International Journal of Hematology

, Volume 78, Issue 5, pp 402–413 | Cite as

Molecular Pharmacodynamics in Childhood Leukemia

  • R. Pieters
  • M. L. den Boer
Progress in hematology

Key words

Pharmacodynamics Acute leukemia Childhood Chemotherapy Drug resistance 


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  1. 1.
    Bosanquet AG. Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay.Lancet. 1991;337:711–714.PubMedCrossRefGoogle Scholar
  2. 2.
    Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R. In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia.Blood. 1997;89:2959–2965.PubMedPubMedCentralGoogle Scholar
  3. 3.
    Pieters R, Huismans DR, Loonen AH, et al. Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia.Lancet. 1991;338:399–403.PubMedCrossRefGoogle Scholar
  4. 4.
    Kaspers GJL, Veerman AJP, Pieters R, et al. In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia.Blood. 1997;90:2723–2729.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Frost BM, Nygren P, Gustafsson G, et al. Increased in vitro cellular drug resistance is related to poor outcome in high-risk childhood acute lymphoblastic leukaemia.Br J Haematol. 2003;122:376–385.PubMedCrossRefGoogle Scholar
  6. 6.
    Schmiegelow K, Nyvold C, Seyfarth J, et al. Post-induction residual leukemia in childhood acute lymphoblastic leukemia quantified by PCR correlates with in vitro prednisolone resistance.Leukemia. 2001;15:1066–1071.PubMedCrossRefGoogle Scholar
  7. 7.
    De Haas V, Kaspers GJ, Oosten L, et al. Is there a relationship between in vitro drug resistance and level of minimal residual disease as detected by polymerase chain reaction at the end of induction therapy in childhood acute lymphoblastic leukaemia?Br J Haematol. 2002;118:1190–1191.PubMedCrossRefGoogle Scholar
  8. 8.
    Klumper E, Pieters R, Veerman AJP, et al. In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia.Blood. 1995;86:3861–3868.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Rots MG, Pieters R, Jansen G, et al. A possible role for methotrexate in the treatment of childhood acute myeloid leukaemia, in particular for acute monocytic leukaemia.Eur J Cancer. 2001;37:492–498.PubMedCrossRefGoogle Scholar
  10. 10.
    Hongo T, Yamada S, Yajima S, et al. Biological characteristics and prognostic value of in vitro three-drug resistance to prednisolone, L-asparaginase, and vincristine in childhood acute lymphoblastic leukemia.IntJ Hematol. 1999;70:268–277.Google Scholar
  11. 11.
    Den Boer ML, Harms DO, Pieters R, et al. Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia.J Clin Oncol. 2003; 21:3262–3268.CrossRefGoogle Scholar
  12. 12.
    Zwaan CM, Kaspers GJL, Pieters R, et al. Cellular drug resistance profiles in childhood acute myeloid leukemia: differences between FAB types and comparison with acute lymphoblastic leukemia.Blood. 2000;96:2879–2886.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Yamada S, Hongo T, Okada S, Watanabe C, Fujii Y, Ohzeki T. Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia.Leukemia. 2001;15:1892–1897.PubMedCrossRefGoogle Scholar
  14. 14.
    Zwaan CM, Kaspers GJ, Pieters R, et al. Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities.Blood. 2002;100:3352–3360.PubMedCrossRefGoogle Scholar
  15. 15.
    Klumper E, Pieters R, Kaspers GJL, et al. In vitro chemosensitivity assessed with the MTT assay in childhood acute non-lymphoblastic leukemia.Leukemia. 1995;9:1864–1869.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Pui CH, Evans WE. Acute lymphoblastic leukemia.N Engl J Med. 1998;339:605–615.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Pieters R, Den Boer ML, Durian M, et al. Relation between age, immunophenotype, and in vitro drug resistance in 395 children with acute lymphoblastic leukemia—implications for treatment of infants.Leukemia. 1998;12:1344–1348.PubMedCrossRefGoogle Scholar
  18. 18.
    Dördelmann M, Reiter A, Borkhardt A, et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.Blood. 1999;94:1209–1217.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Ramakers-Van Woerden NL, Pieters R, Rots MG, et al. Infants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance.Leukemia. 2002;16:949–951.CrossRefGoogle Scholar
  20. 20.
    Maung ZT, Reid MM, Matheson E,Taylor PRA, Proctor SJ, Hall AG. Corticosteroid resistance is increased in lymphoblasts from adults compared with children: preliminary results of in vitro drug sensitivity study in adults with acute lymphoblastic leukaemia.Br J Haematol. 1995;91:93–100.PubMedCrossRefGoogle Scholar
  21. 21.
    Styczynski J, Pieters R, Huismans DR, Schuurhuis GJ, Wysocki M, Veerman AJP. In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukemia.Br J Haematol. 2000;110:813–818.PubMedCrossRefGoogle Scholar
  22. 22.
    Norgaard JM, Olesen G, Kristensen JS, Pedersen B, Hokland P. Leukaemia cell drug resistance and prognostic factors in AML.Eur J Haematol. 1999;63:219–224.PubMedCrossRefGoogle Scholar
  23. 23.
