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15 - Assays and molecular determinants of cellular drug resistance

from Part III - Evaluation and treatment

Published online by Cambridge University Press:  01 July 2010

By
Monique L. den Boer  and
Rob Pieters
Edited by
Ching-Hon Pui
Monique L. den Boer
Affiliation:
Associate Professor, Molecular Pediatric Oncology Head, Research Laboratory Pediatric Oncology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Department of Pediatric Oncology and Hematology, Rotterdam, the Netherlands
Rob Pieters
Affiliation:
Professor and Head, Department of Pediatric Oncology and Hematology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands
Ching-Hon Pui
Affiliation:
St. Jude Children's Research Hospital, Memphis
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Summary

Introduction

Chemotherapy for children with acute leukemia has improved impressively over the past 40 years, despite the use of similar agents throughout this period. The efficacy of antileukemic drugs depends largely on their dosages and schedules of administration. It also depends on the intrinsic and acquired resistance of leukemic cells to drug treatment. Knowledge of the factors contributing to cellular drug resistance was slow to accumulate, but has grown rapidly over the last two decades. This chapter describes some of the prominent methods for assessing drug resistance in leukemia patients and reviews progress in elucidating the molecular determinants of this phenomenon.

Drug cytotoxicity assays

In the early 1980s, drug cytotoxicity was mainly evaluated by clonogenic assays such as colony-forming unit assays and stromal cell layer-supported long-term marrow cultures. These time-consuming assays rely on the in vitro proliferating capacity of cells, a characteristic that in practice is restricted to acute and chronic myeloid blasts. The most frequent type of leukemia in children, acute lymphoblastic leukemia (ALL), cannot be tested with assays of this type because the cells lack any in vitro proliferating capacity. Moreover, the resistance of resting, nondividing cells, which may be an important source of treatment failure, is not detectable with these proliferation-based assays.

Dye exclusion or differential staining cytotoxicity assay

In 1983, Weisenthal and co-workers introduced the dye exclusion assay (DEA), which enables one to test the cytotoxicity of drugs in nonclonogenic cells. This assay exploits trypan-blue dye, which selectively diffuses into damaged cells with permeabilized cell membranes.

Type
Chapter
Information
Childhood Leukemias , pp. 414 - 438
Publisher: Cambridge University Press
Print publication year: 2006

