Skip to main content
Log in

Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Fludarabine, the 5′-monophosphate of 9-β-D-arabinofuranosyl-2-fluoroadenine (FaraAMP), is effective in the treatment of chronic lymphocytic leukemia (CLL) and has been demonstrated to increase natural killer (NK) cell lytic activity (NKa) in humans and mice. To determine the effect of FaraAMP on NK cells in CLL, we analyzed NKa toward K562 targets after in vitro incubation with FaraAMP and after in vivo exposure to fludarabine. Pretreatment analysis of peripheral blood from 12 CLL patients (9 untreated) revealed: median number of NK cells 500/µl (range 290-1160); median NKa lytic unit30/106 cells (range 5–80). These results were similar to those from healthy adult donors. After exposure to 3, 30, or 300 µM FaraAMP, the median maximum stimulation index (NKa FaraAMP/NKa) was 1.2 (range 0.9-1.5), within the range observed in normal adults. FaraA also stimulated NKa in vitro toward autologous CLL cells in two of five patients as measured by a dye-exclusion assay. In three patients following three or more treatment courses of fludarabine (30 mg/m2 per day for 5 days) the NK cell number and NKa were maintained near pretreatment values. Phenotypic analysis of the peripheral mononuclear cells in 34 consecutive CLL patients revealed a marked reduction in CD5/CD20 and CD4 cell numbers after three courses of fludarabine with less effect on CD8 and CD56 cells. These results indicate that fludarabine spares NK cells and may stimulate NKa in some CLL patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Apostolopoulos A, Symeonidis A, Zoumbos N (1990) Prognostic significance of immune function parameters in patients with chronic lymphocytic leukaemia. Eur J Haematol 44:39

    PubMed  CAS  Google Scholar 

  2. Barlozzari T, Leonhardt J, Wiltrout RH, Herberman RB, Reynolds CW (1985) Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol 134:2783

    PubMed  CAS  Google Scholar 

  3. Boldt DH, Von Hoff DD, Kuhn JG, Hersh M (1984) Effects on human peripheral lymphocytes of in vivo administration of 9-β-D-arabinofuranosyl-2-fluoroadenine-5′-monophosphate (NSC 31887), a new purine antimetabolite. Cancer Res 44:4661

    PubMed  CAS  Google Scholar 

  4. Catapano CV, Chandler K, Fernandes DJ (1991) Inhibition of primer RNA formation in CCRF-CEM leukemia cells by fludarabine triphosphate. Cancer Res 51:18295

    Google Scholar 

  5. Cheson BD, Bennett JM, Rai KR, Grever MR, Kay NE, Schiffer CA, Oken MM, Keating MJ, Bolt DH, Kempin SJ, Foon KA (1988) Guidelines for clinical protocols for chronic lymphocytic leukemia: recommendations of the National Cancer Institute-Sponsored Working Group. Am J Hematol 29:152

    Article  PubMed  CAS  Google Scholar 

  6. Foa R, Lauria F, Lusso P, Guibellino MC, Fierro MT, Ferrando ML (1984) Discrepancy between phenotypic and functional features of natural killer T-lymphocytes in B-cell chronic lymphocytic leukaemia. Br J Haematol 58:509

    Article  PubMed  CAS  Google Scholar 

  7. Foa R, Fierro MT, Lusso P, Raspadori D, Ferrando ML, Matera L, Malavasi F, Lauria F (1986) Reduced natural killer T-cells in B-cell chronic lymphocytic leukaemia identified by three monoclonal antibodies: Leu-11, A10, AB8.28. Br J Haematol 62:151

    Article  PubMed  CAS  Google Scholar 

  8. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ (1972) Adenosine deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2:1067

    Article  PubMed  CAS  Google Scholar 

  9. Hanna N, Burton RC (1981) Definitive evidence that natural killer (NK) cells inhibit experimental tumor metastasis in vivo. J Immunol 127:1754

    PubMed  CAS  Google Scholar 

  10. Huang P, Chubb S, Plunkett W (1990) Termination of DNA synthesis by 9-β-D-arabinofuranosyl-2-fluoroadenine J Biol Chem 265:16617

    PubMed  CAS  Google Scholar 

  11. Humphries MJ, Matsumoto K, White SL, Molyneux RJ, Olden K (1988) Augmentation of murine natural killer cell activity by swainsonine, a new antimetastatic immunomodulator. Cancer Res 48:1410

    PubMed  CAS  Google Scholar 

  12. Kay NE, Perri RT (1988) Immunobiology of malignant B-cells and immunoregulatory cells in B-chronic lymphocytic leukemia. Clin Lab Med 8:163

    PubMed  CAS  Google Scholar 

  13. Kay NE, Perri RT (1989) Evidence that large granular lymphocytes from B-CLL patients with hypogammaglobulinemia down-regulate B-cell immunoglobulin synthesis. Blood 73:1016

    PubMed  CAS  Google Scholar 

  14. Kay NE, Zarling J (1985) Restoration of impaired natural killer cell activity of B-chronic lymphocytic leukemia patients by recombinant interleukin-2. Am J Hematol 24:161

    Article  Google Scholar 

  15. Keating MJ, Kantarjian H, Talpaz M, Redman J, Koller C, Barlogie B, Velasquez W, Plunkett W, Freireich EJ, McCredie K (1989) Fludarabine: A new agent with major activity against chronic lymphocytic leukemia. Blood 74:19

    PubMed  CAS  Google Scholar 

  16. Keating MJ, Kantarjian H, O’Brien S, Koller C, Talpaz M, Schachner J, Childs CC, Freireich EJ, McCredie KB (1991) Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia. J Clin Oncol 9:44