    Göker E, Lin JT, Trippett T, et al. Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease.Leukemia. 1993;7:1000–1004.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Ramakers-van Woerden NL, Pieters R, Hoelzer D, et al. In vitro drug resistance profile of Philadelphia positive acute lymphoblastic leukemia is heterogeneous and related to age: a report of the Dutch and German Leukemia Study Groups.Med Ped Oncol. 2002;38:379–386.CrossRefGoogle Scholar
  25. 25.
    Rots MG, Pieters R, Kaspers GJ, et al. Differential methotrexate resistance in childhood T- versus common/preB-acute lymphoblastic leukemia can be measured by an in situ thymidylate synthase inhibition assay, but not by the MTT assay.Blood. 1999;93:1067–1074.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Masson E, Relling MV, Synold TW, et al. Accumulation of methotrexate polyglutamates in lymphoblasts is a determinant of antileukemic effects in vivo. A rationale for high-dose methotrexate.J Clin Invest. 1996;97:73–80.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Pui CH, Ribeiro RC, Campana D, et al. Prognostic factors in the acute lymphoid and myeloid leukemias of infants.Leukemia. 1996; 10:952–956.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Stam RW, den Boer ML, Meijerink JP, et al. Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia.Blood. 2003;101:1270–1276.PubMedCrossRefGoogle Scholar
  29. 29.
    Yamauchi H, Iwata N, Omine M, Maekawa T. In vitro methotrexate polyglutamate formation is elevated in acute lymphoid leukemia cells compared with acute myeloid leukemia and normal bone marrow cells.Nippon Ketsueki Gakkai Zasshi. 1988;51:766–773.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Lin JT, Tong WP, Trippett TM, et al. Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia.Leuk Res. 1991;15:1191–1196.PubMedCrossRefGoogle Scholar
  31. 31.
    Goker E, Kheradpour A, Waltham M, et al. Acute monocytic leukemia: a myeloid leukemia subset that may be sensitive to methotrexate.Leukemia. 1995;9:274–276.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Argiris A, Longo GS, Gorlick R, Tong W, Steinherz P, Bertino JR. Increased methotrexate polyglutamylation in acute megakary- ocytic leukemia (M7) compared to other subtypes of acute myelo- cytic leukemia.Leukemia. 1997;11:886–889.PubMedCrossRefGoogle Scholar
  33. 33.
    Ramakers-van Woerden NL, Pieters R, Loonen AH, et al. TEL/ AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia.Blood. 2000;96:1094–1099.Google Scholar
  34. 34.
    Stams WA, Den Boer ML, Beverloo HB, et al. Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL.Blood. 2003;101:2743–2747.PubMedCrossRefGoogle Scholar
  35. 35.
    Whitehead VM, Payment C, Cooley L, et al. The association of the TEL-AML1 chromosomal translocation with the accumulation of methotrexate polyglutamates in lymphoblasts and with ploidy in childhood B-progenitor cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.Leukemia. 2001;15:1081–1088.PubMedCrossRefGoogle Scholar
  36. 36.
    Kaspers GJL, Smets LA, Pieters R, Van Zantwijk CH, Van Wer-ing ER, Veerman AJP. Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study.Blood. 1995;85:751–756.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ito C, Kumagai M, Manabe A, et al. Hyperdiploid acute lymphoblastic leukemia with 51 to 65 chromosomes: a distinct biological entity with a marked propensity to undergo apoptosis.Blood. 1999;93:1183–1189.Google Scholar
  38. 38.
    Synold TW, Relling MV, Boyett JM, et al. Blast cell methotrexate- polyglutamate accumulation in vivo differs by lineage, ploidy, and methotrexate dose in acute lymphoblastic leukemia.J Clin Invest. 1994;94:1996–2001.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Whitehead VM, Vuchich MJ, Lauer SJ, et al. Accumulation of high levels of methotrexate polyglutamates in lymphoblasts from children with hyperdiploid (greater than 50 chromosomes) B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group study.Blood. 1992;80:1316–1323.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Hongo T, Okada S, Inoue N, et al. Two groups of Philadelphia chromosome-positive childhood acute lymphoblastic leukemia classified by pretreatment multidrug sensitivity or resistance in in vitro testing.Int J Hematol. 2002;76:251–259.PubMedCrossRefGoogle Scholar
  41. 41.
    Biondi A, Cimino G, Pieters R, Pui CH. Biological and therapeutic aspects of infant leukemia.Blood. 2000;96:24–33.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Zwaan CM, Kaspers GJ, Pieters R, et al. Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome.Blood. 2002;99:245–251.PubMedCrossRefGoogle Scholar
  43. 43.
    Yamada S, Hongo T, Okada S, et al. Distinctive multidrug sensitivity and outcome of acute erythroblastic and megakaryoblastic leukemia in children with Down syndrome.Int J Hematol. 2001;74:428–436.PubMedCrossRefGoogle Scholar
  44. 44.
    Tissing WJ, Meijerink JP, Den Boer ML, Pieters R. Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia.Leukemia. 2003;17:17–25.PubMedCrossRefGoogle Scholar
  45. 45.
    Kaspers GJL, Pieters R, Veerman AJP. Glucocorticoid resistance in childhood leukemia.Int J Ped Hematol Oncol. 1997;4:583–596.Google Scholar
  46. 46.
    Haarman EG, Kaspers GJ, Pieters R, et al. In vitro glucocorticoid resistance in childhood leukemia correlates with receptor affinity determined at 37 degrees C, but not with affinity determined at room temperature.Leukemia. 2002;16:1882–1884.PubMedCrossRefGoogle Scholar
  47. 47.
