Clinical Pharmacokinetics

, Volume 39, Issue 1, pp 5–26 | Cite as

Clinical Pharmacokinetics of Nucleoside Analogues

Focus on Haematological Malignancies
  • Stephen A. JohnsonEmail author
Review Articles Drug Disposition


This review establishes the pharmacokinetic characteristics of the major nucleoside analogues with cytotoxic activity. Cytarabine, pentostatin, fludarabine, cladribine and gemcitabine are all prodrugs whose plasma pharmacokinetics do not fully reflect their therapeutic activity; after cellular uptake, these compounds undergo phosphorylation by deoxycytidine kinase before their incorporation into DNA results in cell death. Cytarabine is principally active in the S phase of the cell cycle and is most toxic to replicating cells, whereas pentostatin, fludarabine and cladribine are incorporated into DNA during the process in which strand breaks are repaired and are therefore cytotoxic to slowly replicating cells (although the action of pentostatin results from its inhibition of adenosine deaminase). Gemcitabine is unusual in being highly metabolised in solid tumour cells. The cytotoxic activity of pentostatin, fludarabine and cladribine against the clonal cells of lymphoproliferative disorders is accompanied by damage to normal lymphoid cells, which results in significant and long-lasting immunosuppression.

Useful interactions between nucleoside analogues have been defined. Cells that are primed by exposure to fludarabine or cladribine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine) and an improved therapeutic effect against acute myeloid leukaemia and chronic lymphocytic leukaemia can be achieved by clinical schedules that exploit this effect. Combinations of alkylating agents and fludarabine or cladribine are also synergistic in producing significantly enhanced activity against refractory lymphoid malignancies, but at the cost of increased haematological toxicity. Developments in the clinical administration of gemcitabine are concentrating on efforts to extend the duration of exposure to the drug as a means of counteracting its rapid catabolism in the circulation.

Future developments with this group of agents will further explore the use of fludarabine-based combination therapies to produce a transient period of myelosuppression and immunosuppression that is sufficient to permit the engraftment of allogeneic haemopoietic stem cells and also exploit the immunological benefits of graft-versus-tumour reactions. In addition, the clinical spectrum of activity of gemcitabine is also being extended by combining the drug with other active chemotherapeutic agents, such as cisplatin, and by early studies of its role as a radiosensitiser.


Gemcitabine Chronic Lymphocytic Leukaemia Cytarabine Maximal Tolerate Dose Fludarabine 
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.



I am grateful to Bill Plunkett, Varsha Gandhi, Jan Liliemark and Veronique Ruiz van Haperen among others for encouraging my interest in the application of pharmacological principles to the design of therapeutic schedules. They and others including Simon Rule and John Seymour were kind enough to provide helpful comments on the manuscript; my thanks also to Caroline Ashman for producing the typescript to her customary high standard.


  1. 1.
    King ME, Pfeifle CE, Howell SB. Intraperitoneal cytosine arabinoside therapy in ovarian carcinoma. J Clin Oncol 1984 Jun; 2 (6): 662–9.PubMedGoogle Scholar
  2. 2.
    Ellison RR, Holland JF, Weil M, et al. Arabinosyl cytosine: a useful agent in the treatment of acute leukemia in adults. Blood 1968 Oct; 32 (4): 507–23.PubMedGoogle Scholar
  3. 3.
    Plunkett W, Benjamin RS, Keating MJ, et al. Modulation of 9-β-D-arabinofuranosyladenine 5′-triphosphate and deoxyadenos-ine triphosphate in leukaemic cells by 2′-deoxycoformycin during therapy with 9-β-D-arabinofuranosyladenine. Cancer Res 1982 May; 42: 2092–6.PubMedGoogle Scholar
  4. 4.
    Spiers ASD, Ruckdeschel JC, Horton J. Effectiveness of pentostatin (2′-deoxycoformycin) in refractory lymphoid neoplasms. Scand J Haematol 1984; 32: 130–4.PubMedCrossRefGoogle Scholar
  5. 5.
    Hutton JJ, Von Hoff DD, Kuhn J, et al. Phase I clinical investigation of 9-β-arabinosyl-2-fluoroadenine 5′-monophosphate (NSC 312887) a new purine antimetabolite. Cancer Res 1984 Sep; 44: 4183–6.PubMedGoogle Scholar
  6. 6.
    Carson DA, Wasson DB, Taetle R, et al. Specific toxicity of 2-chlorodeoxyadenosine towards resting and proliferating human lymphocytes. Blood 1983 Oct; 62 (4): 737–43.PubMedGoogle Scholar
  7. 7.
    Hertel LW, Boder GB, Kroin JS, et al. Evaluation of the antitumour activity of gemcitabine (2′2′-difluoro-2′-deoxycytidine). Cancer Res 1990 Jul; 50(14): 4417–22.PubMedGoogle Scholar
  8. 8.
    Giblett ER, Anderson JE, Cohen F, et al. Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 1972 Nov; II: 1067–9.CrossRefGoogle Scholar
  9. 9.
    Cohen A, Hirschhorn R, Horowitz SD, et al. Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci USA 1978 Jan; 75 (1): 472–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Benveniste P, Cohen A. p53 expression is required for thymocyte apoptosis induced by adenosine deaminase deficiency. Proc Natl Acad Sci U S A 1995 Aug; 92 (18): 8373–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Pettit AR, Clarke AR, Cawley JC, et al. Purine analogues kill resting lymphocytes by p53-dependent and -independent mechanisms. Br JHaematol 1999; 105: 986–8.CrossRefGoogle Scholar
  12. 12.
    Seto S, Carrera CJ, Kubota M, et al. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to non-dividing human lymphocytes. J Clin Invest 1985 Feb; 75: 377–83.PubMedCrossRefGoogle Scholar
  13. 13.
    Brager PM, Grever MR. 9-β-D-Arabinofuranosyl-2-fluoro-adenine reduces NAD in normal lymphocytes and neoplastic cells in CLL [abstract 82]. Proc Am Assoc Cancer Res 1986; 27:21.Google Scholar
  14. 14.
    Leoni LM, Chao Q, Cottam HB, et al. Induction of an apoptotic program in cell-free extracts by 2-chloro-2′-deoxyadenosine 5′-triphosphate and cytochrome C. Proc Natl Acad Sci USA 1998 Aug; 95: 9567–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Griffiths M, Beaumont N, Yao SYM, et al. Cloning of a human nucleoside transporter implicated in the cellular uptake of adenosine and chemotherapeutic drugs. Nat Med 1997 Jan; 3 (1): 89–93.PubMedCrossRefGoogle Scholar
  16. 16.
    Gati WP, Paterson AR, Belch AR, et al. Es nucleoside transporter content of acute leukemia cells: role in cell sensitivity to cytarabine (araC). Leuk Lymphoma 1998 Dec; 32(1–2): 45–54.PubMedGoogle Scholar
  17. 17.
    Hammond JR, Lee S, Ferguson PJ. Gemcitabine uptake by nucleoside transporters in human head and neck squamous carcinoma cell line. J Pharmacol Exp Ther 1999 Mar; 288 (3): 1185–91.PubMedGoogle Scholar
  18. 18.
