The clinical horizon of deoxycoformycin

  • Peter J. O’Dwyer
  • Brian Leyland-Jones
  • Daniel F. Hoth
Part of the Cancer Treatment and Research book series (CTAR, volume 36)


Antimetabolites have enjoyed limited success as antitumor agents. Those that are clinically useful — methotrexate, cytosine arabinoside, and 5-fluorouracil, for example, have multiple sites of action and may have several mechanisms by which they are lethal to susceptible cells. On the other hand, several antimetabolites with a single, well-defined mechanism of cytotoxicity have been evaluated in clinical trials. PALA, for example, is a potent inhibitor of aspartate transcarbamylase. Pyrazofurin inhibits orotidylate synthetase irreversibly; both arrest de novo pyrimidine biosynthesis and are cytotoxic to several tumor models in vitro and in vivo. However, in extensive phase II clinical testing by the NCI in the past ten years, neither showed any reproducible activity.


Adenosine Deaminase Hairy Cell Leukemia Purine Nucleoside Phosphorylase Adenosine Deaminase Activity Adenine Arabinoside 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weber G: Biochemical strategy of cancer cells and the design of chemotherapy: GHA Clowes Memorial Lectures. Cancer Res 43:3466–3492, 1983.PubMedGoogle Scholar
  2. 2.
    O’Dwyer PJ, Marsoni S, Alonso MT, and Wittes RE: 2’-deoxycoformycin: Summary and future directions. Cancer Treat Symp 2:1–5, 1984.Google Scholar
  3. 3.
    Van der Weyden MB and Kelley WN: Human adenosine deaminase: Distribution and properties. J Biol Chem 251:5448–5456, 1976.PubMedGoogle Scholar
  4. 4.
    Smyth JF, Paine RM, Jackman AL, Harrap KR, Chassin MM, Adamson RH, and Johns DG: The clinical pharmacology of the adenosine deaminase inhibitor 2’-deoxycoformycin. Cancer Chemother Pharmacol 5:93–101, 1980.PubMedGoogle Scholar
  5. 5.
    Ganeshaguru K, Lee N, Llewellin P, Prentice HG, Hoffbrand AV, Catovsky D, Habeshaw JA, Robinson J, and Greaves MF: Adenosine deminase concentrations in leukemia and lymphoma: Relation to cell phenotypes. Leuk Res 5:215–222, 1981.PubMedGoogle Scholar
  6. 6.
    Smyth JF and Harrap KR: Adenosine deaminase activity in leukemia. Br J Cancer 31:544–549, 1975.PubMedGoogle Scholar
  7. 7.
    Giblett ER, Anderson JE, Cohen F, Pollara B, and Meuwissen HJ: Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2:1067–1069, 1972.PubMedGoogle Scholar
  8. 8.
    Meuwissen HJ, Pollara B, and Pickering RJ: Combined immunodeficiency associated with adenosine deaminase deficiency. J Pediatr 86:169–181, 1975.PubMedGoogle Scholar
  9. 9.
    Coleman MS, Donofrio J, Hutton J, Hahn L, Daoud A, Lampkin B, and Dyminiski J: Identification and quantitation of adenine deoxynucleotides in erythrocytes of a patient with adenosine deaminase deficiency. J Biol Chem 253:1619–1626, 1978.PubMedGoogle Scholar
  10. 10.
    Cohen A, Hirshhorn R, Horowitz SD, Rubinstein A, Polmar SH, Hong R, and Martin DW: Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci USA 75:472–476, 1978.PubMedGoogle Scholar
  11. 11.
    Donofrio J, Coleman MS, Hutton JJ, Daoud A, Lampkin B, and Dyminski J: Overproduction of adenine deoxynucleosides and deoxynucleotides in adenosine deaminase deficiency with severe combined immunodeficiency disease. J Clin Invest 62:884–887, 1978.PubMedGoogle Scholar
  12. 12.
    Mitchell BS and Kelley WN. Purinogenic immunodeficiency disease: Clinical features and molecular mechanisms. Ann Int Med 92:826–831, 1980.PubMedGoogle Scholar
  13. 13.
    Agarwal RP: Inhibitors of adenosine deaminase. Pharmac Ther 17:399–429, 1982.Google Scholar
  14. 14.
    Niida T, Niwa T, Tsuruoka T, Ezaki N, Shomura T, and Umezawa H: Isolation and characteristics of coformycin. Reported at 153rd Scientific Meeting of Japan Antibiotics Research Association, 1967.Google Scholar
  15. 15.
    Sawa T, Fukagawa Y, Homma I, Takeuchi T, and Umezawa H: Mode of inhibition of coformycin on adenosine deaminase. J Antibiot (Tokyo), Ser A 20:227–231, 1967.PubMedGoogle Scholar
  16. 16.
    Nakamura H, Koyama G, Iitaka Y, Ohno M, Yagisawa N, Kondo S, Maeda K, and Umezawa H: Structure of coformycin, an unusual nucleoside of microbial origin. J Am Chem Soc 96:4327–4328, 1974.PubMedGoogle Scholar
  17. 17.
    Cha S: Tight-binding inhibitors: I. Kinetic behavior. Biochem Pharmacol 24:2177–2185, 1975.PubMedGoogle Scholar
  18. 18.
    Cha S: Tight-binding inhibitors: III. A new approach for the determination of competition between tight-binding inhibitors and substrates — inhibition of adenosine deaminase by coformycin. Biochem Pharmacol 25:2695–2702, 1976.PubMedGoogle Scholar
  19. 19.