    Tonko M, Ausserlechner MJ, Bernhard D, Helmberg A, Kofler R. Gene expression profiles of proliferating vs. G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid- induced apoptosis.FASEB J. 2001;15:693–699.PubMedCrossRefGoogle Scholar
  48. 48.
    Ramdas J, Liu W, Harmon JM. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells.Cancer Res. 1999;59:1378–1385.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Yudt MR, Jewell CM, Bienstock RJ, Cidlowski JA. Molecular origins for the dominant negative function of human glucocorticoid receptor beta.Mol Cell Biol. 2003;23:4319–4330.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    de Lange P, Segeren CM, Koper JW, et al. Expression in hematological malignancies of a glucocorticoid receptor splice variant that augments glucocorticoid receptor-mediated effects in transfected cells.Cancer Res. 2001;61:3937–3941.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Rivers C, Levy A, Hancock J, Lightman S, Norman M. Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing.J Clin Endocrinol Metab. 1999;84:4283–4286.PubMedCrossRefGoogle Scholar
  52. 52.
    Ray DW, Davis JR, White A, Clark AJ. Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells.Cancer Res. 1996;56:3276–3280.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Moalli PA, Pillay S, Krett NL, Rosen ST. Alternatively spliced glucocorticoid receptor messenger RNAs in glucocorticoid-resistant human multiple myeloma cells.Cancer Res. 1993;53:3877–3879.PubMedPubMedCentralGoogle Scholar
  54. 54.
    Longui CA, Vottero A, Adamson PC, et al. Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia.Horm Metab Res. 2000;32:401–406.PubMedCrossRefGoogle Scholar
  55. 55.
    Beger C, Gerdes K, Lauten M, et al. Expression and structural analysis of glucocorticoid receptor isoform gamma in human leukaemia cells using an isoform-specific real-time polymerase chain reaction approach.Br J Haematol. 2003;122:245–252.PubMedCrossRefGoogle Scholar
  56. 56.
    Hillmann AG, Ramdas J, Multanen K, Norman MR, Harmon JM. Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in vivo.Cancer Res. 2000;60:2056–2062.PubMedPubMedCentralGoogle Scholar
  57. 57.
    Kojika S, Sugita K, Inukai T, et al. Mechanisms of glucocorticoid resistance in human leukemic cells: implication of abnormal 90 and 70 kDa heat shock proteins.Leukemia. 1996;10:994–999.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Kullmann M, Schneikert J, Moll J, et al. RAP46 is a negative regulator of glucocorticoid receptor action and hormone-induced apoptosis.J Biol Chem. 1998;273:14620–14625.PubMedCrossRefGoogle Scholar
  59. 59.
    Lauten M, Beger C, Gerdes K, et al. Expression of heat-shock protein 90 in glucocorticoid-sensitive and-resistant childhood acute lymphoblastic leukaemia.Leukemia. 2003;17:1551–1556.PubMedCrossRefGoogle Scholar
  60. 60.
    Gerritsen ME, Williams AJ, Neish AS, Moore S, Shi Y, Collins T. CREB-binding protein/p300 are transcriptional coactivators of p65.Proc NatlAcad Sci USA. 1997;94:2927–2932.CrossRefGoogle Scholar
  61. 61.
    Zelcer N, Reid G,Wielinga P, et al. Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4).Biochem J. 2003;371:361–367.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Karssen AM, Meijer OC, van der Sandt IC, De Boer AG, De Lange EC, De Kloet ER. The role of the efflux transporter P-glycoprotein in brain penetration of prednisolone.J Endocrinol. 2002;175:251–260.PubMedCrossRefGoogle Scholar
  63. 63.
    Den Boer ML, Pieters R, Kazemier KM, 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;91:2092–2098.Google Scholar
  64. 64.
    Kearns PR, Pieters R, Rottier MM, Pearson AD, Hall AG. Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia.Blood. 2001;97:393–398.PubMedCrossRefGoogle Scholar
  65. 65.
    Den Boer ML, Pieters R, Kazemier KM, et al. Different expression of glutathione S-transferase a, m and p in childhood acute lymphoblastic and myeloid leukaemia.Br J Haematol. 1999;104:321–327.CrossRefGoogle Scholar
  66. 66.
    Reichardt HM, Kaestner KH, Tuckermann J, et al. DNA binding of the glucocorticoid receptor is not essential for survival.Cell. 1998; 93:531–541.PubMedCrossRefGoogle Scholar
  67. 67.
    Bailey S, Hall AG, Pearson AD, Redfern CP. The role of AP-1 in glucocorticoid resistance in leukaemia.Leukemia. 2001;15:391–397.PubMedCrossRefGoogle Scholar
  68. 68.
    Kordes U, Krappmann D, Heissmeyer V, Ludwig WD, Scheidereit C. Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells.Leukemia. 2000;14:399–402.PubMedCrossRefGoogle Scholar
  69. 69.
    Liptay S, Seriu T, Bartram CR, Schmid RM. Germline configuration of NFkB2, c-REL and BCLl3 in childhood acute lymphoblastic leukemia (ALL).Leukemia. 1997;11:1364–1366.PubMedCrossRefGoogle Scholar
  70. 70.
