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Enzymes of purine metabolism in lymphoid neoplasms, clinical relevance for treatment with enzyme inhibitors

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Summary

A few enzymes of the purine degradative pathway have proved valuable in diagnosis and treatment of lymphomas and lymphocytic leukemia. Of particular interest are the enzymes adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP) and ecto-5′-nucleotidase (5NT). Intact activities of ADA and PNP have been shown to be vital for lymphoid cells. During development, lymphoid precursors go through remarkable changes in the concentrations of these enzymes and the neoplasma derived from them show a “frozen” biochemical profile similar to the corresponding normal cell of origin. Knowledge of the role of these enzymes has led to the pharmacological use of enzyme inhibitors for the specific treatment of lymphoid neoplasms. This review concerns the enzymatic make-up of normal and neoplastic lymphocytes and exploitation of this knowledge for the treatment of lymphomas. Special emphasis will be put on the clinical use of an ADA-inhibitor, deoxycoformycin.

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Abbreviations

ADA:

Adenosine deaminase

ALL:

Acutelymphocytic leukemia

CdA:

2′-Chloradeoxyadenosine

CLL:

Chronic lymphocytic leukemia

dATP:

Deoxyadenosine triphosphate

dCTP:

Deoxycytidine triphosphate

dGTP:

Deoxyguanosine triphosphate

5NT:

Ecto-5′-nucleotidase

PNP:

Purine nucleoside phosphorylase

SAH:

S-adenosylhomocysteine

SAM:

S-adenosyl-methionine

SCID:

Severe combined immunodeficiency disease

References

  1. Agarwal RP, Spector T, Parks RE jr (1977) Inhibition of adenosine deaminase by various inhibitors. Biochem Pharmacol 26:359–367

    Google Scholar 

  2. Barankiewicz J, Cohen A (1984) Evidence for distinct catabolic pathways of adenine ribonucleotides and deoxyribonucleotides in human T-lymphoblastoid cells. J Biol Chem 259:15178–15181

    Google Scholar 

  3. Barton R, Martinuik F, Hirschhorn R, Goldschneider I (1979) The distribution of adenosine deaminase among lymphocyte populations in the rat. J Immunol 122:216–220

    Google Scholar 

  4. Barton R, Martiniuk R, Hirschhorn R, Goldschneider I (1980) Inverse relationship between adenosine deaminase and purine nucleoside phosphorylase in rat lymphocyte populations. Cell Immunol 49:208–214

    Google Scholar 

  5. Biggar WD, Giblett ER, Ozere RL, Grover BD (1978) A new form of nucleoside phosphorylase deficiency in two brothers with defective T-cell function. J Pediatr 92:354–357

    Google Scholar 

  6. Blatt J, Reaman G, Poplack DG (1980) Biochemical markers in lymphoid malignancy. N Engl J Med 303:918–921

    Google Scholar 

  7. Blatt J, Bunn PA jr, Carney DD, Reaman G, Soprey P, Poplack DG (1982) Purine pathway enzymes in the circulating malignant cells of patients with cutaneous T-cell lymphoma. Br J Haematol 52:97–104

    Google Scholar 

  8. Carson DA, Kaye J, Seegmiller JE (1978) Differential sensitivity of human leukemic T-cell lines and B-cell lines to growth inhibition by deoxyadenosine. J Immunol 121:1726–1731

    Google Scholar 

  9. Carson DA, Wasson DB, Taetle R, Yu A (1983) Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood 62:737–743

    Google Scholar 

  10. Chechik BE, Schrader WP, Minowada J (1981) An immunomorphologic study of adenosine deaminase distribution in human thymus tissue, normal lymphocytes, and hematopoietic cell lines. J Immunol 126:3

    Google Scholar 

  11. Cohen A, Hirschhorn R, Horowitz SD, Rubenstein A, Polmar SH, Hong R, Martin DW (1978) Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci USA 75:472–476