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References

Weisenthal, L. M. & Lippman, M. E.Clonogenic and nonclonogenic in vitro chemosensitivity assays. Cancer Treat Rep, 1985; 69: 615–32.Google ScholarPubMed
Weisenthal, L. M., Marsden, J. A., Dill, P. L., et al.A novel dye exclusion method for testing in vitro chemosensitivity of human tumors. Cancer Res, 1983; 43: 749–57.Google ScholarPubMed
Bird, M. C., Bosanquet, A. G., & Gilby, E. D.Semi-micro adaptation of a 4-day differential staining cytotoxicity (DiSC) assay for determining the in-vitro chemosensitivity of haematological malignancies. Leuk Res, 1986; 10: 445–9.CrossRefGoogle ScholarPubMed
Pieters, R., Huismans, D. R., Leyva, A., et al.Comparison of the rapid automated MTT-assay with a dye exclusion assay for chemosensitivity testing in childhood leukaemia. Br J Cancer, 1989; 59: 217–20.CrossRefGoogle ScholarPubMed
Mosmann, T.Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods, 1983; 65: 55–63.CrossRefGoogle ScholarPubMed
Kaspers, G. J. L., Veerman, A. J. P., Pieters, R., et al.Mononuclear cells contaminating leukaemic samples tested for cellular drug resistance using the methyl-thiazol-tetrazolium assay. Br J Cancer, 1994; 70: 1047–52.CrossRefGoogle ScholarPubMed
Tosi, P., Visani, G., Ottaviani, E., et al.Biological and clinical significance of in vitro prednisolone resistance in adult acute lymphoblastic leukemia. Eur J Cancer, 1996; 57: 134–41.Google Scholar
Kirkpatrick, D. L., Duke, M., & Goh, T. S.Chemosensitivity testing of fresh human leukemia cells using both a dye exclusion assay and a tetrazolium dye (MTT) assay. Leuk Res, 1990; 14: 459–66.CrossRefGoogle Scholar
Rots, M. G., Pieters, R., Kaspers, G. J., 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: 1067–74.Google Scholar
Larsson, R., Kristensen, J., Sandberg, C.et al.Laboratory determination of chemotherapeutic drug resistance in tumor cells from patients with leukemia using a fluorometric microculture cytotoxicity assay (FMCA). Int J Cancer, 1992; 50: 177–85.CrossRefGoogle Scholar
Nygren, P., Kristensen, J., Jonsson, B.et al.Feasibility of the fluorometric microculture cytotoxicity assay (FMCA) for cytotoxic drug sensitivity testing of tumor cells from patients with acute lymphoblastic leukemia. Leukemia, 1992; 6: 1121–8.Google ScholarPubMed
Campana, D., Manabe, A., & Evans, W. E.Stroma-supported immunocytometric assay (SIA): a novel method for testing the sensitivity of acute lymphoblastic leukemia cells to cytotoxic drugs. Leukemia, 1993; 7: 482–8.Google ScholarPubMed
Kaspers, G. J. L., Veerman, A. J. P., Pieters, R., et al.In vitro cellular drug resistance and prognosis in newly diagnosed childhood acute lymphoblastic leukemia. Blood, 1997; 90: 2723–9.Google ScholarPubMed
Mollgard, L., Tidefelt, U., Sundman-Engberg, B.et al.In vitro chemosensitivity testing in acute non lymphocytic leukemia using the bioluminescence ATP assay. Leuk Res, 2000; 24: 445–52.CrossRefGoogle ScholarPubMed
Cline, M. J., & Rosenbaum, E.Prediction of in vivo cytotoxicity of chemotherapeutic agents by their in vitro effect on leucocytes from patients with acute leukemia. Cancer Res, 1968; 28: 2516–21.Google ScholarPubMed
Bosanquet, A. G.Correlations between therapeutic response of leukaemias and in-vitro drug-sensitivity assay. Lancet, 1991; 337: 711–14.CrossRefGoogle ScholarPubMed
Hongo, T., Yajima, S., Sakurai, M., et al.In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood, 1997; 89: 2959–65.Google ScholarPubMed
Pieters, R., Huismans, D. R., Loonen, A. H., et al.Relation of cellular drug resistance to long-term clinical outcome in childhood acute lymphoblastic leukaemia. Lancet, 1991; 338: 399–403.CrossRefGoogle ScholarPubMed
Frost, B. M., 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: 376–85.CrossRefGoogle ScholarPubMed
Kaspers, G. J. L., Pieters, R., Zantwijk, C. H., et al.Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs. Blood, 1998; 92: 259–66.Google ScholarPubMed
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: 1066–71.CrossRefGoogle ScholarPubMed
De Haas, V., Kaspers, G. J., 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: 1190–1.CrossRefGoogle Scholar