    Thulasi R, Harbour DV, Thompson EB. Suppression of c-myc is a critical step in glucocorticoid-induced human leukemic cell lysis.J Biol Chem. 1993;268:18306–18312.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Conte D, Liston P, Wong JW, Wright KE, Korneluk RG. Thymo- cyte-targeted overexpression of xiap transgene disrupts T lym- phoid apoptosis and maturation.Proc NatlAcad Sci USA. 2001; 98:5049–5054.CrossRefGoogle Scholar
  72. 72.
    Miller HK, Salzer JS, Balis ME. Amino acid levels following L-asparaginase amidohydrolase (EC. therapy.Cancer Res. 1969;29:183–187.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Ohnuma T, Holland JF, Freeman A, Sinks LF. Biochemical and pharmacological studies with asparaginase in man.Cancer Res. 1970;30:2297–2305.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Hutson RG, Kitoh T, Moraga Amador DA, Cosic S, Schuster SM, Kilberg MS. Amino acid control of asparagine synthetase: relation to asparaginase resistance in human leukemia cells.Am J Physiol. 1997;272:C1691–1699.CrossRefGoogle Scholar
  75. 75.
    Jousse C, Bruhat A, Ferrara M, Fafournoux P. Evidence for multiple signaling pathways in the regulation of gene expression by amino acids in human cell lines.J Nutr. 2000;130:1555–1560.PubMedCrossRefGoogle Scholar
  76. 76.
    Aslanian AM, Fletcher BS, Kilberg MS. Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells.Biochem J. 2001;357:321–328.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Dubbers A, Wurthwein G, Muller HJ, et al. Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity.Br J Haematol. 2000;109:427–429.PubMedCrossRefGoogle Scholar
  78. 78.
    Aslanian AM, Kilberg MS. Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells.Biochem J. 2001;358:59–67.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Iiboshi Y, Papst PJ, Hunger SP, Terada N. L-Asparaginase inhibits the rapamycin-targeted signaling pathway.Biochem Biophys Res Commun. 1999;260:534–539.PubMedCrossRefGoogle Scholar
  80. 80.
    Hu ZB, Minden MD, McCulloch EA. Regulation of drug sensitivity by ribosomal protein S3a.Blood. 2000;95:1047–1055.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Mandelkow E, Mandelkow EM. Microtubules and microtubule- associated proteins.Curr Opin Cell Biol. 1995;7:72–81.PubMedCrossRefGoogle Scholar
  82. 82.
    Kavallaris M, Tait AS, Walsh BJ, et al. Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells.Cancer Res. 2001;61:5803–5809.PubMedPubMedCentralGoogle Scholar
  83. 83.
    Giannakakou P, Nakano M, Nicolaou KC, et al. Enhanced micro- tubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics.Proc Natl Acad Sci USA. 2002;99:10855–10860.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Veerman AJP. 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.CrossRefGoogle Scholar
  85. 85.
    Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Veerman AJP. The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia.Leukemia. 1998;12:912–920.CrossRefGoogle Scholar
  86. 86.
    Siva AC, Raval-Fernandes S, Stephen AG, et al. Up-regulation of vaults may be necessary but not sufficient for multidrug resistance.Int J Cancer. 2001;92:195–202.PubMedCrossRefGoogle Scholar
  87. 87.
    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.PubMedPubMedCentralGoogle Scholar
  88. 88.
    Goasguen JE, Lamy T, Bergeron C, et al. Multifactorial drug resistance phenomenon in acute leukemias: impact of P170-MDR1, LRP56 protein, glutathion-transferases and methallothione systems on clinical outcome.Leuk Lymphoma. 1996;23:567–576.PubMedCrossRefGoogle Scholar
  89. 89.
    Kakihara T, Tanaka A, Watanabe A, et al. Expression of multidrug resistance-related genes does not contribute to risk factors in newly diagnosed childhood acute lymphoblastic leukemia.Pediatr Int. 1999;41:641–647.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Borg AG, Burgess R, Green LM, Scheper RJ, Liu Yin JA. P-glyco- protein and multidrug resistance-associated protein, but not lung resistance protein, lower the intracellular daunorubicin accumulation in acute myeloid leukaemic cells.Br J Haematol. 2000;108:48–54.PubMedCrossRefGoogle Scholar
  91. 91.
    Tsuji K, MotojiT, Sugawara I, et al. Significance of lung resistance- related protein in the clinical outcome of acute leukaemic patients with reference to P-glycoprotein.Br J Haematol. 2000;110:370–378.PubMedCrossRefGoogle Scholar
  92. 92.
    Leith CP, Kopecky KJ, Chen IM, et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1 and LRP in acute myeloid leukemia: a Southwest Oncology Group study.Blood. 1999;94:1086–1099.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Jaffrezou JP, Levade T, Bettaieb A, et al. Daunorubicin-induced apoptosis: triggering of ceramide generation through sphin- gomyelin hydrolysis.Embo J. 1996;15:2417–2424.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Itoh M, Kitano T, Watanabe M, et al. Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia.Clin Cancer Res. 2003;9:415–423.PubMedPubMedCentralGoogle Scholar
  95. 95.
    Bezombes C, de Thonel A, Apostolou A, et al. Overexpression of protein kinase Czeta confers protection against antileukemic drugs by inhibiting the redox-dependent sphingomyelinase activation.Mol Pharmacol. 2002;62:1446–1455.PubMedCrossRefGoogle Scholar
  96. 96.
