Abstract
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.
Similar content being viewed by others
References
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.
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.
Brittenden J, Heys S, Eremin O: L-arginine and malignant disease: a potential therapeutic role? Eur J Surg Oncol 20:189–192, 1994.
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.
Daly JM, Reynolds J, Thorn A, et al: Immune and metabolic effects of arginine in the surgical patient. Arch Surg 208:512–523, 1988.
Anon (Editorial): Aminoacid manipulation and cancer. The Lancet 303–304, 1973.
Milner JA: Metabolic aberrations associated with arginine deficiency. J Nutr 115:516–523, 1985.
Bach SJ, Lasnitzki I: Some aspects of the role of arginine and arginase in mouse carcinoma 63. Enzymologia 12:198–205, 1947.
Vrat V: Inhibitory effects of arginase on mammary carcinoma transplants in strain “A” mice. Permanente Found Med Bul 9:56–59, 1951.
Wiswell OB: Effects of intraperitoneally injected arginase on growth of mammary carcinoma implants in mice. Proc Soc Exp Biol Med 76:588–589, 1951.
Irons WG, Boyd EF: Arginase as anticarcinogenic agent in mice and human beings. Ariz Med 9:39–43, 1952.
Bach SJ, Maw GA: Creatine synthesis by tumor-bearing rats. Biochim Biophys Acta 11:69–78, 1953.
Bach SJ, Simon-Reuss I: Arginase, an antimitotic agent in tissue culture. Biochim Biophys Acta 11:396–402, 1953.
Bach SJ, Killip JD: Purification and crystallisation of arginase. Biochim Biophys Acta 29:273–280, 1958.
Bach SJ, Hawkins RA, Swaine D, A short method for the purification of arginase from ox liver. Biochem J 89:263–265, 1963.
Bach SJ, Swaine D: The effect of arginase on the retardation of tumor growth. Brit J Cancer 19:379–386, 1965.
Gilbert DA, Bergel F: The chemistry of xanthine oxidase. Biochem J 90:350–353, 1964.
Iieberman I, Ove P: Inhibition of growth of cultured mammalian cells by liver extracts. Biochem Biophys Acta 38:153–157, 1960.
Freed JJ, Schatz SA: Chromosome aberrations in cultured cells deprived of single essential amino acids. Exp Cell Res 55:393–409, 1969.
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.
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.
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.
Sasada M, Terayama H: The nature of inhibitors of DNA synthesis in rat-liver hepatoma cells. Biochim Biophys Acta 190:73–87, 1969.
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.
Otsuka H: Difference of the inhibitor of DNA synthesis in liver extract from liver arginase. Cancer Res 29:265–266, 1969.
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.
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.
Storr JM, Burton AF: The effects of arginine deficiency on lymphoma cells. Br J Cancer 30:50–59, 1974.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pohjanpelto P, Hölltä E: Arginase activity of different cells in tissue culture. Biochem Biophys Acta 757:191–195, 1983.
Leu S-Y, Wang S-R: Clinical significance of arginase in colorectal cancer. Cancer 70:733–736, 1992.
Straus B, Cepelak I, Festa G: Arginase: a new marker for mammary carcinoma. Clin Chem Acta 210:5–12, 1992.
Dvorak HE Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659, 1986.
Barbul A, Wasserkrug HT, Seifter E, et al: Immunostimulatory effects of arginine in normal and injured rats. J Surg Res 29:228–235, 1980.
Barile MF, Tevinthan BG: Possible mechanism of Mycoplasm inhibition of lymphocyte transformation induced by phytohaemagglutinin. Nature 219:751–753, 1968.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Müller HJ, Boos J: Use of L-asparaginase in childhood ALL. Crit Rev Oncol Hematol 28:97–113, 1998.
Schimke RT: Enzymes of arginine metabolism in mammalian cell culture. 1. Repression of argininosuccinate synthease and argininosuccinase. J Biol Chem 239:136–145, 1964.
Blethen SL, Boeker EA, Snell EE: Arginine decarboxylase fromEscherichia coli. J Biol Chem 243:1671–1677, 1968.
Wu WH, Morris DR: Biosynthetic arginine decarboxylase fromEscherichia coll. J Biol Chem 248:1687–1695, 1973.
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.
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.
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.
Wheatley DN: Dietary restriction, amino acid deprivation, and cancer. The Cancer J 11:183–189, 1998.
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wheatley, D.N., Campbell, E. Arginine catabolism, liver extracts and cancer. Pathol. Oncol. Res. 8, 18–25 (2002). https://doi.org/10.1007/BF03033696
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF03033696