367.CrossRefGoogle Scholar
  100. 100.
    Hammarqvist F, Wernerman J, Ali R et al. Addition of glutamine to total parenteral nutrition after elective abdominal surgery spares free glutamine in muscle, counteracts the fall in muscle protein synthesis, and improves nitrogen balance. Ann Surg 1989; 209; 455–461.PubMedCrossRefGoogle Scholar
  101. 101.
    Hinshaw DB, Burger JM. Protective effect of glutamine on endothelial cell ATP in oxidant injury. J Surg Res 1990; 49: 222–227.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • Barrie P. Bode
  • Craig Fischer
  • Steven Abcouwer
  • Masafumi Wasa
  • Wiley W. Souba

There are no affiliations available

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