    White JC, Rathmell JP, Capizzi RL. Membrane transport influences the rate of accumulation of cytosine arabinoside in human leukemie cells. J Clin Invest 1987; 79: 380–7.PubMedCrossRefGoogle Scholar
  19. 19.
    Chan TC. Augmentation of l-beta-D-arabinofuranosylcytosine cytotoxicity in human tumor cells by inhibiting drug efflux. Cancer Res 1989; 49 (10): 2656–60.PubMedGoogle Scholar
  20. 20.
    Alessi-Severini S, Gati WP, Belch AR, et al. Intracellular pharmacokinetics of 2-chlorodeoxyadenosine in leukemia cells from patients with chronic lymphocytic leukemia. Leukemia 1995; 9: 1674–9.PubMedGoogle Scholar
  21. 21.
    Norgaard JM, Bukh A, Langkjer ST, et al. MDR1 gene expression and drug resistance in AML cells. Br J Haematol 1998; 100: 534–40.PubMedCrossRefGoogle Scholar
  22. 22.
    Komarov PG, Shtil AA, Holian D, et al. Activation of the LRP (lung resistance protein) gene by short-term exposure of human leukemia cells to phorbol ester and cytarabine. Oncol Res 1998; 10(4): 185–92.PubMedGoogle Scholar
  23. 23.
    Malspeis L, Grever MR, Staubus AE, et al. Pharmacokinetics of 2-F-araA (9-β-D-arabinofuranosyl-2-fluoroadenine) in cancer patients during the phase I clinical investigation of fludarabine phosphate. Semin Oncol 1990 Oct; 17 (5) Suppl. 8: 18–32.PubMedGoogle Scholar
  24. 24.
    Grever MR, Siaw MFE, Jacob WF, et al. The biochemical and clinical consequences of 2′-deoxycoformycin in refractory lymphoid malignancy. Blood 1981 Mar; 57 (3): 406–17.PubMedGoogle Scholar
  25. 25.
    Siaw MF, Coleman MS. In vitro metabolism of deoxycoformycin in human T lymphoblastoid cells: phosphorylation of deoxycoformycin and incorporation into cellular DNA. J Biol Chem 1984 Aug; 259 (15): 9426–33.PubMedGoogle Scholar
  26. 26.
    Saven A, Piro L. Newer purine analogues for the treatment of hairy-cell leukemia. N Engl J Med 1994; 330 (10): 691–7.PubMedCrossRefGoogle Scholar
  27. 27.
    Albertioni F, Lindemalm S, Reichelova V, et al. Pharmacokinetics of cladribine in plasma and its 5′-monophosphate and 5′-triphos-phate in leukemie cells of patients with chronic lymphocytic leukemia. Clin Cancer Res 1998 Mar; 4 (3): 653–8.PubMedGoogle Scholar
  28. 28.
    Kroep JR, van Moorsel CJ, Veerman G, et al. Role of deoxycytidine kinase (dCK), thymidine kinase 2 (TK2) and deoxycytidine deaminase (dCDA) in the antitumor activity of gemcitabine (dFDC). Adv Exp Med Biol 1998; 431: 657–60.PubMedCrossRefGoogle Scholar
  29. 29.
    Arner ESJ, Spasokoukotskaja T, Juliusson G, et al. Phosphorylation of 2-chlorodeoxyadenosine (CdA) in extracts of peripheral blood mononuclear cells of leukaemic patients. Br J Haematol 1994; 87: 715–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Kawasaki H, Carrera CJ, Piro LD, et al. Relationship of deoxycytidine kinase and cytoplasmic 5′-nucleotidase to the chemotherapeutic efficacy of 2-chlorodeoxyadenosine. Blood 1993 Feb; 81 (3)597–601.PubMedGoogle Scholar
  31. 31.
    Dumontet C, Fabianowska-Majewska K, Mantincic D, et al. Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br JHaematol 1999; 106: 78–85.CrossRefGoogle Scholar
  32. 32.
    Kufe DW, Major PP, Egan EM, et al. Correlation of cytotoxicity with incorporation of araC into DNA. J Biol Chem 1980; 225 (19): 8597–9000.Google Scholar
  33. 33.
    Huang P, Plunkett W. Fludarabine and gemcitabine-induced apoptosis: incorporation of analogs into DNA is a critical event. Cancer Chemother Pharmacol 1995; 36: 181–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Crowther PJ, Cooper IA, Woodcock BM. Biology of cell killing by 1-beta-D-arabinofuranosylcytosine and its relevance to molecular mechanisms of cytotoxicity. Cancer Res 1985 Sep; 45 (9): 4291–300.PubMedGoogle Scholar
  35. 35.
    Iwasaki H, Huang P, Keating MJ, et al. Differential incorporation of araC, gemcitabine, and fludarabine into replicating and repairing DNA in proliferating human leukaemia cells. Blood 1997 Jul; 90 (1): 270–8.PubMedGoogle Scholar
  36. 36.
    Preisler HD, Azarnia N, Raza A, et al. Relationship between the percent of marrow cells in S phase and the outcome of remission-induction therapy for acute non-lymphocytic leukaemia. Br JHaematol 1984; 56: 399–407.CrossRefGoogle Scholar
  37. 37.
    Hiddemann W, Aul C, Maschmeyer R, et al. High-dose versus intermediate dose cytarabine combined with mitoxantrone for the treatment of relapsed and refractory acute myeloid leukemia: results of an age-adjusted randomized comparison. Semin Hematol 1991; 3 Suppl. 4: 34–8.Google Scholar
  38. 38.
    Xu YZ, Huang P, Plunkett W. Functional compartmentation of dCTP pools: preferential utilization of salvaged deoxycytidine for DNA repair in human lymphoblasts. J Biol Chem 1995; 270 (2): 631–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Begleiter A, Glazer RI, Israels LG, et al. Induction of DNA strand breaks in chronic lymphocytic leukaemia following treatment with 2′-deoxycoformycin in vivo and in vitro. Cancer Res 1987 May; 47: 2498–503.PubMedGoogle Scholar
  40. 40.
    Robertson LE, Chubb S, Meyn RE, et al. Induction of apoptotic cell death in chronic lymphocytic leukaemia by 2-chloro-2′-deoxyadenosine and 9-β-D-arabinosyl-2-fluoroadenine. Blood 1993 Jan; 81 (1): 143–50.PubMedGoogle Scholar
  41. 41.
    Bromidge TJ, Howe DJ, Johnson SA, et al. Adaptation of the TdT assay for semi-quantitative flow cytometric detection of DNA strand breaks. Cytometry 1995; 20: 257–60.PubMedCrossRefGoogle Scholar
  42. 42.
    Bromidge TJ, Turner DL, Howe DJ, et al. In vitro chemosensitivity of chronic lymphocytic leukaemia to purine analogues — correlation with clinical course. Leukemia 1998; 12: 1230–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Huang P, Chubb S, Plunkett W. Termination of DNA synthesis by 9-β-D-arabinosyl-2-fluoroadenine: a mechanism for cytotoxicity. J Biol Chem 1990 Sep; 265 (27): 16617–25.PubMedGoogle Scholar
  44. 44.
    Huang P, Chubb S, Hertel LW, et al. Action of 2′,2′-dif-luorodeoxycytidine on DNA synthesis. Cancer Res 1991; 51 (22): 6110–7.PubMedGoogle Scholar
  45. 45.