    Woo PWK, Dion HW, Lange SM, Dahl LF, and Durham LJ: A novel adenosine and ara-A deaminase inhibitor, (R)-3-(2-deoxy- p!-D-erythropento-furanosyl)-3–6,7,8-tetrahydroimidazo (4,5-d) (1,3) diazepin-8-ol. J Heterocyclic Chem 11:641–643, 1974.Google Scholar
  20. 20.
    Agarwal RP, Spector T, and Parks RE: Tight-binding inhibitors: IV. Inhibition of adenosine deaminases by various inhibitors. Biochem Pharmacol 26:359–367, 1977.PubMedGoogle Scholar
  21. 21.
    Constine J, Glazer RI, and Johns DG: Adenosine deaminase inhibitors: Differential effects on multiple forms of adenosine deaminase. Biochem Biophys Res Commun 85:198–202, 1978.PubMedGoogle Scholar
  22. 22.
    Schaeffer JH and Schwender DF. Enzyme inhibitors XXVI. Bridging the hydrophobic and hydrophilic regions on adenosine deaminase with some 9-(2-hydroxy-3-alkyl) adenines. J Med Chem 17:6–8, 1974.PubMedGoogle Scholar
  23. 23.
    Agarwal RP, Cha S, Crabtree GN, and Parks RE: In: Chemistry and Biology of Nucleosides and Nucleotides. RE Harmon, RK Robins, and LB Townsend (eds). New York: Academic Press, p 159–197, 1978.Google Scholar
  24. 24.
    Glazer RI: Adenosine deaminase inhibitors: Their role in chemotherapy and immunosuppression. Cancer Chemother Pharmacol 4:227–235, 1980.PubMedGoogle Scholar
  25. 25.
    Henderson JF and Smith CM: Mechanisms of deoxycoformycin toxicity in vivo. In: Nucleosides and Cancer Treatment. MHN Tattersall and RM Fox (eds). Orlando: Academic Press, p 208–217, 1981.Google Scholar
  26. 26.
    Mills GC, Schmalsties FC, Trimmer KB, Goldman AS, and Goldblum RM: Purine metabolism in adenosine deaminase deficiency. Proc Natl Acad Sci 73:2867–2871, 1976.PubMedGoogle Scholar
  27. 27.
    Siaw MFE, Mitchell BS, Koller CA, Coleman MS, and Hutton JJ: ATP depletion as a consequence of adenosine deaminase inhibition in man. Proc Natl Acad Sci 77:6157–6161, 1980.PubMedGoogle Scholar
  28. 28.
    Barankiewicz J and Cohen A. Evidence for distinct catabolic pathways of adenine ribonucleotides and deoxyribonucleotides in human T-lymphoblastoid cells. J Biol Chem 259:15178–15181, 1984.PubMedGoogle Scholar
  29. 29.
    Grever MR, Siaw MFE, Jacob WF, Neidhart JA, Miser JS, Coleman MS, Hutton JJ, and Balcerzak SP. The biochemical and clinical consequences of 2’deoxycoformycin in refractory lymphoproliferative malignancy. Blood 57:406–417, 1981.PubMedGoogle Scholar
  30. 30.
    Kefford RF and Fox RM: Deoxycoformycin-induced response in chronic lymphocytic leukemia: Deoxyadenosine toxicity in nonreplicating lymphocytes. Br J Haematol 50:627–636, 1982.PubMedGoogle Scholar
  31. 31.
    Koller CA, Mitchell BS, Grever MR, Mejias E, Malspeis L, and Metz EN: Treatment of acute lymphoblastic leukemia with 2’-deoxycoformycin: Clinical and biochemical consequences of adenosine deaminase inhibition. Cancer Treat Rep 63:1949–1952, 1979.PubMedGoogle Scholar
  32. 32.
    Yu AL, Bakay B, Kung FH, and Nyhan WL: Effect of 2’-deoxycoformycin on the metabolism of purines and the survival of malignant cells in a patient with T-cell leukemia. Cancer Res 41:2677–2682, 1981.PubMedGoogle Scholar
  33. 33.
    Carson DA, Kaye J, and Seegmiller JE: Lymphospecific toxicity in adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency: Possible role of nucleoside kinase(s). Proc Natl Acad Sci 74:5677–5681, 1977.PubMedGoogle Scholar
  34. 34.
    Lowe JK, Gowans B, and Brox L: Deoxyadenosine metabolism and toxicity in cultured L5178Y cells. Cancer Res 36:1481–1485, 1976.Google Scholar
  35. 35.
    Ullman B, Gudas LJ, Cohen A, and Martin DW: Deoxyadenosine metabolism and cytotoxicity in cultured mouse T lymphoma cells: A model for immunodeficiency disease. Cell 4:365–375, 1978.Google Scholar
  36. 36.
    Carson DA, Kaye J, and Seegmiller JE: Differential sensitivity of human leukemic T-cell lines and B-cell lines to growth inhibition by deoxyadenosine. J Immunol 121:1726–1731, 1978.PubMedGoogle Scholar
  37. 37.
    Mitchell BS, Mejias E, Daddona PE, and Kelley WN: Purinogenic immunodeficiency disease — selective toxicity of deoxyribonucleosides for T-cells. Proc Natl Acad Sci 75:5011–5014, 1978.PubMedGoogle Scholar
  38. 38.
