Pathology Oncology Research

, Volume 8, Issue 1, pp 18–25 | Cite as

Arginine catabolism, liver extracts and cancer

  • Denys N. Wheatley
  • Elaine Campbell


Although it is self evident that cells will not grow in amino acid deficient medium, an observation less well appreciated is that malignant cells are particularly vulnerable to such deprivation, which can lead to their rapid demise. Indeed, the more flagrantly malignant the phenotype (anaplastic the tumor), the more susceptible the cells seem to be to deprivation. While some attempts to employ this strategy in cancer treatment have been made, the difference between normal and malignant cells should be more fully exploited as a means ofselectively eliminating tumor cell populations. To be successful, information on differences between the normal and the deranged cell cycle engine and checkpoints, especially how these are affected by deprivation, is of crucial importance. Since it is only recently that the controls at restriction points have been elucidated, it is little surprise that earlier attempts to control tumor cell growth by limiting the availability of an essential amino acid have met with limited success. Studies havebeen sporadic and isolated, often with little more than anecdotal descriptions as far as clinical work was concerned. This review concentrates on what has been accomplished primarilyin vitro and since about 1950 with regard toarginine catabolism, while recognising that other essential amino acids have also been the focus of attention by some investigators. Treatments have included medium and plasma manipulation, dietary control, enzymatic degradation, and the use of liver extracts. On some occasions, substitution of amino acid analogues has been explored. It is argued that current knowledge, combined with past experience, calls for a much closer examination of the full potential of amino acid (and specifically arginine) deprivation as a means of controlling tumor growth, with greater attention to protocols that might be used to treat human cancers.