    Google Scholar 

  12. Cohen A, Lee JWW, Gelfand EW (1983) Selective toxicity of deoxyguanosine and arabinosyl guanine for T-leukemic cells. Blood 61:660–666

    Google Scholar 

  13. Daenen S, Rojer RA, Smith JW, Halie MR, Nieweg HO (1984) Successful chemotherapy with deoxycoformycin in adult T-cell lymphoma-leukaemia. Br J Haematol 58:723–727

    Google Scholar 

  14. DeFouw NJ, Ma DDF, Michalevicz R, Gray DA, Hoffbrand AV (1984) Differential cytotoxicity of deoxyguanosine and 8-aminoguanosine for human leukemic cell lines and normal bone marrow progenitor cells. Hematol Oncol 2:189–198

    Google Scholar 

  15. Demeocq F, Viallard JL, Boumsell L, Richard Y, Chassagne J, Plagne R, Lemerle J, Bernard A (1982) The correlation of adenosine deaminase and purine nucleoside phosphorylase activities in human lymphocyte subpopulations and in various lymphoid malignancies. Leuk Res 6:211–220

    Google Scholar 

  16. Dornand J, Barbanel AM, Bonnafous JC (1984) AMP-deaminase and cytosolic 5′nucleotidase involvement in lymphocyte maturation. In: Peeters H (ed). Protides of the biological fluids. Pergamon Press, London, pp 663–666

    Google Scholar 

  17. Edwards NL, Cassidy JT, Fox IH (1980) Lymphocyte 5′-nucleotidase deficiency in hypogammaglobulinemia: clinical characteristics. Clin Immunol Immunopathol 17:76–82

    Google Scholar 

  18. Eisenhauer E, Johnston JB, Barr R, Feldmann L, Maksymiuk A, Scott G, Sutton D, Venner P, Walde D, Zaentz D (1986) 2′-Deoxycoformycin in hairy cell leukemia (Abstract). Fifth NCI-EORTC symposium on new drugs in cancer therapy, Amsterdam

  19. El Agnaf MR, Ennis KE, Morris TCM, Robertson JH, Markey G, Alexander HD (1986) Successful remission induction with deoxycoformycin in elderly patients with T-helper prolymphocytic leukaemia. Br J Haematol 63:93–104

    Google Scholar 

  20. Foon KA, Nakano GM, Koller CA, Longo DL, Steis RG (1986) Response to 2′-deoxycoformycin after failure of interferon-alpha in non-splenectomized patients with hairy cell leukemia. Blood 68:297–300

    Google Scholar 

  21. Gan TE, Finch PO, Brumley JL, Hallam LJ, Van der Weyden MB (1984) Pyrimidine and purine enzyme activities in non-Hodgkin's lymphoma. Correlation with histological status and survival. Eur J Clin Oncol 20:361–368

    Google Scholar 

  22. Ganeshaguru K, Lee N, Llewellin P, Prentice HG, Hoffbrand AV, Catovsky D, Habeshaw JA, Robinson J, Greaves MF (1981) Adenosine deaminase concentrations in leukemia and lymphoma: a relation to cell phenotypes. Leuk Res 5:215–222

    Google Scholar 

  23. Gelfand EW, Lee JJ, Dosch HM (1979) Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function. Proc Natl Acad Sci USA 76:1998–2009

    Google Scholar 

  24. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ (1972) Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet II:1067–1069

    Google Scholar 

  25. Giblett ER, Ammann AJ, Wara DW, Sandman R, Diamond LK (1975) Nucleoside-phosphorylase deficiency in a child with severely defective T-cell immunity and normal B-cell immunity. Lancet I:1010–1013

    Google Scholar 

  26. Grever MR, Siaw MFE, Jacob WF, Neidhart JA, Miser JS, Coleman MS, Hutton JJ, Balcerzak SP (1981) The biochemical and clinical consequences of 2′-deoxycoformycin in refractory lymphoproliferative malignancy. Blood 57:406–417