    Kamiya K, Huang P, Plunkett W. Inhibition of the 3′-5′ exonuclease of human DNA polymerase e by fludarabine-terminated DNA. J Biol Chem 1996 Aug; 271 (32): 19428–35.PubMedCrossRefGoogle Scholar
  46. 46.
    Sandoval A, Consoli U, Plunkett W. Fludarabine-mediate inhibition of nucleotide excision repair induces apoptosis in quiescent human lymphocytes. Clin Cancer Res 1996 Oct; 2: 1731–41.PubMedGoogle Scholar
  47. 47.
    Plunkett W, Huang P, Gandhi V. Metabolism and action of fludarabine phosphate. Semin Oncol 1990 Oct; 17 (5) Suppl. 8:3–17.PubMedGoogle Scholar
  48. 48.
    Venner PM, Glazer RI, Blatt J, et al. Levels of 2′-deoxycoformycin, adenosine and deoxyadenosine in patients with acute lymphoblastic leukaemia. Cancer Res 1981 Nov; 41: 4508–11.PubMedGoogle Scholar
  49. 49.
    Major PP, Agarwal RP, Kufe DW. Clinical pharmacology of deoxycoformycin. Blood 1981 Jul; 58 (1): 91–6.PubMedGoogle Scholar
  50. 50.
    Malspeis L, Weinrib AB, Staubus AE, et al. Clinical pharmacokinetics of 2′-deoxycoformycin. Cancer Treat Symp 1984; 2L 7–15.Google Scholar
  51. 51.
    Smyth JF, Paine RM, Jackman AL, et al. The clinical pharmacology of the adenosine deaminase inhibitor 2′-deoxycoformycin. Cancer Chemother Pharmacol 1980; 5: 93–101.Google Scholar
  52. 52.
    Grever MR, Staubus AE, Balcerzak SP, et al. Clinical pharmacokinetics of 2′-deoxycoformycin in renal impairment [abstract 361]. Proc Am Soc Clin Oncol 1993 Mar; 12: 140.Google Scholar
  53. 53.
    Slevin ML, Piall EM, Aherne GW, et al. The pharmacokinetics of cytosine arabinoside in the plasma and cerebrospinal fluid during conventional and high-dose therapy. Med Pediatr Oncol 1982; 1 Suppl. 1: 157–68.CrossRefGoogle Scholar
  54. 54.
    Camiener GW, Smith CG. Studies on the enzymatic deamination of cytosine arabinoside I: enzymatic distribution and species specificity. Biochem Pharmacol 1965; 14: 1405–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Plunkett W, Gandhi V. Pharmacokinetics of arabinosylcytosine. J Infusional Chem 1992; 2 (4): 169–76.Google Scholar
  56. 56.
    Southwest Oncology Group. Cytarabine for acute leukaemia in adults: effect of schedule on therapeutic response. Arch Intern Med 1974 Feb; 133:251–9.CrossRefGoogle Scholar
  57. 57.
    Momparler RL. A model for the chemotherapy of acute leukaemia with 1-β-D-arabinofuranosylcytosine. Cancer Res 1974; 34: 1775–87.PubMedGoogle Scholar
  58. 58.
    Plunkett W, Iacobini S, Estey E, et al. Pharmacologically directed araC therapy for refractory leukaemia. Semin Oncol 1985 Jun; 12 (2) Suppl. 3: 20–30.PubMedGoogle Scholar
  59. 59.
    Donehower RC, Karp JE, Burke PJ. Pharmacology and toxicity of high-dose cytarabine by 72 hour continuous infusion. Cancer Treat Rep 1986 Sep; 70 (9): 1059–65.PubMedGoogle Scholar
  60. 60.
    Capizzi RL, White JC, Powell BL, et al. Effect of dose on the pharmacokinetic and pharmacodynamic effects of cytarabine. Semin Hematol 1991 Jul; 28 (3) Suppl. 4: 54–69.PubMedGoogle Scholar
  61. 61.
    Plunkett W, Gandhi V, Huang P, et al. Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies. Semin Oncol 1993 Oct; 20 (5) Suppl. 7: 2–12.PubMedGoogle Scholar
  62. 62.
    Hersh MR, Kuhn JG, Phillips JL, et al. Pharmacokinetic study of fludarabine phosphate (NSC 312887). Cancer Chemother Pharmacol 1986; 17: 277–80.PubMedCrossRefGoogle Scholar
  63. 63.
    Kemena A, Fernandez M, Bauman J, et al. A sensitive fluorescence assay for quantitation of fludarabine and metabolites in biological fluids. Clin Chim Acta 1991; 200: 95–106.PubMedCrossRefGoogle Scholar
  64. 64.
    Avramis VI, Champagne J, Sato J, et al. Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients. Cancer Res 1990 Nov; 50: 7226–31.PubMedGoogle Scholar
  65. 65.
    Kemena A, Keating M, Plunkett W. Oral bioavailability of plasma fludarabine and fludarabine triphosphate (F-araATP) in peripheral CLL cells. Onkologie 1991; 14: 83.Google Scholar
  66. 66.
    Foran J, Oscier D, Orchard J, et al. Pharmacokinetic study of single doses of oral fludarabine phosphate in patients with ‘lowgrade’ non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukemia. J Clin Oncol 1999 May; 17 (5): 1574–9.PubMedGoogle Scholar
  67. 67.
    Oscier DG, Orchard JA, Culligan D, et al. Comparison of the pharmacokinetics and bioavailability of oral fludarabine administered either fasting or after food [abstract 652]. Ann Oncol 1999; 10 Suppl. 3: 176.Google Scholar
  68. 68.
    Carson DA, Wasson DB, Beutler E. Antileukemic and immunosuppressive activity of 2-chloro2′deoxyadenosine. Proc Natl Acad Sci U S A 1984 Apr; 81: 2232–6.PubMedCrossRefGoogle Scholar
  69. 69.
    Beutier E, Piro LD, Saven A, et al. 2-Chlorodeoxyadenosine (2-CdA): A potent chemotherapeutic and immunosuppressive nucleoside. Leuk Lymphoma 1991; 5: 1–8.CrossRefGoogle Scholar
  70. 70.
    Saven A, Cheung WK, Smith I, et al. Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy. J Clin Oncol 1996 Mar; 14 (3): 978–83.PubMedGoogle Scholar
  71. 71.
    Liliemark J, Albertioni F, Hassan M, et al. On the bioavailability of oral and subcutaneous 2-chloro-2-deoxyadenosine in humans: alternative routes of administration. J Clin Oncol 1992 Oct; 10(10): 1514–8.PubMedGoogle Scholar
  72. 72.
    Liliemark J, Pettersson B, Juliusson G. Determination of 2-chloro-2′-deoxyadenosine in human plasma. Biomed Chromatogr 1991; 5: 262–4.PubMedCrossRefGoogle Scholar
  73. 73.
    Beutler E. Cladribine (2-chlorodeoxyadenosine). Lancet 1992 Oct; 340: 952–6.PubMedCrossRefGoogle Scholar
  74. 74.
    Albertioni F, Pettersson B, Reichelova V, et al. Analysis of 2-chloro-2′-deoxyadenosine in human blood plasma and urine by high-performance liquid chromatography using solid-phase extraction. Ther Drug Monit 1995; 16: 413–8.CrossRefGoogle Scholar
  75. 75.
