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Drug Resistance in Acute Leukemias

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Treatment of Acute Leukemias

Part of the book series: Current Clinical Oncology ((CCO))

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Abstract

Drug resistance in acute leukemia was first described by Farber et al. (1) in cases of acute lymphoblastic leukemia (ALL) and is still the major cause of death in all types of acute leukemia. A mathematical model for the development of drug resistance in tumors was proposed in 1979 by Goldie and Coldman (2), based on the hypothesis that cancer cells have a high spontaneous mutation rate that leads, over time, to the emergence of cells resistant to chemotherapeutic drugs. To reduce the rate of emergence of resistant cells according to this hypothesis, the simultaneous administration of multiple drugs with different targets was suggested. Despite the introduction of combination chemotherapies, treatment failures continued to be observed. Rates of initial treatment failure and relapse were lowest in childhood ALL, whereas adults with ALL or acute myeloid leukemia (AML) mainly died of their disease, regardless of the treatment they received. Over the last 20 years, experimental models and clinical research have identified several causes of drug resistance in tumors. This improved understanding of the mechanisms involved in drug resistance has permitted the development of new therapeutic strategies.

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References

  1. Farber S, Diamond L, Mercer R, et al. Temporary remission in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Engl J Med 1948; 238:787–793.

    Article  PubMed  CAS  Google Scholar 

  2. Goldie J, Coldman A. A mathematical model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Res 1979;63:1727–1731.

    CAS  Google Scholar 

  3. Veerman A, Pieters R. Drug sensitivity assays in leukemia and lymphoma. Br J Haematol 1990;74:381–384.

    Article  PubMed  CAS  Google Scholar 

  4. Delmer A, Marie J, Thevenin D, et al. Multivariate analysis of prognostic factors in acute myeloid leukemia: value of clonogenic leukemic cell properties. J Clin Oncol 1989;7:738–746.

    PubMed  CAS  Google Scholar 

  5. Pieters R, Huismans D, Loonen A, et al. Relation of cellular drug resistance to long term clinical outcome in childhood acute lymphoblastic leukemia. Lancet 1991;338:399–403.

    Article  PubMed  CAS  Google Scholar 

  6. Legrand O, Simonin G, Beauchamp-Nicoud A, Zittoun R, Marie JP. Simultaneous activity of MRP1 and Pgp is correlated with in vitro resistance to daunorubicin and with in vivo resistance in adult acute myeloid leukemia. Blood 1999;94:1046–1056.

    PubMed  CAS  Google Scholar 

  7. Zimm S, Collins J, Riccardi R, et al. Variable bioavailability of oral mercaptopurine: is maintenance chemotherapy in acute lymphoblastic leukema being optimally delivered? N Engl J Med 1983;308:1005–1009.

    Article  PubMed  CAS  Google Scholar 

  8. Biedler J, Riehm H. Cellular resistance to actinomycin D in Chinese hamster in vitro: cross resistance, radioautographic and cytogenetic studies. Cancer Res 1970;30:1174–1180.

    PubMed  CAS  Google Scholar 

  9. Hyde S, Emsley P, Hartshorn M, et al. Structural model of ATPbinding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature 1990;346:362–365.

    Article  PubMed  CAS  Google Scholar 

  10. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455:152–162.

    Article  PubMed  CAS  Google Scholar 

  11. Legrand O, Perrot J, Tang R, et al. Expression of the multidrug resistance-associated protein (MRP) mRNA and protein in normal peripheral blood and bone marrow haematopoietic cells. Br J Haematol 1996;94:23–33.

    Article  PubMed  CAS  Google Scholar 

  12. Chaudary P, Roninson I. Expression and activity of P-gp, a multidrug efflux pump, in human hematopoietic stem cells. Cell 1991;66:85–94.

    Article  Google Scholar 

  13. Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood 1994;83:2451–2458.

    PubMed  CAS  Google Scholar 

  14. Kool M, de Hass M, Scheffer G, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1) in human cancer cell lines. Cancer Res 1997;57:3557–3547.

    Google Scholar 

  15. Beck W, Grogan T, Willman C, et al. Methods to detect P-glycoprotein-associated multidrug resistance in patients’ tumors: consensus recommendations. Cancer Res 1996;56:3010–3020.

    PubMed  CAS  Google Scholar 

  16. Marie J, Huet S, Faussat A, et al. Multicentric evaluation of the MDR phenotype in leukemia. Leukemia 1997;11:1086–1094.

    Article  PubMed  CAS  Google Scholar 

  17. Kühnel J, Perrot J, Faussat A, Marie J, Schwaller M. Functional assay of multidrug resistant cells using JC-1, a carbocyanine fluorescent probe. Leukemia 1997;11:1147–1155.