    PubMed  CAS  Google Scholar 

  17. Kumagai K, Suzuki S, Arai S (1985) Immunoregulatory effects of NK cells. In: Herberman RB, Callewaert DM (eds) Mechanism of cytotoxicity by NK cells. Academic Press, New York, p 489

    Google Scholar 

  18. Lauria F, Rondelli D, Raspadori D, Benfenati D, Tura S (1994) Rapid restoration of natural killer activity following treatment with 2-chlorodeoxyadenosine in 22 patients with hairy-cell leukemia. Eur J Haematol 52:16

    Article  PubMed  CAS  Google Scholar 

  19. Luebke RW, Lawson LD, Rogers RR, Riddle MM, Rowe DG, Smialowicz RJ (1987) Selective immunotoxic effects in mice treated with the adenosine deaminase inhibitor 2’-deoxycoformycin. Immunopharmacology 13:25

    Article  PubMed  CAS  Google Scholar 

  20. Nelson JA, Richie ER, Kandil O, Vidale E, Pan BF (1989) Differential sensitivities of normal and malignant murine lymphocytes to purine nucleosides. Nucleosides Nucleotides, 8:569

    Article  CAS  Google Scholar 

  21. Parker WB, Bapat AR, Shen JX, Townsend AJ, Cheng YC (1988) Interaction of 2-halogenated dATP analogs (F, Cl, and Br) with human DNA polymerase, DNA primase, and ribonucleotide reductase. Mol Pharmacol 34:485

    PubMed  CAS  Google Scholar 

  22. Perri RT, Kay NE (1989) Large granular lymphocytes from B-chronic lymphocytic leukemia patients inhibit normal B cell proliferation. Am J Hematol 31:166

    Article  PubMed  CAS  Google Scholar 

  23. Platsoucas CD, Fernandes G, Gupta SL, Kempin S, Clarkson B, Good RA, Gupta S (1980) Defective spontaneous and antibodydependent cytotoxicity mediated by E-rosette-positive and E-rosette-negative cells in untreated patients with chronic lymphocytic leukemia: augmentation by in vivo treatment with interferon. J Immunol 125:1216

    PubMed  CAS  Google Scholar 

  24. Priebe T, Kandil O, Nakic M, Pan, BF, Nelson JA (1988) Selective modulation of antibody response and natural killer cell activity by purine nucleoside analogues. Cancer Res 48:4799

    PubMed  CAS  Google Scholar 

  25. Priebe T, Platsoucas CD, Nelson JA (1990) Adenosine receptors and modulation of natural killer cell activity by purine nucleosides. Cancer Res 50:4328

    PubMed  CAS  Google Scholar 

  26. Priebe T, Platsoucas CD, Seki H, Fox FE, Nelson JA (1990) Purine nucleoside modulation of functions of human lymphocytes. Cell Immunol 129:321

    Article  PubMed  CAS  Google Scholar 

  27. Priebe T, Ruiz L, Nelson JA (1990) Role of natural killer cells in the modulation of primary antibody production by purine nucleosides and their analogues. Cell Immunol 130:513

    Article  PubMed  CAS  Google Scholar 

  28. Rai KR, Sawitsky A, Cronkite EP (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219

    PubMed  CAS  Google Scholar 

  29. Redman JR, Cabanillas F, Velasquez WS, McLaughlin P, Hagemeister FB, Swan F, Rodriquez MA, Plunkett WK, Keating, MJ (1992) Phase II trial of fludarabine phosphate in lymphoma: An effective new agent in low grade lymphomas. J Clin Oncol 10:790

    PubMed  CAS  Google Scholar 

  30. Robertson LE, Huh YO, Butler JJ, Pugh WC, Hirsch-Ginsberg C, Stass S, Kantarjian H, Keating MJ (1992) Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: Clinical, pathologic, immunophenotypic, and molecular analysis. Blood 80:29

    PubMed  CAS  Google Scholar 

  31. Robertson LE, Denny AW, Keating MJ, Huh YO, Plunkett W, Nelson JA (1994) Fludarabine modulation of NK cell activity in chronic lymphocytic leukemia. Proc. Am. Assoc Cancer Res 35:3147

    Google Scholar 

  32. Roder JC, Lohmann-Matthes M-L, Domzig W, Wigzell H (1979) The beige mutation in the mouse. II. Selectivity of the natural killer (NK) cell defect. J Immunol 5:2174

    Google Scholar 

  33. Seegmiller JE (1985) Overview of possible relation of defects in purine metabolism to immune deficiency. Ann N Y Acad Sci 451:9

    Article  PubMed  CAS  Google Scholar 

  34. Villamor N, Reverter J-C, Montserrat E, Urbano-Ispizua A, Vives-Corrons J-L, Rozman C (1992) Recombinant alpha-2b-interferon may restore natural-killer activity in patients with B-chronic lymphocytic leukemia. Leukemia 6:547

    PubMed  CAS  Google Scholar 

  35. Yang S-W, Huang P, Plunkett W, Becker FF, Chan YH (1992) Dual mode of inhibition of purified DNA ligase I from human cells by 9-β-D-arabinofuranosyl-2-fiuoroadenine triphosphate. J Biol Chem 267:2345

    PubMed  CAS  Google Scholar 

  36. Ziegler HW, Kay NE, Zarling JM (1981) Deficiency of natural killer cell activity in patients with chronic lymphocytic leukemia. Int J Cancer 27:321

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This work was supported by NIH Grant CA-32839 from the National Cancer Institute, Department of Health and Human Services, and by a Physicians Referral Service Award

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robertson, L.E., Denny, A.W., Huh, Y.O. et al. Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine. Cancer Chemother Pharmacol 37, 445–450 (1996). https://doi.org/10.1007/s002800050410

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s002800050410

Key words

Navigation