    Google Scholar 

  27. Grever MR, Bisaccia E, Scarborough DA, Metz EN, Neidhart JA (1983) An investigation of 2′-deoxycoformycin in the treatment of cutaneous T-cell lymphoma. Blood 61:279–282

    Google Scholar 

  28. Grever MR, Leiby JM, Kraut EH, Wilson HE, Neidhart JA, Wall RL, Balcerzak SP (1985) Low-dose deoxycoformycin in lymphoid malignancy. J Clin Oncol 3:1196–1201

    Google Scholar 

  29. Hershfield MS, Kredich NM (1980) Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine on growth, S-adenosyl-homocysteine hydrolase inactivation, and dATP accumulation. Proc Natl Acad Sci USA 77:4292–4296

    Google Scholar 

  30. Hershfield MS, Kredich NM, Koller CA, Mitchell BS, Kurtzberg J, Kinney TR, Faletta JM (1983) S-Adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia with 2′-deoxycoformycin alone and in combination with 9-β-d-arabinofuranosyladenine. Cancer Res 43:3451–3458

    Google Scholar 

  31. Hershfield MS, Buckley RH, Greenberg ML, Melton AL, Schiff R, Hatem C, Kurtzberg J, Markert ML, Kobayashi RH, Kobayashi AL, Abuchowsky A (1987) Treatment of adenosine deaminase deficiency with polyethylene glycolmodified adenosine deaminase. N Engl J Med 316:589–596

    Google Scholar 

  32. Ho AD, Ma DDF, Price G, Hoffbrand AV (1983) Effect of thymosin and phorbol ester on purine metabolic enzymes and cell surface phenotype in a malignant T-cell line (Molt-3). Leuk Res 7:779–786

    Google Scholar 

  33. Ho AD, Stehle B (1985) Characterization of immature T-cell subpopulations in neonatal blood (Letter). Blood 66:507–508

    Google Scholar 

  34. Ho AD, Ma DDF, Price G, Hunstein W, Hoffbrand AV (1983) Biochemical and immunological differentiation of human thymocytes induced by thymic hormones. Immunology 50:471–476

    Google Scholar 

  35. Ho AD, Stehle B, Dietz G, Hunstein W, Hoffbrand AV (1985) Terminal differentiation of cord blood lymphocytes induced by thymosin fraction 5 and thymosin alpha 1. Scand J Immunol 21:221–225

    Google Scholar 

  36. Ho AD, Dörken B, Ma DDF, Pezzutto A, Hunstein W, Hoffbrand AV (1986) Purine degradative enzymes and immunological phenotypes in chronic B-lymphocytic leukemia: indications that leukaemic immunocytoma is a separate entity. Br J Haematol 62:545–555

    Google Scholar 

  37. Ho AD, Dietz G, Trede I, Schwartz R, Hoffbrand AV, Hunstein W (1986) Enzymes of purine metabolism in hairy cell leukemia. Cancer 58:96–99

    Google Scholar 

  38. Ho AD, Ganeshaguru K, Hunstein W, Hoffbrand AV (1986) Biochemical parameters in vitro and in vivo after treatment with deoxycoformycin in T-cell leukemia/lymphoma. Blood 38 (Suppl 1):224

    Google Scholar 

  39. Ho AD, Knauf W, Ganeshaguru K, Hunstein W, Hoffbrand AV (1987) Purine degradative enzymes in circulating malignant cells of patients with chronic B cell neoplasia. Hematol Oncol 5:9–17

    Google Scholar 

  40. Ho AD, Kuse R, Prümmer O, Porzsolt F, Hunstein W (1987) 2′-Deoxycoformycin (Pentostatin) in hairy cell leukemia: Response in patients refractory to interferon-alpha. Klin Wochenschr 65:975–979

    Google Scholar 

  41. Johnson SM, North ME, Asherson GL, Allsop J, Watts RNE, Webster ADB (1977) Lymphocyte purine 5-nucleotidase deficiency in primary hypogammaglobulinemia. Lancet I:168–170