arginine arginase arginine deiminase arginine decarboxylase deprivation cell cycle checkpoints cell death cancer leukemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.2
    Wheatley DN Scott LA, Lamb JL, Smith S: Single amino (arginine) restriction: growth and death of cultured HeLa and normal human diploid fibroblasts. Cell Physiol Biochem 10:37–55, 2000.PubMedCrossRefGoogle Scholar
  2. 2.2
    Currie GA, Basham C: Differential arginine dependence and the selective cytotoxic effects of activated macrophages for malignant cellin vitro. Brit J Cancer 38:653–659, 1978.PubMedGoogle Scholar
  3. 3.2
    Brittenden J, Heys S, Eremin O: L-arginine and malignant disease: a potential therapeutic role? Eur J Surg Oncol 20:189–192, 1994.PubMedGoogle Scholar
  4. 4.2
    Heys S, Ogston K, Miller I, et al: Potentiation of the response to chemotherapy in patients by dietary supplementation with L-arginine; results of a randomised controlled trial. Int J Oncol 12:221–225, 1998.PubMedGoogle Scholar
  5. 5.2
    Daly JM, Reynolds J, Thorn A, et al: Immune and metabolic effects of arginine in the surgical patient. Arch Surg 208:512–523, 1988.Google Scholar
  6. 6.2
    Anon (Editorial): Aminoacid manipulation and cancer. The Lancet 303–304, 1973.Google Scholar
  7. 7.2
    Milner JA: Metabolic aberrations associated with arginine deficiency. J Nutr 115:516–523, 1985.PubMedGoogle Scholar
  8. 8.2
    Bach SJ, Lasnitzki I: Some aspects of the role of arginine and arginase in mouse carcinoma 63. Enzymologia 12:198–205, 1947.PubMedGoogle Scholar
  9. 9.2
    Vrat V: Inhibitory effects of arginase on mammary carcinoma transplants in strain “A” mice. Permanente Found Med Bul 9:56–59, 1951.Google Scholar
  10. 10.2
    Wiswell OB: Effects of intraperitoneally injected arginase on growth of mammary carcinoma implants in mice. Proc Soc Exp Biol Med 76:588–589, 1951.PubMedGoogle Scholar
  11. 11.2
    Irons WG, Boyd EF: Arginase as anticarcinogenic agent in mice and human beings. Ariz Med 9:39–43, 1952.PubMedGoogle Scholar
  12. 12.2
    Bach SJ, Maw GA: Creatine synthesis by tumor-bearing rats. Biochim Biophys Acta 11:69–78, 1953.PubMedCrossRefGoogle Scholar
  13. 13.2
    Bach SJ, Simon-Reuss I: Arginase, an antimitotic agent in tissue culture. Biochim Biophys Acta 11:396–402, 1953.CrossRefGoogle Scholar
  14. 14.2
    Bach SJ, Killip JD: Purification and crystallisation of arginase. Biochim Biophys Acta 29:273–280, 1958.PubMedCrossRefGoogle Scholar
  15. 15.2
    Bach SJ, Hawkins RA, Swaine D, A short method for the purification of arginase from ox liver. Biochem J 89:263–265, 1963.PubMedGoogle Scholar
  16. 16.2
    Bach SJ, Swaine D: The effect of arginase on the retardation of tumor growth. Brit J Cancer 19:379–386, 1965.PubMedGoogle Scholar
  17. 17.2
    Gilbert DA, Bergel F: The chemistry of xanthine oxidase. Biochem J 90:350–353, 1964.PubMedGoogle Scholar
  18. 18.2
    Iieberman I, Ove P: Inhibition of growth of cultured mammalian cells by liver extracts. Biochem Biophys Acta 38:153–157, 1960.CrossRefGoogle Scholar
  19. 19.2
    Freed JJ, Schatz SA: Chromosome aberrations in cultured cells deprived of single essential amino acids. Exp Cell Res 55:393–409, 1969.PubMedCrossRefGoogle Scholar
  20. 20.2
    Holley RW: Evidence that a rat liver“inhibitor” of the synthesis of DNA in cultured mammalian cells is arginase. Biochim Biophys Acta 145:525–527, 1967.PubMedGoogle Scholar
  21. 21.2
    Umeda M, Diringer H, Heidelberger: Inhibition of the growth of cultured cells by arginase and soluble proteins from mouse skin. Isr J Med Sci 4:1216–1222, 1968.PubMedGoogle Scholar
  22. 22.2
    Freed JJ, Sorof S: The nature of the inhibition of replication of cultured cells by a liver macromolecule. Wistar Inst Symp Monogr 7:15–24, 1967.PubMedGoogle Scholar
  23. 23.2
    Sasada M, Terayama H: The nature of inhibitors of DNA synthesis in rat-liver hepatoma cells. Biochim Biophys Acta 190:73–87, 1969.PubMedGoogle Scholar