    Gelfand EW, Lee JJ, and Dosch HM: Selective toxicity of purine deoxynucleosides for human lymphocyte growth and function. Proc Natl Acad Sci 76:1998–2002, 1979.PubMedGoogle Scholar
  39. 39.
    Mitchell BS, Koller CA, and Heyn R: Inhibition of adenosine deaminase results in cytotoxicity to T-lymphoblasts in vivo. Blood 56:556–559, 1980.PubMedGoogle Scholar
  40. 40.
    Kefford RF and Fox RM: Purine deoxyribonucleoside toxicity in nondividing human lymphoid cells. Cancer Res 42:324–330, 1982.PubMedGoogle Scholar
  41. 41.
    Earle MF and Glazer RI. 2’deoxycoformycin toxicity in murine spleen lymphocytes. Mol Pharmacol 23:165–170, 1983.Google Scholar
  42. 42.
    Carson DA, Wasson DB, Lakow E, and Kamatani N: Possible metabolic basis for the different immunodeficient states associated with genetic deficiencies of adenosine deaminase and purine nucleoside phosphorylase. Proc Natl Acad Sci 79:3848–3852, 1982.PubMedGoogle Scholar
  43. 43.
    Fox RM, Kefford RF, Tripp EH, and Taylor IW: G-phase arrest of cultured human leukemic T-cells induced by deoxyadenosine. Cancer Res 41:5141–5150, 1981.PubMedGoogle Scholar
  44. 44.
    Fox RM, Tripp EH, and Taylor IW: Analytical DNA flow cytometric analysis of deoxyadenosine toxicity in cultured human leukemic lymphoblasts. Mol Pharmacol 26:388–394, 1984.PubMedGoogle Scholar
  45. 45.
    Brox L, Ng A, Pollock E, and Belch A: DNA strand breaks induced in human T-lymphocytes by the combination of deoxyadenosine and deoxycoformycin. Cancer Res 44:934–937, 1984.PubMedGoogle Scholar
  46. 46.
    Brox L, Hunting D, and Belch A: Aphidicolin and deoxycoformycin cause DNA breaks and cell death in unstimulated human lymphocytes. Biochem Biophys Res Commun 120:959–963, 1984.PubMedGoogle Scholar
  47. 47.
    Berger NA, Sikorski GW, Petzold SJ, and Kurohara KK: Association of poly(adenosine diphosphoribose) synthesis with DNA damage and repair in normal human lymphocytes. J Clin Invest 63:1164–1171, 1979.PubMedGoogle Scholar
  48. 48.
    Petzold SJ, Booth BA, Leimbach GA, and Berger NA: Purification and properties of poly(ADP-ribose) polymerase from lamb thymus. Biochemistry 20:7075–7081, 1981.PubMedGoogle Scholar
  49. 49.
    Seto S, Carrera CJ, Kubota M, Wasson DB, and Carson DA: Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest 75:377–383, 1985.PubMedGoogle Scholar
  50. 50.
    Yu J, Matsumoto SS, and Yu AL: Inhibition of transcription as a mechanism of lym-phocytotoxicity induced by deoxyadenosine and 2’-deoxycoformycin. Cancer Treat Symp 2:75–79, 1984.Google Scholar
  51. 51.
    Matsumoto SS, Yu J, and Yu AL: Inhibition of RNA synthesis in resting lymphocytes by deoxyadenosine plus deoxycoformycin. J. Immunol 131:2762–2766, 1983.PubMedGoogle Scholar
  52. 52.
    Hershfield MS and Kredich NM: S-adenosylhomocysteine hydrolase is an adenosine-binding protein, a target for adenosine toxicity. Science 202:757–760, 1978.PubMedGoogle Scholar
  53. 53.
    Hershfield MS: Apparent suicide inactivation of human lymphoblast S-adenosylhomocysteine hydrolase by 2’-deoxyadenosine and adenine arabinoside: A basis for direct toxic effects of analogs of adenosine. J Biol Chem 254:22–25, 1979.PubMedGoogle Scholar
  54. 54.
    Chiang PK, Guranowski A, and Segall JE: Irreversible inhibition of S-adenosylhomocysteine hydrolase by nucleoside analogs. Arch Biochem Biophys 207:175–184, 1981.PubMedGoogle Scholar
  55. 55.
    Helland S and Ueland PM: Inactivation of S-adenosylhomocysteine hydrolase by 9-(3-D-arabinofuranosyladenine in intact cells. Cancer Res 42:1130–1136, 1982.PubMedGoogle Scholar
  56. 56.
    Case CE, Seiner M, Ferguson PJ, and Phillips JR: Effects of 2’-deoxyadenosine, 9-£-D-arabinofuranosyladenine, and related compounds on S-adenosyl-L-homocysteine hydrolase activity in synchronous and synchronous cultured cells. Cancer Res 42:4991–4998, 1982.Google Scholar
  57. 57.
    Helland S and Ueland PM: Effect of 2’deoxycoformycin infusion on S-adenosylhomocysteine hydrolase and the amount of S-adenosylhomocysteine and related compounds in tissues of mice. Cancer Res 43:4142–4147, 1983.PubMedGoogle Scholar
  58. 58.
    Chiang PK and Cantoni. GL: Perturbation of biochemical transmethylation by 3-deazaadenosine in vivo. Biochem Pharamacol 28:1897–1902, 1979.Google Scholar
  59. 59.
    Kredich NM and Hershfield MS: S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin. Proc Natl Acad Sci 76:2450–2454, 1979.PubMedGoogle Scholar
  60. 60.