    Batist G, Schecter R, Woo A, Greene D, Lehnert S. Glutathione depletion in human and in rat multi-drug resistant breast cancer cell lines.Biochem Pharmacol. 1991;41:631–635.PubMedCrossRefGoogle Scholar
  97. 97.
    Versantvoort CHM, Broxterman HJ, Bagrij T, Scheper RJ, Twenty-man PR. Regulation of glutathione of drug transport in multidrug- resistant human lung tumour cell lines overexpressing multidrug resistance-associated protein.Br J Cancer. 1995;72:82–89.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kaufmann SH, Karp JE, Jones RJ, et al. Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia.Blood. 1994;83:517–530.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Klumper E, Giaccone G, Pieters R, et al. Topoisomerase IIa gene expression in childhood acute lymphoblastic leukemia.Leukemia. 1995;9:1653–1660.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Gieseler F, Glasmacher A, Kämpfe D, et al. Topoisomerase II activities in AML blasts and their correlation with cellular sensitivity to anthracyclines and epipodophyllotoxins.Leukemia. 1996;10:1177–1180.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Hellin AC, Bentires-Alj M, Verlaet M, et al. Roles of nuclear factor-kappaB, p53, and p21/WAF1 in daunomycin-induced cell cycle arrest and apoptosis.J Pharmacol Exp Ther. 2000;295:870–878.PubMedPubMedCentralGoogle Scholar
  102. 102.
    Holleman A, Den Boer ML, Kazemier KM, Janka-Schaub GE, Pieters R . Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia.Blood. 2003:[Epub ahead of print]. In press.Google Scholar
  103. 103.
    Friesen C, Herr I, Krammer PH, Debatin KM. Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells.Nat Med. 1996;2:574–577.PubMedCrossRefGoogle Scholar
  104. 104.
    Landowski TH, Gleason-Guzman MC, Dalton WS. Selection for drug resistance results in resistance to Fas-mediated apoptosis.Blood. 1997;89:1854–1861.PubMedPubMedCentralGoogle Scholar
  105. 105.
    Labroille G, Dumain P, Lacombe F, Belloc F. Flow cytometric evaluation of Fas expression in relation to response and resistance to anthracyclines in leukemic cells.Cytometry. 2000;39:195–202.PubMedCrossRefGoogle Scholar
  106. 106.
    Debatin KM, Krammer PH. Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a bcl-2 independent anti- apoptotic program.Leukemia. 1995;9:815–820.PubMedPubMedCentralGoogle Scholar
  107. 107.
    Karawajew L, Wuchter C, Ruppert V, et al. Differential CD95 expression and function in T and B lineage acute lymphoblastic leukemia cells.Leukemia. 1997;11:1245–1252.PubMedCrossRefGoogle Scholar
  108. 108.
    Wuchter C, Karawajew L, Ruppert V, et al. Constitutive expression levels of CD95 and Bcl-2 as well as CD95 function and spontaneous apoptosis in vitro do not predict the response to induction chemotherapy and relapse rate in childhood acute lymphoblastic leukaemia.Br J Haematol. 2000;110:154–160.PubMedCrossRefGoogle Scholar
  109. 109.
    Munker R, Andreeff M. Induction of death (CD95/Fas), activation and adhesion (CD54) molecules on blast cells of acute myelogenous leukemias by TNF-a and IFN-gamma.Cytokines Mol Ther. 1996;2:147–160.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Iijima N, Miyamura K, Itou T,Tanimoto M, Sobue R, Saito H. Functional expression of Fas (CD95) in acute myeloid leukemia cells in the context of CD34 and CD38 expression: possible correlations with sensitivity to chemotherapy.Blood. 1997;90:4901–4909.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Chikamori K, Grabowski DR, Kinter M, et al. Phosphorylation of serine 1106 in the catalytic domain of topoisomerase II alpha regulates enzymatic activity and drug sensitivity.J Biol Chem. 2003; 278:12696–12702.PubMedCrossRefGoogle Scholar
  112. 112.
    Bugg BY, Danks MK, Beck WT, Suttle DP. Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide.Proc Natl Acad Sci USA. 1991;88:7654–7658.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Danks MK, Warmoth MR, Friche E, et al. Single-strand conformational polymorphism analysis of the M(r) 170,000 isozyme of DNA topoisomerase II in human tumor cells.Cancer Res. 1993;53:1373–1379.PubMedPubMedCentralGoogle Scholar
  114. 114.
    Rots MG, Pieters R, Kaspers GJ, Veerman AJ, Peters GJ, Jansen G. Classification of ex vivo methotrexate resistance in acute lymphoblastic and myeloid leukaemia.Br J Haematol. 2000;110:791–800.PubMedCrossRefGoogle Scholar
  115. 115.
    Gorlick R, Goker E,Trippett T, et al. Defective transport is a common mechanism of acquired methotrexate resistance in acute lymphocytic leukemia and is associated with decreased reduced folate carrier expression.Blood. 1997;89:1013–1018.PubMedPubMedCentralGoogle Scholar
  116. 116.
    Matherly LH, Taub JW, Wong SC, et al. Increased frequency of expression of elevated dihydrofolate reductase in T-cell versus B-precursor acute lymphoblastic leukemia in children.Blood. 1997;90:578–589.PubMedPubMedCentralGoogle Scholar
  117. 117.