    Article  PubMed  Google Scholar 

  18. Legrand O, Perrot J, Baudard M, et al. JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia. Blood 2001;97:502–508.

    Article  PubMed  CAS  Google Scholar 

  19. Legrand O, Zittoun R, Marie JP. Role of MRP1 in multidrug resistance in acute myeloid leukemia. Leukemia 1999;13:578–584.

    Article  PubMed  CAS  Google Scholar 

  20. Legrand O, Simonin G, Perrot J, Zittoun R, Marie J. P-gp and MRP activities using calcein-AM are prognostic factors in adult myeloid leukemia patients. Blood 1998;91:1180–1188.

    Google Scholar 

  21. Spears C. Clinical resistance to antimetabolites. Hematol/Oncol Clin North Am 1995;9:397–413.

    CAS  Google Scholar 

  22. Moskow J. Methotrexate transport and resistance. Leuk Lymphoma 1998;30:215–224.

    Google Scholar 

  23. Gati W, Paterson A, Larratt L, Turner A, Belch A. Sensitivity of acute leukemia cells to cytarabine is a correlate of cellular as nucleoside transporter site content measured by flow cytometry with SAENTA-fluorescein. Blood 1997;90:346–353.

    PubMed  CAS  Google Scholar 

  24. Rustum Y, Preisler H. Correlation between leukemic cell retention of cytosine arabinoside and response to therapy. Cancer Res 1979; 39:42–49.

    PubMed  CAS  Google Scholar 

  25. Galmarini CM, Thomas X, Calvo F, et al. In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br J Haematol 2002;117:860–868.

    Article  PubMed  CAS  Google Scholar 

  26. Fisher D. Apoptosis in cancer therapy: crossing the threshold. Cell 1994;78:539–542.

    Article  PubMed  CAS  Google Scholar 

  27. Harris C. Structure and function of the p53 tumor suppressor gene: clues for rational cancer therapeutic strategies. J Natl Cancer Inst 1996;88:1442–1455.

    Article  PubMed  CAS  Google Scholar 

  28. Sherr C. Cancer cell cycles. Science 1996;274:1672–1677.

    Article  PubMed  CAS  Google Scholar 

  29. Kohn K. Regulatory genes and drug sensitivity. J Natl Cancer Inst 1996;88:1255–1256.

    Article  PubMed  CAS  Google Scholar 

  30. Reed J. Bcl-2: prevention of apoptosis as a mechanism of drug resistance. Hematol Oncol Clin North Am 1995;9:451–473.

    PubMed  CAS  Google Scholar 

  31. Smyth M, Krasovskis E, Sutton V, Johnstone R. The drug efflux protein P-glycoprotein additionally protects drug resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sei USA 1998;95:7024–7027.

    Article  CAS  Google Scholar 

  32. Johnstone R, Cretney E, Smyth M. P-glycoprotein protects leuke­mia cells against caspase dependent but not caspase independent cell death. Blood 1999;93:1075–1081.

    PubMed  CAS  Google Scholar 

  33. Legrand O, Perrot J, Baudard M, et al. The immunophenotype of 177 adult myeloid leukemias: proposal for a prognostic score. Blood 2000;96:870–877.

    PubMed  CAS  Google Scholar 

  34. te Boekhorst P, de Leeuw K, Schoester M, et al. Predominance of functional multidrug resistance (MDR-1) phenotype in CD34+ acute myeloid leukemia cells. Blood 1993;82:3157–3162.

    Google Scholar 

  35. Paietta E, Andersen J, Racevskis J, et al. Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, mo­lecular and functional analyses. Leukemia 1994;8:968–973.

    PubMed  CAS  Google Scholar 

  36. Drach D, Zhao S, Drach J, Andreeff M. Low incidence of MDR1 expression in acute promyelocytic leukemia. Br J Hematol 1995; 90:369–374.

    Article  CAS  Google Scholar 

  37. Leith C, Kopecky K, Godwin J, et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytoge­netics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997;89:3323–3329.

    PubMed  CAS  Google Scholar 

  38. Nüssler V, Pelka-Fleischer R, Zwierzina H, et al. P-glycoprotein expression in patients with acute leukemia—clinical relevance. Leukemia 1996;10:(suppl 3): S23-S31.

    PubMed  Google Scholar 

  39. List A, Spiers C, Grogan T, et al. Overexpression of the major vault transporter protein lung-resistance protein predicts treatment out­come in acute myeloid leukemia. Blood 1996;87:2464–2469.