    Hershfield MS and Kredich NM: Resistance of an adenosine kinase-deficient human lymphoblastoid cell line to effects of deoxyadenosine or growth, S-adenosylhomocysteine hydrolase inactivation, and dATP accumulation. Proc Natl Acad Sci 77:4292–4296, 1980.PubMedGoogle Scholar
  61. 61.
    Hershfield MS, Kredich NM, Ownby H, and Buckley R: In vivo inactivation of adenosyl-homocysteine hydrolase by 2’deoxycoformycin in adenosine deaminase deficient patients. J Clin Invest 63:807–811, 1979.PubMedGoogle Scholar
  62. 62.
    Hershfield MS, Kredich NM, Koller CA, Mitchell BS, Kurtzberg J, Kinney TR, and Falletta JM, S-adenosylhomocysteine catabolism and basis for acquired resistance during treatment of T-cell acute lymphoblastic leukemia and 2’-deoxycoformycin alone and in combination with 9-beta-D-arabinofuranosyladenine. Cancer Res 43:3451–3458, 1983.PubMedGoogle Scholar
  63. 63.
    Kefford RF, Helmer MA, and Fox RM. S-adenosylhomocysteine hydrolase inhibition in deoxyadenosine-treated human T-lymphoblasts and resting peripheral blood lymphocytes. Cancer Res 42:3822–3827, 1982.PubMedGoogle Scholar
  64. 64.
    Lee N, Russell N, Ganeshaguru K, Jackson BFA, Piga A, Prentice HG, Foa R, and Hoffbrand AV. Mechanisms of deoxyadenosine toxicity in human lymphoid cells in vitro: Relevance to the therapeutic use of inhibitors of adenosine deaminase. Brit J Haematol 56:107–119, 1984.Google Scholar
  65. 65.
    Smith CM, Belch A, and Henderson JF: Hemolysis in mice treated with deoxycoformycin, an inhibitor of adenosine deaminase. Biochem Pharmacol 29:1209–1210, 1980.PubMedGoogle Scholar
  66. 66.
    Koller CA and Mitchell BS: Alterations in erythrocyte adenine nucleotide pools resulting from 2’deoxycoformycin therapy. Cancer Res 43:1409–1414, 1983.PubMedGoogle Scholar
  67. 67.
    Chen S-H, Ochs HD, Scott CR, Giblett ER, and Tingle AJ: Adenosine deaminase deficiency: Disappearance of adenosine deoxynucleotides from a patient’s erythrocytes after successful marrow transplantation. J Clin Invest 62:1386–1389, 1978.PubMedGoogle Scholar
  68. 68.
    Koller CA, Orringer EP, Berkowitz LR, and Mulhern AT: Role of glycolysis in deoxyadenosine induced ATP depletion and dATP accumulation in red cells. In: The Red Cell: Sixth Ann Arbor Conference. Alan R. Liss, New York: Inc, p 227–239, 1984.Google Scholar
  69. 69.
    Siaw MFE and Coleman MS: Identification and quantitation of 2’deoxycoformycin nucleotides in human lymphoblastoid cells. Cancer Treat Symp 2:37–41, 1984.Google Scholar
  70. 70.
    Siaw MFE and Coleman MS. In vitro metabolism of deoxycoformycin in human T-lymphoblastoid cells. Phosphorylation of deoxycoformycin and incorporation into cellular DNA. J Biol Chem 259:9426–9433, 1984.PubMedGoogle Scholar
  71. 71.
    Duncan GS, Wolberg G, Schmitges CJ, Deeprose RD, and Zimmerman TP: Inhibition of lymphocyte-mediated cytolysis and cyclic AMP phosphodiesterase by erythro-9-(2-hyroxy-3-nonly) adenosine. J Immunopharmacol 4:79–100, 1982.PubMedGoogle Scholar
  72. 72.
    Cande WZ: Inhibition of spindle elongation in permeabilized mitotic cells by erythro-9-[3-(2-hydroxynonyl)] adenine. Nature 295:700–701, 1982.PubMedGoogle Scholar
  73. 73.
    North TW and Cohen SS: Erythro-9-(2-hydroxy-3-nonyl) adenine as a specific inhibitor of herpes simplex virus replication in the presence and absence of adenosine analogues. Proc Natl Acad Sci 75:4684–4688, 1978.PubMedGoogle Scholar
  74. 74.
    Huang AT, Logue GL, and Engelbrecht HL: Two biochemical markers in lymphocyte populations. Br J Haematol 34:631–638, 1981.Google Scholar
  75. 75.
    Barton R, Martiniuk F, Hirschhorn R, and Goldschneider I: The distribution of adenosine deaminase among lymphocyte populations in the rat. J Immunol 122:316–320, 1979.Google Scholar
  76. 76.
    Smyth JF, Poplack DG, Holiman BJ, Leventhal BG, and Yarbro G: Correlation of adenosine deaminase activity with cell surface markers in acute lymphoblastic leukemia. J Clin Invest 59:710–712, 1978.Google Scholar
  77. 77.
    Carson DA, Kaye J, Matsumoto S, Seegmiller JE, and Thompson L: Biochemical basis for the enhanced toxicity of deoxyribonucleosides toward malignant human T-cell lines. J Immunol 126:348–352, 1981.PubMedGoogle Scholar
  78. 78.