    Google Scholar 

  42. Kazmers IS, Mitchell BS, Dadonna PE, Wotring LL, Townsend LB, Kelley WN (1981) Inhibition of purine nucleoside phosphorylase by 8-aminoguanosine: Selective toxicity for T-lymphoblasts. Science 214:1137–1139

    Google Scholar 

  43. Kefford RF, Fox RM (1982) Purine deoxynucleoside toxicity in nondividing human lymphoid cells. Cancer Res 42:324–330

    Google Scholar 

  44. Kramers MTC, Catovsky D, Cherchi M, Galton DAG (1977) 5′-Nucleotidase in cord blood lymphocytes. Leuk Res 1:279–281

    Google Scholar 

  45. Kraut EH, Bouroncle BA, Grever MR (1986) Low dose deoxycoformycin in the treatment of hairy cell leukemia. Blood 68:1119–1122

    Google Scholar 

  46. La Mantia K, Conklyn M, Quagliata F, Silber R (1977) Lymphocyte 5′-nucleotidase: Absence of detectable protein in chronic lymphocytic leukemia. Blood 50:683–688

    Google Scholar 

  47. Lennert K (1978) Malignant lymphomas other than Hodgkin's disease. Springer, Berlin Heidelberg New York

    Google Scholar 

  48. Ma DDF, Sylwestrowicz TA, Granger S, Massaia M, Franks R, Janossy G, Hoffbrand AV (1982) Distribution of terminal deoxynucleotidyl transferase and purine degradative and synthetic enzymes in subpopulations of human thymocytes. J Immunol 129:1430–1435

    Google Scholar 

  49. Ma DDF, Massaia M, Sylwestrowicz A, Price G, Hoffbrand AV (1983) Comparison of purine degradative enzymes and terminal deoxynucleotidyl transferase in T-cell leukaemias an in normal thymic and post-thymic T-cells. Br J Haematol 54:451–457

    Google Scholar 

  50. Ma DDF, Sylwestrowicz T, Janossy G, Hoffbrand AV (1983) The role of purine metabolic enzymes and terminal deoxynucleotidyl transferase in intrathymic T-cell differentiation. Immunol Today 4:65–68

    Google Scholar 

  51. Major PP, Agarwal RP, Kufe DW (1981) Clinical pharmacology of deoxycoformycin. Blood 58:91–96

    Google Scholar 

  52. Massaia M, Ma DDF, Sylwestrowicz TA, Tidman N, Price G, Janossy G, Hoffbrand AV (1982) Enzymes of purine metabolism in human peripheral lymphocyte subpopulations. Clin Exp Immunol 50:148–154

    Google Scholar 

  53. Massaia M, Ma DDF, Boccadoro M, Golzio F, Gavarotti P, Dianzani U, Pileri A (1985) Decreased ecto-5′-nucleotidase activity of peripheral blood lymphocytes in human monoclonal gammopathies: correlation with tumor cell kinetics. Blood 65:530–534

    Google Scholar 

  54. Mills GC, Schmalsties FC, Trimmer KB, Goldman AS, Goldblum RM (1976) Purine metabolism in adenosine deaminase deficiency. Proc Natl Acad Sci USA 73:2867–2871

    Google Scholar 

  55. Mitchell BS, Koller CA, Heyn R (1980) Inhibition of adenosine deaminase activity results in cytotoxicity to T-lymphoblasts in vivo. Blood 56:556–562

    Google Scholar 

  56. Poplack DG, Sallan SE, Rivera G, Holcenberg J, Murphy SB, Blatt J, Lipton JM, Venner P, Glaubiger DL, Ungerleider R, Johns D (1981) Phase I-study of 2′-deoxycoformycin in acute lymphoblastic leukemia. Cancer Res 41:3343–3346

    Google Scholar 

  57. Prentice HG, Ganeshaguru K, Bradstock KF, Goldstone AH, Smyth JF, Wonke B, Janossy G, Hoffbrand AV (1980) Remission induction with adenosine deaminase inhibitor 2′-deoxycoformycin in thy-lymphoblastic leukaemia. Lancet 26:170–172