    Liliemark J, Juliusson G. On the pharmacokinetics of 2-chloro-2′-deoxyadenosine (CdA) in cerebrospinal fluid (CSF) [abstract]. Blood 1992; 80 Suppl. 1: 471a.Google Scholar
  76. 76.
    Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I clinical, plasma and cellular pharmacology study of gemcitabine. J Clin Oncol 1991 Mar; 9 (3): 491–8.PubMedGoogle Scholar
  77. 77.
    Pollera CF, Ceribelli A, Crecco M, et al. Weekly gemcitabine in advanced or metastatic tumours: a clinical phase I study. Invest New Drugs 1994; 12: 111–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Grunewald R, Kantarjian H, Du M, et al. Gemcitabine in leukemia: a phase I clinical, plasma and cellular pharmacological study. J Clin Oncol 1992; 10 (3): 406–13.PubMedGoogle Scholar
  79. 79.
    Pollera CF, Ceribelli A, Crecco M, et al. Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels. Invest New Drags 1997; 15: 115–21.CrossRefGoogle Scholar
  80. 80.
    Brand R, Capadano M, Tempero M. A phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumours. Invest New Drags 1997; 15: 331–41.CrossRefGoogle Scholar
  81. 81.
    Touroutoglu N, Gravel D, Raber MN, et al. Clinical results of a pharmodynamically based strategy for higher dosing of gemcitabine in patients with solid tumours. Ann Oncol 1998; 9: 1003–8.CrossRefGoogle Scholar
  82. 82.
    Plunkett W, Liliemark JO, Adams TM, et al. Saturation of l β-D-arabinofuranosylcytosine 5′-triphosphate accumulation in leukemia cells during high-dose 1 ′-D-arabinofuranosylcytosine therapy. Cancer Res 1987; 47: 3005–11.PubMedGoogle Scholar
  83. 83.
    White JC, Capizzi RL. Relationship of membrane transport capacity to araCTP retention in human leukemia cells. Proc Am Assoc Cancer Res 1988; 29: 346.Google Scholar
  84. 84.
    Ho DHW, Brown NS, Benvenuto J, et al. Pharmacologic studies of continuous infusion of arabinosylcytosine by liquid infusion system. Clin Pharmacol Ther 1977; 22: 371–4.PubMedGoogle Scholar
  85. 85.
    Estey EH, Keating MJ, McCredie KB, et al. Cellular araCTP pharmacokinetics, response and karyotype in newly diagnosed acute myelogenous leukemia. Leukemia 1990; 4: 95–9.PubMedGoogle Scholar
  86. 86.
    Preisler HD, Rustum Y, Priore RL. Relationship between leukemic cell retention of cytosine arabinoside triphosphate and the duration of remission in patients with acute non-lympho-cytic leukemia. Eur J Cancer Clin Oncol 1985; 21: 23–30.PubMedCrossRefGoogle Scholar
  87. 87.
    Danhauser L, Plunkett W, Keating M, et al. 9-β-D-Arabinofuranosyl-2-fluoroadenine 5′ monophosphate pharmacokinetics in plasma and tumour cells of patients with relapsed leukemia and lymphoma. Cancer Chemother Pharmacol 1986; 18: 145–52.PubMedCrossRefGoogle Scholar
  88. 88.
    Gandhi V, Kemena A, Keating MJ, etal. Cellular pharmacology of fludarabine triphosphate in chronic lymphocytic leukemia cells during fludarabine therapy. Leuk Lymphoma 1993; 10: 49–56.PubMedCrossRefGoogle Scholar
  89. 89.
    Liliemark J, Juliusson G. Cellular pharmacokinetics of 2-chloro-2′-deoxyadenosine nucleotides: comparison of intermittent and continuous intravenous infusion and subcutaneous and oral administration in leukemia patients. Clin Cancer Res 1995; 1: 385–90.PubMedGoogle Scholar
  90. 90.
    Grunewald R, Abbruzzese JL, Tarassoff P, et al. Saturation of 2′,2′-difluoro-deoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991 Jan; 27: 258–62.PubMedCrossRefGoogle Scholar
  91. 91.
    Plunkett W, Huang P, Searcy CE, et al. Gemcitabine: preclinical pharmacology and mechanisms of action. Semin Oncol 1996 Oct; 23 (5) Suppl. 10: 3–15.PubMedGoogle Scholar
  92. 92.
    Ruiz van Haperen VWT, Veerman G, Boven E, et al. Schedule dependence of sensitivity to 2′,2′-difluorodeoxycytidine (gemcitabine) in relation to accumulation and retention of its triphosphate in solid tumour cell lines and solid tumours. Biochem Pharmacol 1994; 48: 1327–39.PubMedCrossRefGoogle Scholar
  93. 93.
    Tempero M, Plunkett W, Ruiz van Haperen V, et al. Randomized phase II trial of dose intense gemcitabine by standard infusion vs fixed dose rate in metastatic pancreatic adenocarcinoma [abstract 1048]. Proc Am Assoc Clin Oncol 1999; 18: 273a.Google Scholar
  94. 94.
    Griffig J, Koob R, Blakley RL. Mechanisms of inhibition of DNA synthesis by 2-chlorodeoxyadenosine in human lymphoblastic cells. Cancer Res 1989; 49: 6923–8.PubMedGoogle Scholar
  95. 95.
    Tseng WC, Derse D, Cheng YC. In vitro biological activity of 9-β-D-arabinofuranosyl-2-fluoroadenine and the biochemical actions of its triphosphate on DNA polymerases and ribonucleotide reductase from Hel cells. Mol Pharmacol 1982; 21: 474–7.PubMedGoogle Scholar
  96. 96.
    Heinemann V, Xu YZ, Chubb S, et al. Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorode-oxycytidine. Mol Pharmacol 1990; 38: 567–72.PubMedGoogle Scholar
  97. 97.
    Gandhi V, Estey E, Keating MJ, et al. Biochemical modulation of arabinosylcytosine for therapy of leukaemias. Leuk Lymphoma 1993; 10 Suppl.: 109–14.PubMedCrossRefGoogle Scholar
  98. 98.
    Gandhi V, Kemena A, Keating MJ, et al. Fludrabine infusion potentiates arabinosylocytosine metabolism in lymphocytes of patients with chronic lymphocytic leukemia. Cancer Res 1992; 52: 897–903.PubMedGoogle Scholar
  99. 99.
    Gandhi V, Estey E, Keating MJ, et al. Fludarabine potentiates metabolism of cytarabine in patients with acute myelogenous leukemia during therapy. J Clin Oncol 1993; 11: 116–24.PubMedGoogle Scholar
  100. 100.
    Seymour JF, Huang P, Plunkett W, et al. Influence of fludarabine on pharmacokinetics and pharmacodynamics of cytarabine: implications for a continuous infusion schedule. Clin Cancer Res 1996 Apr; 2: 653–8.PubMedGoogle Scholar
  101. 101.
    Braess J, Wegendt C, Jahns-Strembel G, et al. Modulation of high-dose araC metabolism in acute myeloid leukemia by hematopoietic growth factors (G-CSF; GM-CSF) and ribonu-cleotide reductase inhibitors (fludarabine, gemcitabine) [abstract 1591]. Blood 1998; 92 Suppl. 1: 385a.Google Scholar
  102. 102.