    Zhang L, Taub JW, Williamson M, et al. Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy.Clin Cancer Res. 1998;4:2169–2177.PubMedPubMedCentralGoogle Scholar
  118. 118.
    Rots MG, Pieters R, Peters GJ, et al. Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia.Br J Haematol. 2000;109:629–634.PubMedCrossRefGoogle Scholar
  119. 119.
    Belkov VM, Krynetski EY, Schuetz JD, et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation.Blood. 1999;93:1643–1650.PubMedPubMedCentralGoogle Scholar
  120. 120.
    Laverdiere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M. Polymorphism G80A in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood acute lymphoblastic leukemia.Blood. 2002;100:3832–3834.PubMedCrossRefGoogle Scholar
  121. 121.
    Whetstine JR, Gifford AJ, Witt T, et al. Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high- frequency G/A variant at position 80 and transport properties of the His(27) and Arg(27) carriers.Clin Cancer Res. 2001;7:3416–3422.PubMedPubMedCentralGoogle Scholar
  122. 122.
    Gifford AJ, Haber M, Witt TL, et al. Role of the E45K-reduced folate carrier gene mutation in methotrexate resistance in human leukemia cells.Leukemia. 2002;16:2379–2387.PubMedCrossRefGoogle Scholar
  123. 123.
    Mantadakis E, Smith AK, Kamen BA. Ratio of methotrexate to folate uptake by lymphoblasts in children with B-lineage acute lymphoblastic leukemia: a pilot study.J Pediatr Hematol Oncol. 2000;22:221–226.PubMedCrossRefGoogle Scholar
  124. 124.
    Zeng H, Chen ZS, Belinsky MG, Rea PA, Kruh GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport.Cancer Res. 2001;61:7225–7232.PubMedPubMedCentralGoogle Scholar
  125. 125.
    Chen ZS, Lee K, Walther S, et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system.Cancer Res. 2002;62:3144–3150.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Assaraf YG, Rothem L, Hooijberg JH, et al. Loss of multidrug resistance protein 1 expression and folate efflux activity results in a highly concentrative folate transport in human leukemia cells.J Biol Chem. 2003;278:6680–6686.PubMedCrossRefGoogle Scholar
  127. 127.
    Whitehead VM, Rosenblatt DS, Vuchich MJ, Shuster JJ, Witte A, Beaulieu D. Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis.Blood. 1990;76:44–49.PubMedPubMedCentralGoogle Scholar
  128. 128.
    Mantadakis E, Smith AK, Hynan L, Winick NJ, Kamen BA. Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate.J Pediatr Hematol Oncol. 2002;24:636–642.PubMedCrossRefGoogle Scholar
  129. 129.
    Galpin AJ, Schuetz JD, Masson E, et al. Differences in folylpolyg- lutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity.Mol Pharmacol. 1997;52:155–163.PubMedCrossRefGoogle Scholar
  130. 130.
    Barredo JC, Synold TW, Laver J, Relling MV, Pui CH, Priest DG, Evans WE. Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia.Blood. 1994;84:564–569.PubMedPubMedCentralGoogle Scholar
  131. 131.
    Longo GS, Gorlick R, Tong WP, Ercikan E, Bertino JR. Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells.Blood. 1997;90:1241–1245.PubMedPubMedCentralGoogle Scholar
  132. 132.
    Goker E, Waltham M, Kheradpour A, et al. Amplification of the dihydrofolate reductase gene is a mechanism of acquired resistance to methotrexate in patients with acute lymphoblastic leukemia and is correlated with p53 gene mutations.Blood. 1995; 86:677–684.PubMedPubMedCentralGoogle Scholar
  133. 133.
    Spencer HT, Sorrentino BP, Pui CH, Chunduru SK, Sleep SE, Blakley RL. Mutations in the gene for human dihydrofolate reductase: an unlikely cause of clinical relapse in pediatric leukemia after therapy with methotrexate.Leukemia. 1996;10:439–446.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidy- late synthase gene and outcome of acute lymphoblastic leukaemia.Lancet. 2002;359:1033–1034.PubMedCrossRefGoogle Scholar
  135. 135.
    Chiusolo P, Reddiconto G, Casorelli I, et al. Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate.Ann Oncol. 2002;13:1915–1918.PubMedCrossRefGoogle Scholar
  136. 136.
    Taub JW, Matherly LH, Ravindranath Y, Kaspers GJ, Rots MG, Zantwijk CH. Polymorphisms in methylenetetrahydrofolate reductase and methotrexate sensitivity in childhood acute lymphoblastic leukemia.Leukemia. 2002;16:764–765.PubMedCrossRefGoogle Scholar
  137. 137.
    Dervieux T, Blanco JG, Krynetski EY, Vanin EF, Roussel MF, Relling MV. Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells.Cancer Res. 2001;61:5810–5816.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Coulthard SA, Hogarth LA, Little M, et al. The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs.Mol Pharmacol. 2002;62:102–109.PubMedCrossRefGoogle Scholar
  139. 139.
    Davidson JD. Studies on the mechanism of action of 6-mercaptopurine in sensitive and resistance L1210 leukemia in vitro.Cancer Res. 1960;20:225.PubMedPubMedCentralGoogle Scholar
  140. 140.