    Google Scholar 

  58. Prentice HG, Lee N, Blacklock H, Smyth JF, Russell NH, Ganeshaguru K, Piga A, Hoffbrand AV (1981) Therapeutic selectivity of and prediction of response to 2′-deoxycoformycin in acute leukaemia. Lancet 5:1250–1253

    Google Scholar 

  59. Quagliata F, Faig D, Conklyn M, Silber R (1974) Studies on the lymphocyte 5′-nucleotidase in chronic lymphocytic leukemia, infectious mononucleosis, normal subpopulations and phytohemagglutinin-stimulated cells. Cancer Res 34:3197–3202

    Google Scholar 

  60. Ratech H, Borer WZ, Winberg CD, Rappaport H (1985) Enzymatic differences between chronic lymphocytic leukemia and prolymphocytic leukemia. Leuk Res 9:1271–1275

    Google Scholar 

  61. Reaman GH, Levin N, Muchmore A, Holiman J, Poplack DG (1979) Diminished lymphoblast 5′-nucleotidase activity in acute lymphoblastic leukemia with T-cell characteristics. N Engl J Med 300:1374

    Google Scholar 

  62. Reaman GH, Blatt J, Poplack DG (1981) Lymphoblast purine pathway enzymes in B-cell acute lymphoblastic leukemia. Blood 58:330

    Google Scholar 

  63. Reinherz EL, Kung PC, Goldstein G, Levey RH, Schlossman SF (1980) Discrete stages of human intrathymic differentiation: Analysis of normal thymocytes and leukemic lymphoblasts of T-lineage. Proc Natl Acad Sci USA 77:1588–1595

    Google Scholar 

  64. Rowe M, De Gast CG, Platts-Mills TAE, Asherson GL, Webster ADB, Johnson SM (1979) 5′-Nucleotidase of B- and T-lymphocytes isolated from human peripheral blood. Clin Exp Immunol 36:97–101

    Google Scholar 

  65. Rowe M, De Gast GC, Platts-Mills AE, Asherson GL, Webster ADB, Johnson SM (1980) Lymphocyte 5′-nucleotidase in primary hypogammaglobulinaemia and cord blood. Clin Exp Immunol 39:337–343

    Google Scholar 

  66. Russell NH, Prentice HG, Lee N, Piga A, Ganeshaguru K, Smyth JF, Hoffbrand AV (1981) Studies on the biochemical sequelae of therapy in thy-acute lymphoblastic leukemia with the adenosine deaminase inhibitor 2′-deoxycoformycin. Br J Haematol 49:1–9

    Google Scholar 

  67. Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA (1985) Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 75:377–383

    Google Scholar 

  68. Siaw MFE, Coleman MS (1984) In vitro metabolism of deoxycoformycin in human T-lymphoblastoid cells. J Biol Chem 259:9426–9433

    Google Scholar 

  69. Smyth JF, Harrap KR (1975) Adenosine deaminase activity in leukemia. Br J Cancer 31:544–549

    Google Scholar 

  70. Smyth JF, Poplack DG, Holiman BJ, Levinthal BG, Yarbro G (1978) Correlation of adenosine deaminase activity with cell surface markers in acute lymphoblastic leukemia. J Clin Invest 62:710–712

    Google Scholar 

  71. Smyth JF, Paine RM, Jackman AL, Harrap KR, Chassin MM, Adamson RH, Johns DG (1980) The clinical pharmacology of the adenosine deaminase inhibitor 2′-deoxycoformycin. Cancer Chemother Pharmacol 5:93–101

    Google Scholar 

  72. Spiers ASD, Ruckdeschel JC, Horton J (1984) Effectiveness of Pentostatin (2′-deoxycoformycin) in refractory lymphoid neoplasms. Scand J Haematol 32:130–134