    Preisler H, Davis RB, Kirschner J, et al. Comparison of three remission induction regimes and two post induction strategies for the treatment of acute non-lymphocytic leukemia: a Cancer and Leukemia Group B study. Blood 1987 May; 69 (5): 1441–9.PubMedGoogle Scholar
  103. 103.
    Dillman RO, Davis RB, Green MR, et al. Acomparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukaemia Group B. Blood 1991 Nov; 78 (10): 2520–6.PubMedGoogle Scholar
  104. 104.
    Early AP, Preisler HD, Slocum H, et al. A pilot study of highdose 1-β-D-arabinofuranosyl cytosine for acute leukemia and refractory lymphoma: clinical response and pharmacology. Cancer Res 1982; 42: 1587–94.PubMedGoogle Scholar
  105. 105.
    Castleberry RP, Crist WM, Holbrook T, et al. The cytosine arabinoside syndrome (araC). Med Pediatr Oncol 1981; 9: 257–61.PubMedCrossRefGoogle Scholar
  106. 106.
    Herzig RH, Hines JD, Herzig GP, et al. Cerebellar toxicity with high-dose cytosine arabinoside. J Clin Oncol 1987 Jun; 5 (6): 927–32.PubMedGoogle Scholar
  107. 107.
    Ho DHW, Frei E III. Clinical pharmacology of 1-β-D-arabino-furanosylcytosine. Clin Pharmacol Ther 1971; 12: 944–54.PubMedGoogle Scholar
  108. 108.
    Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999 Oct; 17 (10): 3110–6.PubMedGoogle Scholar
  109. 109.
    Prentice HG, Smyth JF, Ganeshaguru K, et al. Remission induction with adenosine deaminase inhibitor 2′-deoxycoformycin in thy- lymphoblastic leukaemia. Lancet 1980; II: 170–2.CrossRefGoogle Scholar
  110. 110.
    Murphy SB, Sinkule JA, Rivera G. Phase I-II clinical and pharmacodynamic study of effects of 2′-deoxycoformycin administered by continuous infusion in children with refractory acute lymphoblastic leukemia. Cancer Treat Symp 1984; 2: 55–61.Google Scholar
  111. 111.
    Grever MR, Coleman MS, Gray DP, et al. Definition of safe, effective dosing regimen of 2′-deoxycoformycin with biochemical investigation. Cancer Treat Symp 1984; 2: 43–9.Google Scholar
  112. 112.
    Spiers ASD, Parekh SJ, Bishop MB. Hairy cell leukemia: induction of complete remission with pentostatin (2′-deoxycofor-mycin). J Clin Oncol 1984 Dec; 2 (12): 1336–42.PubMedGoogle Scholar
  113. 113.
    Major PP, Agarwal RP, Kufe DW. Deoxycoformycin: neurological toxicity. Cancer Chemother Pharmacol 1981; 5: 193–6.PubMedCrossRefGoogle Scholar
  114. 114.
    Grever MR, Bisaccia E, Scarborough DA, et al. An investigation of 2′-deoxycoformycin in the treatment of cutaneous T-cell lymphoma. Blood 1983 Feb; 61 (2): 279–82.PubMedGoogle Scholar
  115. 115.
    Tobinai K, Shimoyama M, Inoue S, et al. Phase I study of YK-176 (2′-deoxycoformycin) in patients with adult T-cell leukemia-lymphoma. Jpn J Clin Oncol 1992; 22: 164–71.PubMedGoogle Scholar
  116. 116.
    Johnson SA, Catovsky D, Child JA, et al. Phase I/II evaluation of pentostatin (2′-deoxycoformycin) in a five day schedule for the treatment of relapsed/refractory B-cell chronic lymphocytic leukaemia. Invest New Drugs 1998; 16: 155–60.PubMedCrossRefGoogle Scholar
  117. 117.
    Seymour JF, O’Brien S, Kurzrock R, et al. A phase I study of seven day continuous infusion deoxycoformycin [abstract 1328]. Proc Am Soc Clin Oncol 1994; 13: 390.Google Scholar
  118. 118.
    Steis RG, Urba WJ, Kopp WC, et al. Kinetics of recovery of CD4+ T-cells in peripheral blood of deoxycoformycin-treated patients. J Natl Cancer Inst 1991 Nov; 83 (22): 1678–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Seymour JF, Talpaz M, Kurzrock R. Response duration and recovery of CD4+ lymphocytes following deoxycoformycin in interferon-alpha resistant hairy cell leukemia: 7 year follow-up. Leukaemia 1997; 11 (1): 42–7.CrossRefGoogle Scholar
  120. 120.
    Warrel Jr RP, Berman E. Phase I and II study of fludarabine phosphate in leukemia: therapeutic efficacy with delayed central nervous system toxicity. J Clin Oncol 1986 Jan; 4(1): 74–9.Google Scholar
  121. 121.
    Spriggs DR, Stopa E, Mayer RJ, et al. Fludarabine phosphate (NSC 312878) infusions for the treatment of acute leukemia: phase I and neuropathological study. Cancer Res 1986 Nov; 46: 5953–8.PubMedGoogle Scholar
  122. 122.
    Rodriguez G. Fludarabine phosphate: a new anticancer drug with significant activity in patients with chronic lymphocytic leukemia and in patients with lymphoma. Invest New Drugs 1994; 12:75–92.PubMedCrossRefGoogle Scholar
  123. 123.
    Grever MR, Kopecky KJ, Coltman CA, et al. Fludarabine monophosphate: a potentially useful agent in chronic lymphocytic leukaemia. Nouv Rev Fr Hematol 1988; 30: 457–9.PubMedGoogle Scholar
  124. 124.
    Keating MJ, Kantarjian H, Talpaz M, et al. Fludarabine therapy in chronic lymphocytic leukemia (CLL). Nouv Rev Fr Hematol 1988; 30: 461–6.PubMedGoogle Scholar
  125. 125.
    Rai KR, Peterson B, Kolitz J, et al. Fludarabine induces a high complete remission rate in previously untreated patients with active chronic lymphocytic leukemia (CLL): a randomized Inter-Group Study [abstract 2414]. Blood 1995; 86 (1) Suppl. 1:607a.Google Scholar
  126. 126.
    French Co-operative Group on CLL, Johnson S, Smith AG, et al. Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. Lancet 1996; 347: 1432–7.PubMedGoogle Scholar
  127. 127.
    Leiby JM, Snider KM, Kraut EH, et al. Phase II trial of 9-β-D-arabinosyl-2-fluoroadenine 5′-monophosphate in non-Hodg-kin’s lymphoma: prospective comparison of response with deoxycytidine kinase activity. Cancer Res 1987; 47: 2719–22.PubMedGoogle Scholar
  128. 128.
    Puccio CA, Mittelman A, Lichtman SM, et al. A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia. J Clin Oncol 1991 (Sep); 9 (9): 1562–9.Google Scholar
  129. 129.
    Robertson LE, O’Brien S, Kantarjian H, et al. A 3-day schedule of fludarabine in previously treated chronic lymphocytic leukemia. Leukemia 1995; 9: 1444–9.PubMedGoogle Scholar
  130. 130.