    Carson DA, Kaye J, Matsumoto S, Seegmiller JE, and Thompson L: Biochemical basis for the enhanced toxicity of deoxyribonucleosides toward malignant human T-cell lines. Proc Natl Acad Sci 76:2430–2433, 1979.PubMedGoogle Scholar
  79. 79.
    Wortmann RL, Mitchell BS, Edwards NL, and Fox IH: Biochemical basis for the differential deoxyadenosine toxicity to T and B lymphoblasts: Role for the 5’-nucleotidase. Proc Natl Acad Sci 76:2434–2438, 1979.PubMedGoogle Scholar
  80. 80.
    Fox RM, Tripp EH, Piddington SK, and Tattersall MHN: Sensitivity of leukemic human lymphocytes to deoxynucleosides. Cancer Res 40:3383–3386, 1980.PubMedGoogle Scholar
  81. 81.
    Carson DA and Wasson DB: Characterization of an adenosine 5’-triphosphate and deoxyadenosine 5’-triphosphate-activated nucleotidase from human malignant lymphocytes. Cancer Res 42:4321–4324, 1982.PubMedGoogle Scholar
  82. 82.
    Fox RM, Piddington SK, Tripp EH, and Tattersall MHN: Ecto-adenosine triphosphate deficiency in cultured human T and null leukemia lymphocytes. J Clin Invest 86:544–552, 1981.Google Scholar
  83. 83.
    Mitchell BS and Edwards NL: Purine-metabolizing enzymes as predictors of lymphoblast sensitivity to deoxyadenosine. J Lab Clin Med 104:414–424, 1984.PubMedGoogle Scholar
  84. 84.
    Mitchell, BS, Edwards NL, and Koller CA: Deoxyribonucleoside triphosphate accumulation by leukemia cells. Blood 62:419–424, 1983.PubMedGoogle Scholar
  85. 85.
    Matsumoto SS, Yu AL, Bleeker LC, Bakay B, Kung FH, and Nyhan WL: Biochemical correlates of the differential sensitivity to subtypes of human leukemia to deoxyadenosine and deoxycoformycin. Blood 60:1096–1102, 1082.Google Scholar
  86. 86.
    Belch AR, Henderson JF, and Brox LW: Treatment of multiple myeloma with deoxycoformycin. Cancer Chemother Pharmacol 14:49–52, 1985.PubMedGoogle Scholar
  87. 87.
    Goday A, Simmonds HA, Morris GS, and Fairbanks LD: Human B lymphocytes and thymocytes but not peripheral blood mononuclear cells accumulate high dATP levels in conditions simulating ADA deficiency. Biochem Pharmacol 34:3561–3569, 1985.PubMedGoogle Scholar
  88. 88.
    Ballet JJ, Insel R, Merler E, and Rosen FS: Inhibition of maturation of human precursor lymphocytes by coformycin, an inhibitior of the enzyme adenosine deaminase. J Exp Med 143:1271–1276, 1976.PubMedGoogle Scholar
  89. 89.
    Lum CT, Schmidtke JR, Sutherland DER, and Najarian JS: Inhibition of human T-cell rosette formation by the adenosine deaminase inhibitor erythro-9-(2-hydroxyl-3-nonyl) adenine hydrochloride (EHNA). Clin Immunol Immunopathol 10:258–261, 1978.PubMedGoogle Scholar
  90. 90.
    Hirschhorn R and Sela E: Adenosine deaminase and immunodeficiency: An in vitro model. Cell Immunol 32:350–360, 1977.PubMedGoogle Scholar
  91. 91.
    Carson DA and Seegmiller JE: Effect of adenosine deaminase inhibition upon human lymphocyte blastogenesis. J Clin Invest 57:274–282, 1976.PubMedGoogle Scholar
  92. 92.
    Hovi T, Smyth JF, Allison AC, and Williams SC: Role of adenosine deaminase in lymphocyte proliferation. Clin Exp Immunol 23:395–403, 1976.PubMedGoogle Scholar
  93. 93.
    Grever MR, Siaw MFE, Coleman MS, Whisler RL, and Balcerzak SP: Inhibition of K and NK lymphocyte cytotoxicity by an inhibitor of adenosine deaminase and deoxyadeno-sine. J Immunol 129:365–369, 1982.Google Scholar
  94. 94.
    Tedde A, Balis ME, Ikehara S, Pahwa R, Good RA, and Trotta PP: Animal model for immune dysfunction associated with adenosine deaminase deficiency. Proc Natl Acad Sci 77:4899–4903, 1980.PubMedGoogle Scholar
  95. 95.
    Seegmiller JE, Watanabe T, and Schrier MH: The effect of adenosine on lymphoid cell proliferation and antibody formation. In: Purine and Pyrimidine Metabolism. Ciba Foundation Symposium K Elliot and DW Fitzsimons (eds). Amsterdam: Elsevier, p 249–276, 1977.Google Scholar
  96. 96.
    Nicholson JKA, Gordon DS, and McDougal JS: Inhibition of adenosine deaminase leads to enhanced antibody responses in the mouse. Cell Immunol 79:320–333, 1983.PubMedGoogle Scholar
  97. 97.
    Ratech H, Bell MK, Hirschhorn R, and Thorbecke GJ: Effects of deoxycoformycin in mice. I. Suppression and enhancement of in vivo antibody responses to thymus-dependent and -independent antigens. J Immunol 132:3071–3076, 1984.PubMedGoogle Scholar
  98. 98.
    Ballow M and Pantschenko AG: In vitro effects of adenosine deaminase inhibitors on lymphoctye mitogen responsiveness in the mouse. Cell Immunol 64:29–43, 1981.PubMedGoogle Scholar
  99. 99.