Klumper, E., Pieters, R., Veerman, A. J. P., et al.In vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood, 1995; 86: 3861–8.Google ScholarPubMed
Rots, M. G., Pieters, R., Peters, G. J., et al.Methotrexate resistance in relapsed childhood acute lymphoblastic leukaemia. Br J Haematol, 2000; 109: 629–34.CrossRefGoogle ScholarPubMed
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. Int J Hematol, 1999; 70: 268–77.Google ScholarPubMed
Boer, M. L., Harms, D. O., Pieters, R.et al.Patient stratification based on prednisolone-vincristine-asparaginase resistance profiles in children with acute lymphoblastic leukemia. J Clin Oncol, 2003; 21: 3262–8.CrossRefGoogle Scholar
Zwaan, C. M., Kaspers, G. J. L., 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: 2879–86.Google ScholarPubMed
Yamada, S., Hongo, T., Okada, S.et al.Clinical relevance of in vitro chemoresistance in childhood acute myeloid leukemia. Leukemia, 2001; 15: 1892–7.CrossRefGoogle ScholarPubMed
Zwaan, C. M., Kaspers, G. J., Pieters, R.et al.Cellular drug resistance in childhood acute myeloid leukemia is related to chromosomal abnormalities. Blood, 2002; 100: 3352–60.CrossRefGoogle ScholarPubMed
Klumper, E., Pieters, R., Kaspers, G. J. L., et al.In vitro chemosensitivity assessed with the MTT assay in childhood acute non-lymphoblastic leukemia. Leukemia, 1995; 9: 1864–9.Google ScholarPubMed
Klumper, E., Ossenkoppele, G. J., Pieters, R.et al.In vitro resistance to cytosine arabinoside, not to daunorubicin, is associated with the risk of relapse in de novo acute myeloid leukaemia. Br J Haematol, 1996; 93: 903–10.CrossRefGoogle Scholar
Norgaard, J. M., Olesen, G., Kristensen, J. S., et al.Leukaemia cell drug resistance and prognostic factors in AML. Eur J Haematol, 1999; 63: 219–24.CrossRefGoogle ScholarPubMed
Pui, C. H. & Evans, W. E.Acute lymphoblastic leukemia. N Engl J Med, 1998; 339: 605–15.CrossRefGoogle ScholarPubMed
Pieters, R., Boer, M. L., 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: 1344–8.CrossRefGoogle ScholarPubMed
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: 1209–17.Google ScholarPubMed
Ramakers-van Woerden, N. L., Pieters, R., Rots, M. G., et al.Infants with acute lymphoblastic leukemia: no evidence for high methotrexate resistance. Leukemia, 2002; 16: 949–51.CrossRefGoogle ScholarPubMed
Maung, Z. T., Reid, M. M., Matheson, E.et al.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.CrossRefGoogle ScholarPubMed
Styczynski, J., Pieters, R., Huismans, D. R., et al.In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukemia. Br J Haematol, 2000; 110: 813–18.CrossRefGoogle Scholar
Göker, E., Lin, J. T., Trippett, T.et al.Decreased polyglutamylation of methotrexate in acute lymphoblastic leukemia blasts in adults compared to children with this disease. Leukemia, 1993; 7: 1000–4.Google ScholarPubMed
Ramakers-van Woerden, N. L., 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: 379–86.CrossRefGoogle ScholarPubMed
Masson, E., Relling, M. V., Synold, T. W., 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.CrossRefGoogle ScholarPubMed
Niehues, T., Kapaun, P., Harms, D. O., et al.A classification based on T cell selection-related phenotypes identifies a subgroup of childhood T-ALL with favorable outcome in the COALL studies. Leukemia, 1999; 13: 614–17.CrossRefGoogle Scholar
Ferrando, A. A., Neuberg, D. S., Staunton, J.et al.Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. Cancer Cell, 2002; 1: 75–87.CrossRefGoogle ScholarPubMed
Pui, C. H., Ribeiro, R. C., Campana, D.et al.Prognostic factors in the acute lymphoid and myeloid leukemias of infants. Leukemia, 1996; 10: 952–6.Google ScholarPubMed
Stam, R. W., Boer, M. L., Meijerink, J. P., 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: 1270–6.CrossRefGoogle ScholarPubMed
Yamauchi, H., Iwata, N., Omine, M.et al.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: 766–73.Google ScholarPubMed
Lin, J. T., Tong, W. P., Trippett, T. M., et al.Basis for natural resistance to methotrexate in human acute non-lymphocytic leukemia. Leuk Res, 1991; 15: 1191–6.CrossRefGoogle ScholarPubMed