    Kemena A, O’Brien S, Kantarjian H, et al. Phase II clinical trial of fludarabine in chronic lymphocytic leukemia on a weekly low-dose schedule. Leuk Lymphoma 1993; 10: 187–93.PubMedCrossRefGoogle Scholar
  131. 131.
    Chun HG, Leyland-Jones B, Cheson BD. Fludarabine phosphate: a synthetic purine antimetabolite with significant activity against lymphoid malignancies. J Clin Oncol 1991 Jan; 9 (1): 175–88.PubMedGoogle Scholar
  132. 132.
    Kraut EH, Crowley JJ, Grever MR, et al. Phase II study of fludarabine phosphate in multiple myeloma: a Southwest Oncology Group study. Invest New Drugs 1990; 8: 199–200.PubMedCrossRefGoogle Scholar
  133. 133.
    Solal-Celigny P, Brice P, Brousse N, et al. Phase II trial of fludarabine monophosphate as first-line treatment in patients with advanced follicular lymphoma: a multicenter study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 1996 Feb; 14(2): 514–9.PubMedGoogle Scholar
  134. 134.
    Wijermans PW, Gerrits WBJ, Haak HL. Severe immunodeficiency in patients treated with fludarabine monophosphate. Eur J Haematol 1993; 50: 292–6.PubMedCrossRefGoogle Scholar
  135. 135.
    Schilling PJ, Vadhan-Raj S. Concurrent cytomegalovirus and pneumocystis pneumonia after fludarabine therapy for chronic lymphocytic leukemia. N Engl J Med 1990; 323: 833–4.PubMedCrossRefGoogle Scholar
  136. 136.
    O′Brien S, Kantarjian H, Beran M, et al. Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 1993; 82 (6): 1695–1700.PubMedGoogle Scholar
  137. 137.
    Piro LD, Carrera CJ, Carson DA, et al. Lasting remissions in hairy cell leukaemia induced by a single infusion of 2-chlorodeoxyadenosine. N Engl J Med 1990; 322: 1117–21.PubMedCrossRefGoogle Scholar
  138. 138.
    Saven A, Kawasaki H, Carrera CJ, et al. 2-Chlorodeoxyadenosine dose-escalation in non-hematological malignancies. J Clin Oncol 1993 Apr; 11 (4): 671–8.PubMedGoogle Scholar
  139. 139.
    Weiss GR, Kuhn JG, Rizzo J, et al. A phase I and pharmacokinetics study of 2-chlorodeoxyadenosine in patients with solid tumours. Cancer Chemother Pharmacol 1995; 35: 397–402.PubMedCrossRefGoogle Scholar
  140. 140.
    Santana VM, Mirro Jr J, Harwood FC, et al. A phase I clinical trial of 2-chlorodeoxyadenosine in pediatric patients with acute leukemia. J Clin Oncol 1991 Mar; 9 (3): 416–22.PubMedGoogle Scholar
  141. 141.
    Santana VM, Mirro Jr J, Kearns C, et al. 2-Chlorodeoxyadenosine produces a high rate of complete hematologic remission in relapsed acute myeloid leukaemia. J Clin Oncol 1992 Mar; 10 (3): 364–70.PubMedGoogle Scholar
  142. 142.
    Vahdat L, Wong ET, Wile MJ, et al. Therapeutic and neurotoxic effects of 2-chlorodeoxyadenosine in adults with acute myeloid leukemia. Blood 1994 Nov; 84 (10): 3429–34.PubMedGoogle Scholar
  143. 143.
    Kobayashi K, Vogelzang NJ, O’Brien SM, et al. Aphase I study of intermittent infusion cladribine in patients with solid tumors. Cancer 1994; 74: 168–73.PubMedCrossRefGoogle Scholar
  144. 144.
    Larson RA, Mick R, Spielberger RT, et al. Dose-escalation trial of cladribine using five daily intravenous infusions in patients with advanced hematologic malignancies. J Clin Oncol 1996 Jan; 14(1): 188–95.PubMedGoogle Scholar
  145. 145.
    Raemaekers J, vt Veer M, Verhoef G, et al. Two-hours iv infusion of 2-chlorodeoxyadenosine (2-CDA) in hairy cell leukaemia (HCL) is effective and may produce less CD4/CD8 ratio impairment: results from the HOVON-23 study [abstract 1392]. Blood 1995; 86 Suppl. 1: 351a.Google Scholar
  146. 146.
    Von Rohr A, Bacchi M, Fey MF, et al. 2-Chlorodeoxyadenosine (CDA) by subcutaneous bolus injection: a phase II study in hairy cell leukemia (HCL) [abstract 1386]. Blood 1995; 86 Suppl. 1: 350a.Google Scholar
  147. 147.
    Juliusson G, Heidal D, Hippe E, et al. Subcutaneous injections of 2-chlorodeoxyadenosine for symptomatic hairy cell leukaemia. J Clin Oncol 1995 Apr; 13 (4): 989–95.PubMedGoogle Scholar
  148. 148.
    Delannoy A, Martiat P, Gala JL, et al. 2-Chlorodeoxyadenosine (CdA) for patients with previously untreated chronic lymphocytic leukemia. Leukemia 1995 Jul: 9 (7): 1130–5.PubMedGoogle Scholar
  149. 149.
    Robak T, Blasinka-Morawiec M, Krykowski E, et al. Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma 1996; 22: 509–14.PubMedCrossRefGoogle Scholar
  150. 150.
    Juliusson G, Christiansen I, Hansen MM, et al. Oral cladribine as primary therapy for patients with B-cell chronic lymphocytic leukemia. J Clin Oncol 1996 Jul; 14 (7): 2160–6.PubMedGoogle Scholar
  151. 151.
    Betticher DC, Ratschiller D, Hsu-Schmitz S-F, et al. Reduced dose of subcutaneous cladribine induces identical response rates but decreased toxicity in pre-treated chronic lymphocytic leukemia. Ann Oncol 1998; 9: 721–6.PubMedCrossRefGoogle Scholar
  152. 152.
    Seymour JF, Kurzrock R, Freireich EJ, et al. 2-Chlorodeoxy-adenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia. Blood 1994 May; 83 (10): 2906–11.PubMedGoogle Scholar
  153. 153.
    Hansen HH, Sorenson JB. Efficacy of single-agent gemcitabine in advanced non-small cell lung cancer: a review. Semin Oncol 1997 Apr; 24 (2) Suppl. 7: 38–41.Google Scholar
  154. 154.
    Storniolo AM, Enas NH, Brown CA, et al. An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 1999; 85: 1261–8.PubMedCrossRefGoogle Scholar
  155. 155.
    Carmichael J, Possinger K, Phillip P, et al. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol 1995; 13: 2731–6.PubMedGoogle Scholar
  156. 156.
    Lund B, Hansen OP, Theilade K, et al. Phase II study of gemcitabine (2′,2′-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 1994; 86: 1530–3.PubMedCrossRefGoogle Scholar
  157. 157.
    Catimel G, Vermorken JB, Clavel M, et al. A phase II study of gemcitabine (LY188011 ) in patients with advanced squamous cell carcinoma of the head and neck. Ann Oncol 1994; 5: 543–7.PubMedGoogle Scholar
  158. 158.