    Johnston JB, Begleiter A, Pugh L, Leith MK, Wilkins JA, Cavers DJ, and Israels LG. Biochemical changes induced in hairy-cell leukemia following treatment with the adenosine deaminase inhibitors 2’-deoxycoformycin. Cancer Res 46:2179–2184, 1986.PubMedGoogle Scholar
  100. 100.
    Lambe CU and Nelson DJ: Pharmacokinetics of inhibition of adenosine deaminase by erythro-9-(2-hydroxy-3-nonyl)adenine in CBA mice. Biochem Pharmacol 31:535–539, 1982.PubMedGoogle Scholar
  101. 101.
    Plunkett W and Cohen SS: Two approaches that increase the activity of analogues of adenine nucleosides in animal cells. Cancer Res 35:1547–1554, 1975.PubMedGoogle Scholar
  102. 102.
    Chen S-F, Stoeckler JD, and Parks RE: Transport of deoxycoformycin in human erythrocytes. Measurement by adenosine deaminase titration and radioisotope assays. Biochem Pharmacol 33:4069–4079, 1984.PubMedGoogle Scholar
  103. 103.
    Chello PL, Sirotnak FM, Dorick DM, Yang C-H, and Montgomery JA: Initial rate kinetics and evidence for duality of mediated transport of adenosine, related purine nucleosides, and nucleoside analogues in L1210 cells. Cancer Res 43:97–103, 1983.PubMedGoogle Scholar
  104. 104.
    McConnell WR, Suling WJ, Rice LS, Shannon WM, and Hill DL: Use of microbiologic and enzymatic assays in studies on the disposition of 2’-deoxycoformycin in the mouse. Cancer Treat Rep 62:1153–1159, 1978.PubMedGoogle Scholar
  105. 105.
    Borondy PE, Chang T, and Maschenske: Inhibition of adenosine deaminase by co-vidarabine and its effect on the metabolic disposition of adenine arabinoside (vidarabine). Ann NY Acad Sci 284:9–20, 1977.PubMedGoogle Scholar
  106. 106.
    Chassin MM, Adamson RH, Zaharevitz DW, and Johns DG: Enzyme inhibition titration assay for 2’-deoxycoformycin and its application to the study of the relationship between drug concentration and tissue adenosine deaminase in dogs and rats. Biochem Pharmacol 28:1849–1855, 1979.PubMedGoogle Scholar
  107. 107.
    Lambe C, Bugge CJL, LaFon SW, Nelson DJ, and Elion GB: Inhibition of adenosine deaminase (ADA) in vivo in CBA-J mice by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA) and its metabolic consequence. Fed Proc 38:670, 1979.Google Scholar
  108. 108.
    McConnell WR, EL Dareer SM, and Hill DC: Metabolism and disposition of erythro-9-(2-hydroxy-3-nonyl) [adenine] in the Rhesus monkey. Drug Metab Dispos 8:5–7, 1980.PubMedGoogle Scholar
  109. 109.
    Venner PM, Glazer RI, Blatt J, Sallan S, Rivera G, Holcenberg JS, Upton J, Murphy SB, and Poplack DG. Levels of 2’-deoxycoformycin, adenosine, and deoxyadenosine in patients with acute lumphoblastic leukemia. Cancer Res 41:4508–4511, 1981.PubMedGoogle Scholar
  110. 110.
    Malspeis L, Weinrib AB, Staubus AE, Grever MR, Balcerzak SP, and Neidhart JA: Clinical pharmacokinetics of 2’-deoxycoformycin. Cancer Treat Symp 2:7–15, 1984.Google Scholar
  111. 111.
    Major PP, Agarwal RP, and Kufe DW: Clinical pharmacology of deoxycoformycin. Blood 58:91–96, 1981.PubMedGoogle Scholar
  112. 112.
    Schneider R, Korngold C, Vale K, Woodcock T, Tan C, and Young C: Clinical and pharmacologic investigation of deoxycoformycin. Proc Am Assoc Cane Res 21:185, 1980.Google Scholar
  113. 113.
    Poplack DG, Sallan SE, Rivera G, Holcenberg J, Murphy SB, Blatt J, Lipton JM, Venner P, Glaubiger DL, Ungerleider R, and Johns D: Phase I study of 2’-deoxycoformycin in acute lymphoblastic leukemia. Cancer Res 41:3343–3346, 1981.PubMedGoogle Scholar
  114. 114.
    Agarwal RP: Recovery of 2’-deoxycoformycin-inhibited adenosine deaminase of mouse erythrocytes and leukemia L1210 in vivo. Cancer Res 39:1425–1427, 1979.PubMedGoogle Scholar
  115. 115.
    Grever MR, Leiby JM, Kraut EH, Wilson HE, Neidhart JA, Wall RL, and Balcerzak SP: Low dose deoxycoformycin and lymphoid malignancy. J Clin Oncol 3:1196–1201, 1985.PubMedGoogle Scholar
  116. 116.
    Grever MR, Coleman MS, Gray DP, Malspeis L, Balcerzak SP, and Neidhart JA: Definition of safe, effective dosing regimen of 2’-deoxycoformycin with biochemical investigation. Cancer Treat Symp 2:43–49, 1984.Google Scholar
  117. 117.
    Roller CA and Mitchell BS: Alterations in erythrocyte adenine nucleotide pools resulting for 2’-deoxycoformycin therapy. Cancer Res 43:1409–1414, 1983.Google Scholar
  118. 118.