    PubMed  CAS  Google Scholar 

  40. Pirker R, Pohl G, Stranzl T, et al. Expression of the LRP predicts poor outcome in the de novo AML. Blood 1997;90(suppl 1): 566a.

    Google Scholar 

  41. Leith C, Kopescky K, Chen I, et al. Frequency and clinical signifi­cance of expression of the multidrug resistance proteins, MDR1, MRP and LRP in AML patients less than 65 years old. Blood 1997; 90(suppl): 389a.

    Google Scholar 

  42. Michieli M, Damiani D, Ermacora A, et al. P-glycoprotein and lung resistance-related protein (LRP) expression and function in leu-kaemic blast cells. Br J Haematol 1997;96:356–365.

    Article  PubMed  CAS  Google Scholar 

  43. Legrand O, Simonin G, Zittoun R, Marie JP. Lung resistance pro­tein (LRP) gene expression in adult acute myeloid leukemia: a criti­cal evaluation by three techniques. Leukemia 1998; 12:1367–1374.

    Article  PubMed  CAS  Google Scholar 

  44. Schroder JK, Kirch C, Seeber S, Schutte J. Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br J Haematol 1998;103:1096–1103.

    Article  PubMed  CAS  Google Scholar 

  45. Legrand O, Simonin G, Zittoun R, Marie J. Cellular pharmaco­logical resistance to anthracyclines and cytosine arabinoside is correlated to in vitro resistance in adult AML. Blood 1998;92 (suppl l):Abstract 2460.

    Google Scholar 

  46. Radosevic N, Delmer A, Tang R, Marie JP, Ajchenbaum-Cymbalista F. Cell cycle regulatory protein expression in fresh acute myeloid leukemia cells and after drug exposure. Leukemia 2001;15:559–566.

    Article  PubMed  CAS  Google Scholar 

  47. Pearson L, Leith C, Duncan M, et al. MDR1 expression and func­tional dye/drug efflux is highly correlated with the t(8;21) chromo­somal translocation in pediatric acute myeloid leukemia. Leukemia 1996;10:1274–1282.

    PubMed  CAS  Google Scholar 

  48. den Boer M, Pieters R, Kazemier K, et al. Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia. Blood 1998;91:2092–208.

    Google Scholar 

  49. Legrand O, Marie JP, Marjanovic Z, et al. Prognostic factors in elderly acute lymphoblastic leukaemia. Br J Haematol 1997;97: 596–602.

    Article  PubMed  CAS  Google Scholar 

  50. Pui CH, Dahl GV, Rivera G, Murphy SB, Costlow ME. The rela­tionship of blast cell glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia. Leuk Res 1984;8:579–585.

    Article  PubMed  CAS  Google Scholar 

  51. Bailey S, Hall AG, Pearson AD, Reid MM, Redfern CP. Glucocor­ticoid resistance and the AP-1 transcription factor in leukaemia. Adv Exp Med Biol 1999;457:615–619.

    Article  PubMed  CAS  Google Scholar 

  52. Ivy S, Olshefski R, Taylor B, Patel K, Reaman G. Correlation of P-glycoprotein expression and function in childhood acute leuke­mia: a Children’s Cancer Group study. Blood 1996;88:309–318.

    PubMed  CAS  Google Scholar 

  53. den Boer ML, Pieters R, Kazemier KM, et al. Relationship between the intracellular daunorubicin concentration, expression of major vault protein/lung resistance protein and resistance to anthracyclines in childhood acute lymphoblastic leukemia. Leu­kemia 1999;13:2023–2030.

    Article  Google Scholar 

  54. Goasguen J, Dossot J, Fardel O, et al. Expression of the multidrug resistance P-glycoprotein (P-170) in 59 de novo acute lym­phoblastic leukemia: prognostic implications. Blood 1993;81: 2394–2398.

    PubMed  CAS  Google Scholar 

  55. Wattel E, Lepelley P, Merlat A, et al. Expression of the P-gp in newly diagnosed adult ALL: absence of correlation with response to treatment. Leukemia 1995;11:1870–1874.

    Google Scholar 

  56. Ohnishi H, Guo SX, Ida K, et al. Alterations of pi 6 and pl5 genes in acute leukemia with MLL gene rearrangements and their corre­lation with clinical features. Leukemia 1997; 11:2120–2124.

    Article  PubMed  CAS  Google Scholar 

  57. Faded S, Kantarjian HM, Manshouri T, et al. The prognostic significance of pl6INK4a/pl4ARF and pl5INK4b deletions in adult acute lymphoblastic leukemia. Clin Cancer Res 1999;5: 1855–1861.

    Google Scholar 

  58. Kuwazuru Y, Hanada S, Furukawa T, et al. Expression of P-glycoprotein in adult T-cell leukemia cells. Blood 1990; 10: 2065–2071.