    Bernell P, Ohm L. Promising activity of gemcitabine in refractory high-grade non-Hodgkin’s lymphoma. Br J Haematol 1998; 101: 203–4.PubMedCrossRefGoogle Scholar
  159. 159.
    Kaye SB. Gemcitabine: current status of phase I and II trials. J Clin Oncol 1994 Aug; 12 (8): 1527–31.PubMedGoogle Scholar
  160. 160.
    Gatzmeier U, Shepherd FA, Le Chevalier T, et al. Activity of gemcitabine in patients with non-small cell lung cancer: a multicentre extended phase II study. Eur J Cancer 1996; 32A: 243–8.CrossRefGoogle Scholar
  161. 161.
    Bergman AM, Ruiz van Haperen VWT, Veermann G, et al. Synergistic interaction between cisplatin and gemcitabine in vitro. Clin Cancer Res 1996; 2: 521–30.PubMedGoogle Scholar
  162. 162.
    Zinzani PL, Magagnoli M, Bendandi M, et al. Therapy with gemcitabine in pretreated peripheral T-cell lymphoma patients. Ann Oncol 1998; 9: 1351–3.PubMedCrossRefGoogle Scholar
  163. 163.
    Tesch H, Santoro A, Fiedler F, et al. Phase II study of gemcitabine in pretreated Hodgkin’s disease: results of a multicenter study [abstract 1514]. Blood 1997; 90 Suppl. 1: 339a.Google Scholar
  164. 164.
    Gandhi V, Plunkett W. Modulation of arabinosyl nucleoside metabolism by arabinosyl nucleotides in human leukemia cells. Cancer Res 1988; 48: 329–34.PubMedGoogle Scholar
  165. 165.
    Rayappa C, McCulloch EA. A cell culture model for the treatment of acute myeloblastic leukemia with fludarabine and cytosine arabinoside. Leukemia 1993; 7: 992–9.PubMedGoogle Scholar
  166. 166.
    Gandhi V, Estey E, Du M, et al. Modulation of the cellular metabolism of cytarabine and fludarabine by granulocytecolony stimulating factor during therapy for acute myelogenous leukemia. Clin Cancer Res 1995; 1 (2): 169–78.PubMedGoogle Scholar
  167. 167.
    Estey E, Thall P, Andreeff M, et al. Use of granulocyte colonystimulating factor before, during, and after fludarabine cytarabine induction therapy of newly diagnosed acute myelogenous leukemia or myelodysplastic syndromes: comparison with fludarabine plus cytarabine without granulocyte colony-stimulating factor. J Clin Oncol 1994 Apr; 12 (4): 671–8.PubMedGoogle Scholar
  168. 168.
    Estey EH, Thall PF, Pierce S, et al. Randomised phase II study of fludarabine + cytosine arabinoside + idarubicin ± all-trans retinoic acid ± granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome. Blood 1999 Apr; 93 (8): 2478–84.PubMedGoogle Scholar
  169. 169.
    Estey E, Thall P, Beran M, et al. Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 1997 Oct; 90 (8): 2969–77.PubMedGoogle Scholar
  170. 170.
    Kornblau SM, Cortes-Franco J, Estey E. Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia. Leukemia 1993 Mar; 7 (3): 378–83.PubMedGoogle Scholar
  171. 171.
    Gandhi V, Estey E, Keating MJ, et al. Chlorodeoxyadenosine and arabinosylcytosine in patients with acute myelogenous leukaemia: pharmacokinetic, pharmacodynamic, and molecular interactions. Blood 1996 Jan; 87 (1): 256–64.PubMedGoogle Scholar
  172. 172.
    Gandhi V, Robertson LE, Keating MJ, et al. Combination of fludarabine and arabinosylcytosine for treatment of chronic lymphocytic leukemia: clinical efficacy and modulation of arabinosylcytosine pharmacology. Cancer Chemother Pharmacol 1994; 34: 30–6.PubMedCrossRefGoogle Scholar
  173. 173.
    Robertson LE, Hall R, Keating MJ, et al. High-dose cytosine arabinoside in chronic lymphocytic leukemia: a clinical and pharmacologic analysis. Leuk Lymphoma 1993; 10: 43–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Yang L-Y, Li L, Keating MJ, et al. Arabinosyl-2-fluoroadenine augments cisplatin cytotoxicity and inhibits cisplatin-DNA cross-link repair. Mol Pharmacol 1995; 47: 1072–9.PubMedGoogle Scholar
  175. 175.
    Robertson LE, Kantarjian H, O’Brien S, et al. Cisplatin, fludarabine and araC (PFA): a regimen for advanced refractory chronic lymphocytic leukemia [abstract 1014]. Proc Am Soc Clin Oncol 1993; 12: 308.Google Scholar
  176. 176.
    Giles FJ, O’Brien S, Kantarjian HM, et al. Sequential cis-platinum, fludarabine and arabinosyl cytosine (PFA) or cyclophosphamide, fludarabine and arabinosyl cytosine (CFA) in patients with Richter’s Syndrome: a pilot study [abstract 360]. Blood 1996; 88 (10) Suppl. 1: 93a.Google Scholar
  177. 177.
    Seymour JF, Grigg A, Szer J, et al. Fludarabine, cisplatin, and araC in patients with anthracycline-refractory intermediate-grade and high-grade non-Hodgkin’s lymphoma: the International Oncology Study Group (IOSG) NHL 2 study [abstract 506]. Int JHematol 1996; 64 Suppl. 1: S131.Google Scholar
  178. 178.
    Child JA, Johnson SA, Rule S, et al. FluDAP: salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin’s lymphoma. Leuk Lymphoma 2000 Apr; 37(3–4): 309–17.PubMedGoogle Scholar
  179. 179.
    Peters GJ, Ruiz van Haperen VWT, Bergman AM, et al. Preclinical combination therapy with gemcitabine and mechanisms of resistance. Semin Oncol 1996; 23 Suppl. 10: 16–24.Google Scholar
  180. 180.
    Shephard FA, Burkes R, Cormier Y, et al. Phase I dose-escalation trial of gemcitabine and cisplatin for advanced non-small cell lung cancer: usefulness of mathematic modeling to determine maximum tolerated dose. J Clin Oncol 1996; 14: 1656–62.Google Scholar
  181. 181.
    Abratt RP, Bezwoda WR, Goedhals L, et al. Weekly gemcitabine with monthly cisplatin: effective chemotherapy for advanced non-small cell lung cancer. J Clin Oncol 1997; 15: 744–9.PubMedGoogle Scholar
  182. 182.
    Einhorn LH. Phase II trial of gemcitabine plus cisplatin in non-small cell lung cancer: a Hoosier Oncology Group Study. Semin Oncol 1997; 24 Suppl. 8: 24–6.Google Scholar
  183. 183.
    Steward WP, Dunlop DJ, Dabouis G, et al. Phase I-II study of gemcitabine and weekly cisplatin in the treatment of advanced non-small cell lung cancer — preliminary results. Semin Oncol 1996; 23 Suppl. 10: 43–7.Google Scholar
  184. 184.
    Shepherd FA, Cormier Y, Burkes R, et al. Phase II trial of gemcitabine and weekly cisplatin for advanced non-small cell lung cancer. Semin Oncol 1997; 24 Suppl. 8: 27–30.Google Scholar
  185. 185.