  24. 24.2
    Miyamoto M, Terayama H: Nature of rat liver cell sap factors inhibiting the DNA synthesis in tumor cells. Biochim Biophys Acta 228:324–330, 1971.PubMedGoogle Scholar
  25. 25.2
    Otsuka H: Difference of the inhibitor of DNA synthesis in liver extract from liver arginase. Cancer Res 29:265–266, 1969.PubMedGoogle Scholar
  26. 26.2
    McMahon JB, Type PT: Specific inhibition of proliferation of non-malignant rat hepatic cells by a factor from rat liver. Cancer Res 40:1249–1254, 1980.PubMedGoogle Scholar
  27. 27.2
    Osunkoya BC, Adler WH, Smith RT: Effect of arginine deficiency on synthesis of DNA and immunoglobulin receptor of Burkitt lymphoma cells. Nature 227:398–400, 1970.PubMedCrossRefGoogle Scholar
  28. 28.2
    Storr JM, Burton AF: The effects of arginine deficiency on lymphoma cells. Br J Cancer 30:50–59, 1974.PubMedGoogle Scholar
  29. 29.2
    Koji T Terayama H: Arginase as one of the inhibitory principles in the density-dependent as well as plasma membrane-mediated inhibition of liver cell growth in vitro. Experimental Cell Research 155:359–370, 1984.PubMedCrossRefGoogle Scholar
  30. 30.2
    Barra R, Parsons J, Koch MR, Tea MA: Soluble factors from liver and hepatomas which inhibit [3H]-thymidine incorporation into DNA of Novikoff hepatoma cells. Cancer Res 39:1655–1660, 1979.PubMedGoogle Scholar
  31. 31.2
    Miyamoto M, Terayama H: Nature of rat liver cell sap factors inhibiting the DNA synthesis in tumor cells. Biochim Biophys Acta 228:324–330, 1971.PubMedGoogle Scholar
  32. 32.2
    Terayama H, Koji T, Kontani M, Okumoto T: Arginase is an inhibitory principle in liver plasma membranes arresting the growth of various mammalian cellsin vitro. Biochim Biophys Acta 720:188–192, 1982.PubMedCrossRefGoogle Scholar
  33. 33.2
    Savoca KV, Davis FF, Van Es T, et al: Cancer therapy with chemically modified enzyme: II. The therapeutic effectiveness of arginase modified by the covalent attachment of polyethylene glycol, on a Taper liver tumor and the L5178Y murine leukaemia. Cancer Biochem Biophys 7:261–268, 1984.PubMedGoogle Scholar
  34. 34.2
    Scott LA, Lamb JL, Smith S, Wheatley DN: Single amino (arginine) deprivation: rapid and selective cells death of cultured transformed and malignant cells. Brit J Cancer 83:800–810, 2000.PubMedCrossRefGoogle Scholar
  35. 35.2
    Snodgrass PJ, Lin RC: Differing effects of arginine deficiency on the urea cycle enzymes of rat liver, cultured hepatocytes and hepatoma cells. J Nutr 117:1827–1837, 1987.PubMedGoogle Scholar
  36. 36.2
    Höllta KG, Pohjanpelto P: Polyamine dependence of Chinese hamster ovary cells in serum-free culture is due to deficient arginase activity. Biochim Biophys Acta 721:321–327, 1982.CrossRefGoogle Scholar
  37. 37.2
    Anehus S, Pohjanpelto P, Baldetrop B, et al: Polyamine starvation prolongs the S and G2 phases pf polyamine-dependent (arginase-deficient) CHO cells. Mol Cell Biol 4:915–922, 1984.PubMedGoogle Scholar
  38. 38.2
    Finlay IG, Seifert JK, Stuart GJ, Morris DL: Resection with cryotherapy of colorectal hepatic metastasis has the same survival as hepatic resection alone. Eur J Surg Oncol 26:199–202, 1998.CrossRefGoogle Scholar
  39. 39.2
    Pohjanpelto P, Hölltä E: Arginase activity of different cells in tissue culture. Biochem Biophys Acta 757:191–195, 1983.PubMedGoogle Scholar
  40. 40.2
    Leu S-Y, Wang S-R: Clinical significance of arginase in colorectal cancer. Cancer 70:733–736, 1992.PubMedCrossRefGoogle Scholar
  41. 41.2
    Straus B, Cepelak I, Festa G: Arginase: a new marker for mammary carcinoma. Clin Chem Acta 210:5–12, 1992.CrossRefGoogle Scholar
  42. 42.2
    Dvorak HE Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659, 1986.PubMedGoogle Scholar
  43. 43.2
    Barbul A, Wasserkrug HT, Seifter E, et al: Immunostimulatory effects of arginine in normal and injured rats. J Surg Res 29:228–235, 1980.PubMedCrossRefGoogle Scholar