    Murphy SB, Sinkule JA, and Rivera G: Phase I-II clinical and pharmacodynamic study of effects of 2’-deoxycoformycin administration by continuous infusion in children with refractory acute lymphoblastic leukemia. Cancer Treat Symp 2:55–61, 1984.Google Scholar
  119. 119.
    Yu AL, Matsumoto S, Bleeker L, Alvarez A, Bakay B, Nyhan WL, and Kung F: Biochemical basis for the differential effects of deoxycoformycin on human leukemias. Adv Exp Med Biol 165:305–308, 1984.PubMedGoogle Scholar
  120. 120.
    Kanofsky JR, Roth DG, Smyth JF, Baron JM, Sweet DL, and Ultmann JE: Treatment of lymphoid malignancies with 2’-deoxycoformycin. A pilot study. Am J Clin Oncol 5:179–182, 1982.Google Scholar
  121. 121.
    Major PP, Agarwal RP, and Kufe DW: Deoxycoformycin: Neurological toxicity. Cancer Chemother Pharmacol 5:193–196, 1981.PubMedGoogle Scholar
  122. 122.
    2’-Deoxycoformycin, NSC 218321. Annual Report to the Food and Drug Administration. National Cancer Institute, Bethesda MD, February, 1985.Google Scholar
  123. 123.
    Grever MR, Siaw MFE, Jacob WF, Neidhart JA, Miser JJ, Coleman MS, Hutton JJ, and Balcerzak SP: The biochemical and clinical consequences of 2’-deoxycoformycin in refractory lymphoproliferation malignancy. Blood 57:406–417, 1981.PubMedGoogle Scholar
  124. 124.
    Symth JF, Prentice HG, Proctor S, and Hoffbrand AV: Deoxycoformycin in the treatment of leukemias and lymphomas. Ann NY Acad Sci 451:123–128, 1985.Google Scholar
  125. 125.
    Grever MR, Bisaccia E, Scarborough DA, Metz EN, and Neidhart JA. An investigation of 2’-deoxycoformycin in the treatment of cutaneous T-cell lymphoma. Blood 61:279–282, 1983.PubMedGoogle Scholar
  126. 126.
    Grever MR, Leiby MJ, Kraut EH, Wilson HE, Neidhart JA, Wall RL, and Balcerzak SP: Low-dose deoxycoformycin in lymphoid malignancy. J Clin Oncol 3:1196–1201, 1985.PubMedGoogle Scholar
  127. 127.
    Johnston JB, Israels LG, and Glazer RI: The treatment of hairy-cell leukemia with 2’-deoxycoformycin. Ann NY Acad Sci 451:319–320, 1985.Google Scholar
  128. 128.
    O’Dwyer PJ, Spiers ASD, and Marsoni S: Association of severe and fatal infections and treatment with pentostatin. Cancer Treat Rep 70:1117–1120, 1986.PubMedGoogle Scholar
  129. 129.
    Bouroncle BA, Wiseman BK, and Doan CA: Leukemic reticuloendotheliosis. Blood 13:609–630, 1958.PubMedGoogle Scholar
  130. 130.
    Quesada JR, Reuben J, Manning JT, Hersh EM, and Gutterman JU: Alpha interferon for induction of remission in hairy-cell leukemia. N Eng J Med 310:15–19, 1984.Google Scholar
  131. 131.
    Spiers ASD, Parekh SJ, and Bishop MD: Hairy-cell leukemia: Induction of complete remission with pentostatin (2’-deoxycoformycin). J Clin Oncol 2:1336–1342, 1984.PubMedGoogle Scholar
  132. 132.
    Kraut EH, Bouroncle BA, and Grever MR: Treatment of hairy-cell leukemia with low dose 2’-deoxycoformycin. Blood 66:203a, 1985.Google Scholar
  133. 133.
    Spiers ASD, Parekh SJ, Ramnes CR, Cassileth PA, Oken MM, and the Eastern Cooperative Oncology Group (ECOG): Hairy-cell leukemia (HCL): Pentostatin (dCF, 2’-deoxycoformycin) is effective both as initial treatment and after failure of splenectomy and alpha interferon. Blood 66:208a, 1985.Google Scholar
  134. 134.
    Foon KA, Nakano GM, Koller CA, Longo DL, and Steis RG: Rapid response to 2’-deoxycoformycin after failure of recombinant leukocyte A interferon (rIFN-alpha A) in two patients with hairy cell leukemia (HCL). Blood 66:199z, 1985.Google Scholar
  135. 135.
    Grever MR, Leiby JM, Kraut EH, Wilson HE, Neidhart JA, Wall RL, and Balcerzak SP: Low dose deoxycoformycin in lymphoid malignancy. J Clin Oncol 3:1196–1201, 1985.PubMedGoogle Scholar
  136. 136.
    LePage GA, Worth LS, and Kimball AP: Enhancement of the antitumor activity of arabinofuranosyladenine by 2’-deoxycoformycin. Cancer Res 36:1481–1485, 1976.PubMedGoogle Scholar
  137. 137.
    Johns DG and Adamson RE: Enhancement of the biological activity of cordycepin (3’deoxyadenosine) by the adenosine deaminase inhibitor 2’-deoxycoformycin. Biochem Pharmacol 25:1441–1444, 1976.PubMedGoogle Scholar
  138. 138.