Goker, E., Kheradpour, A., Waltham, M.et al.Acute monocytic leukemia: a myeloid leukemia subset that may be sensitive to methotrexate. Leukemia, 1995; 9: 274–6.Google ScholarPubMed
Argiris, A., Longo, G. S., Gorlick, R.et al.Increased methotrexate polyglutamylation in acute megakaryocytic leukemia (M7) compared to other subtypes of acute myelocytic leukemia. Leukemia, 1997; 11: 886–9.CrossRefGoogle ScholarPubMed
Rots, M. G., 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: 492–8.CrossRefGoogle ScholarPubMed
Ramakers-van Woerden, N. L., Pieters, R., Slater, R. M., et al.In vitro drug resistance and prognostic impact of p16INK4A/P15INK4B deletions in childhood T-cell acute lymphoblastic leukaemia. Br J Haematol, 2001; 112: 680–90.CrossRefGoogle ScholarPubMed
Ramakers-van Woerden, N. L., Pieters, R., Loonen, A. H., et al.TEL/AML1 gene fusion is related to in vitro drug sensitivity for L-asparaginase in childhood acute lymphoblastic leukemia. Blood, 2000; 96: 1094–9.Google ScholarPubMed
Stams, W. A., Boer, M. L., Beverloo, H. B., et al.Sensitivity to L-asparaginase is not associated with expression levels of asparagine synthetase in t(12;21)+ pediatric ALL. Blood, 2003; 101: 2743–7.CrossRefGoogle ScholarPubMed
Whitehead, V. M., 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: 1081–8.CrossRefGoogle ScholarPubMed
Kaspers, G. J. L., Smets, L. A., Pieters, R.et al.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: 751–6.Google ScholarPubMed
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: 1183–9.Google ScholarPubMed
Synold, T. W., Relling, M. V., Boyett, J. M., 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.CrossRefGoogle ScholarPubMed
Whitehead, V. M., Vuchich, M. J., Lauer, S. J., 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: 1316–23.Google ScholarPubMed
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: 251–9.CrossRefGoogle ScholarPubMed
Biondi, A., Cimino, G., Pieters, R.et al.Biological and therapeutic aspects of infant leukemia. Blood, 2000; 96: 24–33.Google ScholarPubMed
Zwaan, C. M., Kaspers, G. J., 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: 245–51.CrossRefGoogle ScholarPubMed
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: 428–36.CrossRefGoogle ScholarPubMed
Tissing, W. J., Meijerink, J. P., Boer, M. L., et al.Molecular determinants of glucocorticoid sensitivity and resistance in acute lymphoblastic leukemia. Leukemia, 2003; 17: 17–25.CrossRefGoogle ScholarPubMed
Kaspers, G. J. L., Pieters, R., & Veerman, A. J. P.Glucocorticoid resistance in childhood leukemia. Int J Pediat Hematol/Oncol, 1997; 4: 583–96.Google Scholar
Haarman, E. G., Kaspers, G. J., 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: 1882–4.CrossRefGoogle Scholar
Tonko, M., Ausserlechner, M. J., Bernhard, D.et al.Gene expression profiles of proliferating versus G1/G0 arrested human leukemia cells suggest a mechanism for glucocorticoid-induced apoptosis. FASEB J, 2001; 15: 693–9.CrossRefGoogle Scholar
Ramdas, J., Liu, W., & Harmon, J. M.Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res, 1999; 59: 1378–85.Google ScholarPubMed
Breslin, M. B., Geng, C. D., & Vedeckis, W. V.Multiple promoters exist in the human GR gene, one of which is activated by glucocorticoids. Mol Endocrinol, 2001; 15: 1381–95.CrossRefGoogle ScholarPubMed
Yudt, M. R., Jewell, C. M., Bienstock, R. J., et al.Molecular origins for the dominant negative function of human glucocorticoid receptor beta. Mol Cell Biol, 2003; 23: 4319–30.CrossRefGoogle ScholarPubMed
de Lange, P., Segeren, C. M., Koper, J. W., 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: 3937–41.Google ScholarPubMed
Rivers, C., Levy, A., Hancock, J., et al.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: 4283–6.CrossRefGoogle ScholarPubMed
Ray, D. W., Davis, J. R., White, A., et al.Glucocorticoid receptor structure and function in glucocorticoid-resistant small cell lung carcinoma cells. Cancer Res, 1996; 56: 3276–80.Google ScholarPubMed
Moalli, P. A., Pillay, S., Krett, N. L., et al.Alternatively spliced glucocorticoid receptor messenger RNAs in glucocorticoid-resistant human multiple myeloma cells. Cancer Res, 1993; 53: 3877–9.Google ScholarPubMed