    Brockman RW. A mechanism of resistance to 6-mercaptopurine: metabolism of hypoxanthine and 6-mercaptopurine by sensitive and resistant neoplasms.Cancer Res. 1960;20:643.PubMedPubMedCentralGoogle Scholar
  141. 141.
    Ellis DB, LePage GA. Biochemical studies of resistance to 6-thioguanine.Cancer Res. 1963;23:436.Google Scholar
  142. 142.
    Zimm S, Johnson GE, Chabner BA, Poplack DG. Cellular pharma- cokinetics of mercaptopurine in human neoplastic cells and cell lines.Cancer Res. 1985;45:4156–4161.PubMedPubMedCentralGoogle Scholar
  143. 143.
    Brockman RW. Resistance to purine antagonists in experimental leukemia systems.Cancer Res. 1965;25:1596–1605.PubMedPubMedCentralGoogle Scholar
  144. 144.
    Curt GA, Clendeninn NJ, Chabner BA. Drug resistance in cancer.Cancer Treat Rep. 1984;68:87–99.PubMedPubMedCentralGoogle Scholar
  145. 145.
    Pieters R, Huismans DR, Loonen AH, et al. Hypoxanthine-guanine phosphoribosyltransferase in child-hood leukemia: relation with immunophenotype, differentiation stage, in vitro drug resistance and clinical prognosis.IntJ Cancer. 1992;51:213–217.CrossRefGoogle Scholar
  146. 146.
    Pieters R, Huismans DR, Loonen AH, et al. Adenosine deaminase and purine nucleoside phosphorylase in childhood leukemia; relation with differentiation stage, clinical prognosis and in vitro drug resistance.Leukemia. 1992;6:375–380.PubMedPubMedCentralGoogle Scholar
  147. 147.
    Rosman M, Lee MH, Creasey WA, Sartorelli AC. Mechanisms of resistance to 6-thiopurines in human leukemia.Cancer Res. 1974; 34:1952–1956.PubMedPubMedCentralGoogle Scholar
  148. 148.
    Pieters R, Huismans DR, Loonen AH, et al. Relation of 5’-nucleotidase and phosphatase activities with immunophenotype, drug resistance and clinical prognosis in childhood leukemia.Leuk Res. 1992;16:873–880.PubMedCrossRefGoogle Scholar
  149. 149.
    Veerman AJP, Hogeman PHG, Van Zantwijk CH, Bezemer PD. Prognostic value of 5’nucleotidase in acute lymphoblastic leukemia with the common-ALL phenotype.Leuk Res. 1985;9:1227–1229.PubMedCrossRefGoogle Scholar
  150. 150.
    Pieters R, Huismans DR, Veerman AJ. Are children with lymphoblastic leukaemia resistant to 6-mercaptopurine because of 5’-nucleotidase?Lancet. 1987;2:1471.PubMedCrossRefGoogle Scholar
  151. 151.
    Pieters R, Thompson LF, Broekema GJ, et al. Expression of 5’-nucleotidase (CD73) related to other differentiation antigens in leukemias of B-cell lineage.Blood. 1991;78:488–492.PubMedPubMedCentralGoogle Scholar
  152. 152.
    Lennard L, Lilleyman JS. Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia.J Clin Oncol. 1989;7:1816–1823.PubMedCrossRefGoogle Scholar
  153. 153.
    Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia.Lancet. 1994;343:1188–1190.PubMedCrossRefGoogle Scholar
  154. 154.
    McLeod HL, Relling MV, Liu Q, Pui CH, Evans WE. Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia.Blood. 1995;85:1897–1902.PubMedPubMedCentralGoogle Scholar
  155. 155.
    Lennard L, Welch JC, Lilleyman JS. Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity.Br J Clin Pharmacol. 1997;44:455–461.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Krynetski EY, Tai HL, Yates CR, et al. Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms.Pharmacogenetics. 1996;6:279–290.PubMedCrossRefGoogle Scholar
  157. 157.
    Coulthard SA, Howell C, Robson J, Hall AG. The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia.Blood. 1998;92:2856–28622.PubMedPubMedCentralGoogle Scholar
  158. 158.
    McLeod HL, Krynetski EY, Relling MV, Evans WE. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia.Leukemia. 2000;14:567–572.PubMedCrossRefGoogle Scholar
  159. 159.
    Relling MV, Hancock ML, Boyett JM, Pui CH, Evans WE. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia.Blood. 1999;93:2817–2823.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Owens JK, Shewach DS, Ullman B, Mitchell BS. Resistance to 1-beta-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene.Cancer Res. 1992;52:2389–2393.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Flasshove M, Strumberg D, Ayscue L, et al. Structural analysis of the deoxycytidine kinase gene in patients with acute myeloid leukemia and resistance to cytosine arabinoside.Leukemia. 1994;8:780–785.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Van den Heuvel-Eibrink MM, Wiemer EA, Kuijpers M, Pieters R, Sonneveld P. Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML).Leukemia. 2001;15:855–856.CrossRefGoogle Scholar
  163. 163.
    Taub JW, Huang X, Matherly LH, et al. Expression of chromosome 21-localized genes in acute myeloid leukemia: differences between Down syndrome and non-Down syndrome blast cells and relationship to in vitro sensitivity to cytosine arabinoside and daunorubicin.Blood. 1999;94:1393–1400.PubMedPubMedCentralGoogle Scholar
  164. 164.