    Cass CE and Au-Yeung TH: Enhancement of 9-p-arabinofuranosyladenine cytotoxicity to mouse leukemia L1210 in vitro by 2’-deoxycoformycin. Cancer Res 36:1486–1491, 1976.PubMedGoogle Scholar
  139. 139.
    Caron N, Lee SH, and Kimball AP: Effects of 2’-deoxycoformycin, 9-p-ara-binofuranosyladenine 5’-phosphate, and 1-p-D-arabinofuranosylcytosine triple combination therapy on intracerebral leukemia L1210. Cancer Res 37:3274–3279, 1977.PubMedGoogle Scholar
  140. 140.
    Adamson RH, Zaharevitz DW, and Johns DG: Enhancement of the biological activity of adenosine analogs by the adenosine deaminase inhibitor 2’-deoxycoformycin. Pharmacology 15:84–89, 1977.PubMedGoogle Scholar
  141. 141.
    Lee SH, Caron N, and Kimball AP: Therapeutic effects of 9-p-D-arabinofura-nosyladenine and 2’-deoxycoformycin combinations on intracerebral leukemia. Cancer Res 37:1953–1955, 1977.PubMedGoogle Scholar
  142. 142.
    Shewach DS and Plunkett W: Correlation of cytotoxicity with total intracellular exposure to 9-p-D-arabinofuranosyladenine 5’-triphosphate. Cancer Res 42:3637–3641, 1982.PubMedGoogle Scholar
  143. 143.
    Plunkett W, Alexander L, Chubb S, and Loo TL: Biochemical basis of the increased toxicity of 9-p-D-arabinofuranosyladenine in the presence of inhibitors of adenosine deaminase. Cancer Res 39:3655–3660, 1979.PubMedGoogle Scholar
  144. 144.
    Plunkett W, Benjamin RS, Keating MJ, and Freireich EJ: Modulation of 9-p-D-arabinofuranosyladenine 5’-triphosphate and deoxyadenosine triphosphate in leukemia cells by 2’-deoxycoformycin during therapy with 9-p-D-arabinofuranosyladenine. Cancer Res 42:2092–2096, 1982.PubMedGoogle Scholar
  145. 145.
    Helland S and Ueland PM: Interaction of 9-p-D-arabinofuranosyladenine, 9-p-D-arabinofuranosyladenine 5’-monophosphate and 9-p-D-arabinofuranosyladenine 5’-triphosphate with S-adenosylhomocysteinase. Cancer Res 41:673–678, 1981.PubMedGoogle Scholar
  146. 146.
    Glazer RI, Lott TJ, and Peale AL: Potentiation by 2’-deoxycoformycin of the inhibitory effect of 3’deoxyadenosine (cordycepin) on nuclear RNA synthesis in L1210 cells in vitro. Cancer Res 38:2233–2238, 1978.PubMedGoogle Scholar
  147. 147.
    Schroder HC, Nitzgen DE, Bernd A, Kurelec B, Zahn RK, Gramzow M, and Muller WEG: Inhibition of nuclear envelope nucleoside triphosphatase-regulated nucleocytoplas-mic messenger RNA translocation by 9-p-D-arabinofuranosyladenine 5’-triphosphate in rodent cells. Cancer Res 44:3812–1319, 1984.PubMedGoogle Scholar
  148. 148.
    Agarwal RP, Blatt J, Miser J, Sallan S, Lipton JM, Reaman GH, Holcenberg J, and Poplack DG: Clinical pharmacology 9-p-D-arabinofuranosyladenine in combination with 2’-deoxycoformycin. Cancer Res 42:3884–3886, 1982.PubMedGoogle Scholar
  149. 149.
    Major PP, Agarwal RP, and Kufe DW: Clinical pharmacology of arabinofuranosyladenine in combination with deoxycoformycin. Cancer Chemother Pharmacol 10:125–128, 1983.PubMedGoogle Scholar
  150. 150.
    Kufe DW: Clinical and cellular pharmacology of 2’-deoxycoformycin and vidarabine. Cancer Treat Symp 2:85–95, 1984.Google Scholar
  151. 151.
    Miser J, Blatt J, Sallan S, Holcenberg J, Reaman G, and Poplack D: Phase I trial of 2’-deoxycoformycin (dCF) and adenine arabinoside (ARA-A) in the treatment of hematologic malignancies in children. Proc Am Soc Clin Oncol 2:182, 1983.Google Scholar
  152. 152.
    Murphy SB, Stass S, Kalwinsky D, and Rivera G: Phenotypic conversion of acute leukemia from T-lymphoblastic to myeloblastic induced by therapy with 2’-deoxycoformycin. Brit J Haematol 55:285–293, 1983.Google Scholar
  153. 153.
    Hershfield MS, Kurtzberg J, Harden E, Moore JO, Whang-Peng J, and Haynes BF: Conversion of a stem-cell leukemia from a T-lymphoid to a myeloid phenotype induced by the adenosine deaminase inhibitor 2’-deoxycoformycin. Proc Natl Acad Sci 81:253–257, 1984.PubMedGoogle Scholar
  154. 154.
    Elion GB: Selectivity — key to chemotherapy: Presidential address. Cancer Res 45:2943–2950, 1985.PubMedGoogle Scholar

Copyright information

© Martinus Nijhoff Publishers, Boston 1987

Authors and Affiliations

  • Peter J. O’Dwyer
  • Brian Leyland-Jones
  • Daniel F. Hoth

There are no affiliations available

Personalised recommendations