    Google Scholar 

  73. Spiers ASD, Moore D, Cassileth PA, Harrington DP, Cummings FJ, Neiman RS, Bennett JM, O'Connell MJ (1987) Remissions in hairy cell leukemia with pentostatin (2′-deoxycoformycin). N Engl J Med 316:825–820

    Google Scholar 

  74. Sylwestrowicz TA, Ma DDF, Murphey PP, Massaia M, Prentice HG, Hoffbrand AV, Greaves MG (1982) 5′-Nucleotidase, adenosine deaminase and purine nucleoside phosphorylase activities in acute leukaemia. Leuk Res 6:475–482

    Google Scholar 

  75. Thompson LF, Boss GR, Spiegelberg HL, Jansen IV, O'Connor RD, Waldmann TA, Hamburger RN, Seegmiller JE (1979) Ecto-5′-nucleotidase activity in T- and B-lymphocytes from normal subjects and patients with congenital X-linked agammaglobulinemia. J Immunol 123:2475–2477

    Google Scholar 

  76. Thompson F, Saxon A, O'Connor R, Fox RI (1983) Ecto-5′-nucleotidase activity in human T-cell subsets. Decreased numbers of ecto-5′-nucleotidase positive cells from both OKT4+ and OKT8+ cells in patients with hypogammaglobulinemia. J Clin Invest 71:892–899

    Google Scholar 

  77. Tidman N, Janossy G, Bodger M, Granger S, Kung PC, Goldstein G (1981) Delineation of human thymocyte differentiation pathways utilizing double-staining techniques with monoclonal antibodies. Clin Exp Immunol 45:457–467

    Google Scholar 

  78. Tung R, Silber R, Quagliara F, Conklyn M, Gottesman J, Hirschhorn R (1976) Adenosine deaminase activity in chronic lymphocytic leukemia: Relationship to B- and T-cell subpopulations. J Clin Invest 57:756–761

    Google Scholar 

  79. Van Laarhoven JPRM, De Gast GC, Spierenburg GTH, De Bruyn CHMM (1983) Enzymological studies in chronic lymphocytic leukemia. Leuk Res 7:261–267

    Google Scholar 

  80. Van Laarhoven JPRM, Spierenburg GTH, Bakkeren JAJM, Schouten TJ, De Bruyn CHMM, Geerts SJ, Schretlen EDAM (1983) Purine metabolism in childhood acute lymphoblastic leukemia: Biochemical markers for diagnosis and chemotherapy. Leuk Res 7:407–420

    Google Scholar 

  81. Veerman AJP, Hogeman PHG, Van Zantwijk CH, Bezember PD (1985) Prognostic value of 5′-nucleotidase in acute lymphoblastic leukemia with the common-all phenotype. Leuk Res 9:1227–1229

    Google Scholar 

  82. Vertongen F, Cauchie C, Courtois P, Fondu P, Mandelbaum IM (1984) Enzymes of purine metabolism in B-chronic lymphocytic leukemia. Am J Hematol 17:61–70

    Google Scholar 

  83. Woo PWK, Dion HW, Lange SM, Dahl LF, Durham LJ (1974) A novel adenosine and araA deaminase inhibitor, (R)-3-(2-deoxy-β-d-erythro-pento-furanosyl)-3,6,7,8-tetrahydroimidazo (4,5-d) (1,3) diazepin-8-ol. J Heterocyclic Chem 11:641–643

    Google Scholar 

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  1. Abteilung für Innere Medizin V und Poliklinik, Universität Heidelberg, Germany

    A. D. Ho

  2. Department of Haematology, Royal Free Hospital and School of Medicine, London

    K. Ganeshaguru

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  1. A. D. Ho
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Dedicated to Professor Werner Hunstein on the occasion of his 60th birthday

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Ho, A.D., Ganeshaguru, K. Enzymes of purine metabolism in lymphoid neoplasms, clinical relevance for treatment with enzyme inhibitors. Klin Wochenschr 66, 467–474 (1988). https://doi.org/10.1007/BF01876167

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