    Google Scholar 

  59. Lau A, Nightingale S, Taylor GP, Gant TW, Cann AJ. Enhanced MDR1 gene expression in human T-cell leukemia virus-I-infected patients offers new prospects for therapy. Blood 1998 ;91:2467–2474.

    PubMed  CAS  Google Scholar 

  60. Ikeda K, Oka M, Yamada Y, et al. Adult T-cell leukemia cells over-express the multidrug-resistance- protein (MRP) and lung-resistance-protein (LRP) genes. Int J Cancer 1999;82:599–604.

    Article  PubMed  CAS  Google Scholar 

  61. Ford J. Modulators of multidrug resistance: preclinical studies. Hematol Oncol Clin North Am 1995;9:337–361.

    PubMed  CAS  Google Scholar 

  62. Hyafil F, Vergely C, Du Vignaud P, Grand-Perret T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboximide derivative. Cancer Res 1993;53:4595–4602.

    PubMed  CAS  Google Scholar 

  63. Solary E, Witz B, Caillot D, et al. Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicentric study. Blood 1996;88:1198–1205.

    PubMed  CAS  Google Scholar 

  64. List A, Kopecky K, Willman C, et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 2001;98:3212–20.

    Article  PubMed  CAS  Google Scholar 

  65. Lee EJ, George SL, Caligiuri M, et al. Parallel phase I studies of daunorubicin given with cytarabine and etoposide with or without the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age or older with acute myeloid leukemia: results of cancer and leukemia group B study 9420. J Clin Oncol 1999;17:2831–2839.

    PubMed  CAS  Google Scholar 

  66. Sievers EL, Appelbaum FR, Spielberger RT, et al. Selective ablation of acute myeloid leukemia using antibody-targeted chemotherapy: a phase I study of an anti-CD33 calicheamicin immunoconjugate. Blood 1999;93:3678–3684.

    PubMed  CAS  Google Scholar 

  67. Rowinsky E, Smith L, Wang Y, et al. Phase I and pharmacokinetic study of paclitaxel in combination with biricodar, a novel agent that reverses multidrug resistance conferred by overexpression of both MDR1 and MRP. J Clin Oncol 1998;16:2964–2976.

    PubMed  CAS  Google Scholar 

  68. Plunkett W, Gandhi V, Grunewald R, et al. Pharmacologically directed design of AML therapy. In: Acute myelogenous Leukemia: Progress and Controversies. (Gale P, ed.) New York: Wiley Liss, 1990. pp. 481–492.

    Google Scholar 

  69. Zittoun R, Zittoun J, Marquet J, Rustum Y, Creaven P. Modulation of 1--arabinosylcytosine metabolism by thymidine in human leukemia. Cancer Res 1985;45:5186–5192.

    PubMed  CAS  Google Scholar 

  70. Terpstra W, Löwenberg B. Application of myeloid growth factors in the treatment of acute myeloid leukemia. Leukemia 1997; 11:315–327.

    Article  PubMed  CAS  Google Scholar 

  71. Campos L, Guyotat D, Archimbaud E, et al. Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 1992;79:473–476.

    PubMed  CAS  Google Scholar 

  72. Hunault M, Zhou D, Delmer A, et al. Multidrug resistance gene expression in acute myeloid leukemia: major prognosis significance for in vivo drug resistance to induction treatment. Ann Hematol 1997;74:65–71.

    Article  PubMed  CAS  Google Scholar 

  73. van den Heuvel-Eibrink MM, van der Holt B, te Boekhorst PA, et al. MDR 1 expression is an independent prognostic factor for response and survival in de novo acute myeloid leukaemia. Br J Haematol 1997;99:76–83.

    Article  PubMed  Google Scholar 

  74. Del Poeta G, Stasi R, Aronica G, et al. Clinical relevance of P-glycoprotein expression in de novo acute myeloid leukemia. Blood 1996;87:1997–2004.

    PubMed  Google Scholar 

  75. Willman CL. The prognostic significance of the expression and function of multidrug resistance transporter proteins in acute myeloid leukemia: studies of the Southwest Oncology Group Leukemia Research Program. Semin Hematol 1997;34 (suppl 5): 25–33.

    PubMed  CAS  Google Scholar 

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Marie, SP., Legrand, O. (2003). Drug Resistance in Acute Leukemias. In: Pui, CH. (eds) Treatment of Acute Leukemias. Current Clinical Oncology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-307-1_39

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  • DOI: https://doi.org/10.1007/978-1-59259-307-1_39

  • Publisher Name: Humana Press, Totowa, NJ

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