  44. 44.2
    Barile MF, Tevinthan BG: Possible mechanism of Mycoplasm inhibition of lymphocyte transformation induced by phytohaemagglutinin. Nature 219:751–753, 1968.CrossRefGoogle Scholar
  45. 45.2
    Kraemer PM, Defendi V, Hayflick L, Manson LA: Mycoplasma (PPLO) strains with lytic activity for murine lymphoma cells in vitro. Proc Soc Exp Biol Med 112:381–387, 1963.PubMedGoogle Scholar
  46. 46.2
    Gill P, Pan J: Inhibition of cell division in L5178Y cells by arginine-degrading mycoplasma: the role of arginine deiminase. Can J Microbiol 16:415–419, 1970.PubMedCrossRefGoogle Scholar
  47. 47.2
    Miyazaki K, Takaku H, Umeda M, et al: Potent growth inhibition of human tumor cells in culture by arginine deiminase purified from a culture medium of a mycoplasma-infected cell line. Cancer Res 50:4522–4527, 1990.PubMedGoogle Scholar
  48. 48.2
    Sugimura K, Ohno T, Kusuyama T, Azuma I: High sensitivity of human melanoma cell lines to the growth inhibitory activity of arginine deiminasein vitro. Melanoma Res 2:190–196, 1992.CrossRefGoogle Scholar
  49. 49.2
    Takaku H, Takase M, Abe SI, et al:In vivo anti-tumor activity of arginine deiminase purified fromMycoplasma argini. Int J Cancer 51:244–249, 1992.PubMedCrossRefGoogle Scholar
  50. 50.2
    Claesson MH, Tscherning T, Nissen MH, Lind K: Inhibitory effect of mycoplasma-released arginase. Activity in mixedlymphocyte and tumor cell cultures. Scand J Immunol 32:623–630, 1990.PubMedCrossRefGoogle Scholar
  51. 51.2
    Komada Y, Zhang XL, Zhou YW, et al: Apoptotic cell death of human T lymphoblastoid cells induced by arginine deiminase. Int J Hematol 65:129–141, 1997.PubMedCrossRefGoogle Scholar
  52. 52.2
    Gong H, Zölzer F, von Recklinghausen G, et al: Arginine deiminase inhibits cell proliferation by arresting cell cycle and inducing apoptosis. Biochem Biophys Res Comm 261:10–14, 1999.PubMedCrossRefGoogle Scholar
  53. 53.2
    Gong H Zölzer F, von Recklinghausen G, et al: Arginine deiminase inhibits proliferation of human leukaemia cells more potently than asparginase by inducing cell cycle arrest and apoptosis. Leukemia 14:826–829, 2000.PubMedCrossRefGoogle Scholar
  54. 54.2
    Müller HJ, Boos J: Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol 28:97–113, 1998.PubMedCrossRefGoogle Scholar
  55. 55.2
    Schimke RT: Enzymes of arginine metabolism in mammalian cell culture. 1. Repression of argininosuccinate synthease and argininosuccinase. J Biol Chem 239:136–145, 1964.PubMedGoogle Scholar
  56. 56.2
    Blethen SL, Boeker EA, Snell EE: Arginine decarboxylase fromEscherichia coli. J Biol Chem 243:1671–1677, 1968.PubMedGoogle Scholar
  57. 57.2
    Wu WH, Morris DR: Biosynthetic arginine decarboxylase fromEscherichia coll. J Biol Chem 248:1687–1695, 1973.PubMedGoogle Scholar
  58. 58.2
    Morrissey J, McCracken R, Ishidoya S, et al: Partial cloning and characterization of an arginine decarboxylase in the kidney. Kidney Internat 47:1458–1461, 1995.CrossRefGoogle Scholar
  59. 59.2
    Buch JK, Boyle SM: Biosynthetic arginine decarboxylase inEscherichia coli is synthesized as a precursor and located in the cell envelope. J Bacteriol 163:522–527, 1985.PubMedGoogle Scholar
  60. 60.2
    Galea E, Regunathan S, Eliopoulos V, et al: Inhibition of mammalian nitric oxide synthases by agmatine, an endogenous polyamine formed by decarboxylation of arginine. Biochemical J 316:247–249, 1996.Google Scholar
  61. 61.2
    Wheatley DN: Dietary restriction, amino acid deprivation, and cancer. The Cancer J 11:183–189, 1998.Google Scholar
  62. 62.2
    Joshi M: The importance of L-arginine metabolism in melanoma: an hypothesis for the role of nitric oxide and polyamines in tumor angiogenesis. Free Radic Biol Med 22:573–578, 1997.PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2002

Authors and Affiliations

  1. 1.Department of Cell PathologyUniversity of AberdeenAberdeenUK

Personalised recommendations