    Veuger MJ, Honders MW, Landegent JE, Willemze R, Barge RM. High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia.Blood. 2000;96:1517–1524.PubMedPubMedCentralGoogle Scholar
  165. 165.
    Veuger MJ, Heemskerk MH, Honders MW, Willemze R, Barge RM. Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells.Blood. 2002;99:1373–1380.PubMedCrossRefGoogle Scholar
  166. 166.
    Boos J, Hohenlochter B, Schulze-Westhoff P, et al. Intracellular retention of cytosine arabinoside triphosphate in blast cells from children with acute myelogenous and lymphoblastic leukemia.Med Pediatr Oncol. 1996;26:397–404.PubMedCrossRefGoogle Scholar
  167. 167.
    Braess J, Wegendt C, Feuring-Buske M, et al. Leukaemic blasts differ from normal bone marrow mononuclear cells and CD34+ haemopoietic stem cells in their metabolism of cytosine arabinoside.BrJ Haematol. 1999;105:388–393.CrossRefGoogle Scholar
  168. 168.
    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.PubMedCrossRefGoogle Scholar
  169. 169.
    Verschuur AC, Van Gennip AH, Leen R, Meinsma R, Voute PA, van Kuilenburg AB. In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia.Br J Haematol. 2000;110:161–169.PubMedCrossRefGoogle Scholar
  170. 170.
    Van den Heuvel-Eibrink MM, Sonneveld P, Pieters R. The prognostic significance of membrane transport-associated multidrug- resistance (MDR) proteins in leukemia.Int J Clin Pharmacol Ther. 2000;38:94–110.PubMedCrossRefGoogle Scholar
  171. 171.
    Steinbach D, Wittig S, Cario G, et al. The multidrug resistance- associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype.Blood. 2003: [Epub ahead of print]. In press.PubMedCrossRefGoogle Scholar
  172. 172.
    Steinbach D, Lengemann J, Voigt A, Hermann J, Zintl F, Sauerbrey A. Response to chemotherapy and expression of the genes encoding the multidrug resistance-associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia.Clin Cancer Res. 2003;9:1083–1086.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Van den Heuvel-Eibrink MM, Wiemer EA, Prins A, et al. Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML).Leukemia. 2002;16:833–839.PubMedCrossRefGoogle Scholar
  174. 174.
    Steinbach D, Sell W, Voigt A, Hermann J, Zintl F, Sauerbrey A. BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia.Leukemia. 2002;16:1443–1447.PubMedCrossRefGoogle Scholar
  175. 175.
    Sargent JM, Williamson CJ, Maliepaard M, Elgie AW, Scheper RJ, Taylor CG. Breast cancer resistance protein expression and resistance to daunorubicin in blasts from patients with acute myeloid leukemia.Br J Haematol. 2001;115:257–262.PubMedCrossRefGoogle Scholar
  176. 176.
    Sauerbrey A, Sell W, Steinbach D, Voigt A, Zintl F. Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia.Br J Haematol. 2002;118:147–150.PubMedCrossRefGoogle Scholar
  177. 177.
    Schimmer AD, Pedersen IM, Kitada S, et al. Functional blocks in caspase activation pathways are common in leukemia and predict patient response to induction chemotherapy.Cancer Res. 2003;63:1242–1248.PubMedPubMedCentralGoogle Scholar
  178. 178.
    Salomons GS, Smets LA, Verwijs-Janssen M, et al. Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome.Leukemia. 1999;13:1574–1580.PubMedCrossRefGoogle Scholar
  179. 179.
    Coustan-Smith E, Kitanaka A, Pui CH, et al. Clinical relevance of bcl-2 overexpression in childhood acute lymphoblastic leukemia.Blood. 1996;87:1140–1146.PubMedPubMedCentralGoogle Scholar
  180. 180.
    Wuchter C, Ruppert V, Schrappe M, Dorken B, Ludwig WD, Karawajew L. In vitro susceptibility to dexamethasone- and doxorubicin-induced apoptotic cell death in context of maturation stage, responsiveness to interleukin 7, and early cytoreduction in vivo in childhood T-cell acute lymphoblastic leukemia.Blood. 2002;99:4109–4115.PubMedCrossRefGoogle Scholar
  181. 181.
    Cheok MH, Yang W, Pui CH, et al. Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells.Nat Genet. 2003;34:85–90.PubMedCrossRefGoogle Scholar
  182. 182.
    Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling.Cancer Cell. 2002;1:133–143.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Armstrong SA, Staunton JE, Silverman LB, et al. MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia.Nat Genet. 2002;30:41–47.PubMedPubMedCentralCrossRefGoogle Scholar
  184. 184.
    Ross ME, Zhou X, Song G, et al. Classification of pediatric acute lymphoblastic leukemia by gene expression profiling.Blood. 2003; 102:2951–2959.PubMedCrossRefGoogle Scholar
  185. 185.
    Yagi T, Morimoto A, Eguchi M, et al. Identification of a gene expression signature associated with prognosis of pediatric AML.Blood. 2003;102:1849–1856.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Armstrong SA, Kung AL, Mabon ME, et al. Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification.Cancer Cell. 2003;3:173–183.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2003

Authors and Affiliations

  1. 1.Erasmus MCUniversity Medical Center Rotterdam, Sophia Childrens Hospital, Pediatric Oncology/HematologyRotterdamThe Netherlands

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