    Crino L, Scagliotti G, Marangolo M, et al. Cisplatin-gemcitabine combination in advanced non-small cell lung cancer. J Clin Oncol 1997; 15: 297–303.PubMedGoogle Scholar
  186. 186.
    Abratt RP, Sandier A, Crino L, et al. Combined cisplatin and gemcitabine for non-small cell lung cancer: influence of scheduling on toxicity and drug delivery. Semin Oncol 1998; 25 Suppl. 9: 35–43.Google Scholar
  187. 187.
    Van Moorsel CJA, Kroep JR, Pinedo HM, et al. Pharmacokinetic schedule finding study of the combination of gemcitabine and cisplatin in patients with solid tumors. Ann Oncol 1999; 10:441–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Kroep JR, Peters GJ, van Moorsel CJA, et al. Gemcitabine-cisplatin: a schedule finding study. Ann Oncol 1999; 10:1503–10.PubMedCrossRefGoogle Scholar
  189. 189.
    Haider K, Kornek GV, Kwasny W, et al. Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony-stimulating factor. Breast Cancer Res Treat 1999; 55: 203–11.PubMedCrossRefGoogle Scholar
  190. 190.
    Delord JP, Raymond E, Chaouche M, et al. Adose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies. Ann Oncol 2000; 11: 73–9.PubMedCrossRefGoogle Scholar
  191. 191.
    Lorusso V, Carpagnano F, Frasci G, et al. Phase I/II study of gemcitabine plus vinorelbine as first-line chemotherapy of non-small cell lung cancer. J Clin Oncol 2000; 18: 405–11.PubMedGoogle Scholar
  192. 192.
    Kroep JR, Giaccone G, Voorn DA, et al. Gemcitabine and paclitaxel: pharmacokinetic and pharmacodynamic interaction in patients with non-small cell lung cancer. J Clin Oncol 1999; 17: 2190–7.PubMedGoogle Scholar
  193. 193.
    Robertson LE, O’Brien S, Kantarjian H, et al. Fludarabine plus doxorubicin in previously treated chronic lymphocytic leukemia. Leukemia 1995; 9: 943–5.PubMedGoogle Scholar
  194. 194.
    McLaughlin P, Hagemeister FB, Swan Jr F, et al. Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 1994 Mar; 12 (3); 575–9.PubMedGoogle Scholar
  195. 195.
    McLaughlin P, Hagemeister FB, Romaguera JE, et al. Fludarabine, mitoxantrone and dexamethasone: an effective new regimen for indolent lymphoma. J Clin Oncol 1996 Apr; 14 (4): 1262–8.PubMedGoogle Scholar
  196. 196.
    Seymour JF, Grigg AP, Szer J, et al. Fludarabine and mitoxantrone: a highly effective and well-tolerated salvage therapy for low-grade lymphoproliferative disorders [abstract 1530]. Blood 1997; 90 Suppl. 1: 343a.Google Scholar
  197. 197.
    Saven A, Lee T, Kosty M, et al. Cladribine and mitoxantrone dose escalation in indolent non-Hodgkin’s lymphoma. J Clin Oncol 1996 Jul; 14(7): 2139–44.PubMedGoogle Scholar
  198. 198.
    Koehl U, Li L, Nowak B, et al. Fludarabine and cyclophosphamide: synergistic cytotoxicity associated with inhibition of interstrand cross-link removal [abstract 10]. Proc Am Assoc Cancer Res 1997; 38: 2.Google Scholar
  199. 199.
    Weiss M, Spiess T, Berman E, et al. Concomitant administration of chlorambucil limits dose intensity of fludarabine in previously treated patients with chronic lymphocytic leukemia. Leukemia 1994 Aug; 8 (8): 1290–3.PubMedGoogle Scholar
  200. 200.
    Elias L, Stock-Novack D, Head DR, et al. A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study. Leukemia 1993 Mar; 7 (3): 361–5.PubMedGoogle Scholar
  201. 201.
    Tefferi A, Witzig TE, Reid JM, et al. Phase I study of combined 2-chlorodeoxyadenosine and chlorambucil in chronic lymphoid leukaemia and lymphoma. J Clin Oncol 1994 Mar; 12 (3): 569–74.PubMedGoogle Scholar
  202. 202.
    Hochster H, Oken M, Winter NJ, et al. Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: results and and long-term follow-up: a report from the Eastern Cooperative Oncology Group. J Clin Oncol 2000 Mar; 18 (5): 987–94.PubMedGoogle Scholar
  203. 203.
    O’Brien S, Kantarjian H, Beran M, et al. Fludarabine and cyclophosphamide therapy in chronic lymphocytic leukemia [abstract 1910]. Blood 1996; 88 Suppl. 1: 480a.Google Scholar
  204. 204.
    Frewin R, Turner D, Tighe M, et al. Combination therapy with fludarabine and cyclophosphamide as salvage treatment in lymphoproliferative disorders. Br J Haematol 1999; 104: 612–3.PubMedCrossRefGoogle Scholar
  205. 205.
    Giralt S, Estey E, Albitar M, et al. Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997 Jun; 89 (12): 4531–6.PubMedGoogle Scholar
  206. 206.
    Slavin S, Nagler A, Naparstek F, et al. Non-myeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non-malignant hematologic diseases. Blood 1998 Feb; 91 (3): 756–63.PubMedGoogle Scholar
  207. 207.
    Khouri IF, Keating M, Korbling M, et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based non-ablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998 Aug; 16 (8): 2817–24.PubMedGoogle Scholar
  208. 208.
    Grigg A, Bardy P, Byron K, et al. Fludarabine-based non-myeloablative chemotherapy followed by infusion of HLA-identical stem cells for relapsed leukemia and lymphoma. Bone Marrow Transplant 1999; 23: 107–10.PubMedCrossRefGoogle Scholar
  209. 209.
    Gregoire V, Hittelman WN, Rosier JF. Chemo-radiotherapy: radiosensitizing nucleoside analogues. Oncol Rep 1999; 6(5): 949–57.PubMedGoogle Scholar
  210. 210.
    Jayanth RV, Hittelman WN. 9-β-D-Arabinofuranosyl-2-fluoro-adenine (F-ara-A) inhibits both the fast and slow components of chromosomal repair. In: Chapman JD, Dewey WC, Whitmore GF, editors. Radiation research: a twentieth century perspective. Vol. 1. San Diego (CA): Academic Press, 1991:411.Google Scholar
  211. 211.
    Gregoire V, Beauduin M, Bruniaux M, et al. Radiosensitization of mouse sarcoma cells by fludarabine (F-ara-A) or gemcitabine (dFdC), two nucleoside analogues, is not mediated by an increased induction or a repair inhibition of DNA double strand breaks as measured by pulsed field gel electrophoresis. Int J Rad Biol 1998; 73: 511–20.PubMedCrossRefGoogle Scholar
  212. 212.
    Lawrence TS, Eisbruch A, Shewach DS. Gemcitabine mediated radiosensitization. Semin Oncol 1997 Apr; 24 (2) Suppl. 7: 24–8.Google Scholar

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© Adis Internotionol Limited 2000

Authors and Affiliations

  1. 1.Department of HaematologyTaunton and Somerset HospitalTaunton SomersetEngland

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