Longui, C. A., Vottero, A., Adamson, P. C., et al.Low glucocorticoid receptor alpha/beta ratio in T-cell lymphoblastic leukemia. Horm Metab Res, 2000; 32: 401–6.CrossRefGoogle ScholarPubMed
Haarman, E. G., Kaspers, G. J. L., Pieters, R., et al.Glucocorticoid receptor alpha, beta and gamma expression versus in vitro glucocorticod resistance in childhood leukemia. Leukemia, 2004; 18: 530–7.CrossRefGoogle Scholar
Hillmann, A. G., Ramdas, J., Multanen, K., et al.Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in vivo. Cancer Res, 2000; 60: 2056–62.Google ScholarPubMed
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: 994–9.Google ScholarPubMed
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: 14 620–5.CrossRefGoogle ScholarPubMed
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: 1551–6.CrossRefGoogle ScholarPubMed
Gerritsen, M. E., Williams, A. J., Neish, A. S., et al.CREB-binding protein/p300 are transcriptional coactivators of p65. Proc Natl Acad Sci U S A, 1997; 94: 2927–32.CrossRefGoogle ScholarPubMed
Tissing, W. J., Meijerink, J. P., Boer, M. L., et al.mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL. Leukemia, 2005; 19: 727–33.CrossRefGoogle Scholar
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: 361–7.CrossRefGoogle Scholar
Boer, M. L., Pieters, R., Kazemier, K. M., 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: 2092–8.Google Scholar
Kearns, P. R., Pieters, R., Rottier, M. M., et al.Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia. Blood, 2001; 97: 393–8.CrossRefGoogle ScholarPubMed
Boer, M. L., Pieters, R., Kazemier, K. M., et al.Different expression of glutathione S-transferase α, μ and π in childhood acute lymphoblastic and myeloid leukaemia. Br J Haematol, 1999; 104: 321–7.CrossRefGoogle Scholar
Reichardt, H. M., Kaestner, K. H., Tuckermann, J., et al.DNA binding of the glucocorticoid receptor is not essential for survival. Cell, 1998; 93: 531–41.CrossRefGoogle ScholarPubMed
Bailey, S., Hall, A. G., Pearson, A. D., et al.The role of AP-1 in glucocorticoid resistance in leukaemia. Leukemia, 2001; 15: 391–7.CrossRefGoogle ScholarPubMed
Kordes, U., Krappmann, D., Heissmeyer, V., et al.Transcription factor NF-kappaB is constitutively activated in acute lymphoblastic leukemia cells. Leukemia, 2000; 14: 399–402.CrossRefGoogle ScholarPubMed
Liptay, S., Seriu, T., Bartram, C. R., et al.Germline configuration of NFkB2, c-REL and BCLl3 in childhood acute lymphoblastic leukemia (ALL). Leukemia, 1997; 11: 1364–6.CrossRefGoogle Scholar
Thulasi, R., Harbour, D. V., & Thompson, E. B.Suppression of c-myc is a critical step in glucocorticoid-induced human leukemic cell lysis. J Biol Chem, 1993; 268: 18 306–12.Google ScholarPubMed
Conte, D., Liston, P., Wong, J. W., et al.Thymocyte-targeted overexpression of xiap transgene disrupts T lymphoid apoptosis and maturation. Proc Natl Acad Sci U S A, 2001; 98: 5049–54.CrossRefGoogle Scholar
Miller, H. K., Salzer, J. S., & Balis, M. E.Amino acid levels following L-asparaginase amidohydrolase (EC.3.5.1.1) therapy. Cancer Res, 1969; 29: 183–7.Google ScholarPubMed
Ohnuma, T., Holland, J. F., Freeman, A., et al.Biochemical and pharmacological studies with asparaginase in man. Cancer Res, 1970; 30: 2297–305.Google ScholarPubMed
Jousse, C., Bruhat, A., Ferrara, M., et al.Evidence for multiple signaling pathways in the regulation of gene expression by amino acids in human cell lines. J Nutr, 2000; 130: 1555–60.CrossRefGoogle ScholarPubMed
Aslanian, A. M., Fletcher, B. S., & Kilberg, M. S.Asparagine synthetase expression alone is sufficient to induce l-asparaginase resistance in MOLT-4 human leukaemia cells. Biochem J, 2001; 357: 321–8.CrossRefGoogle ScholarPubMed
Stams, W. A., Boer, M. L., Holleman, A., et al.Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML 1-positive pediatric acute lymphoblastic leukemia. Blood, 2005; 105: 4223–5.CrossRefGoogle ScholarPubMed
Dubbers, A., Wurthwein, G., Muller, H. J., et al.Asparagine synthetase activity in paediatric acute leukaemias: AML-M5 subtype shows lowest activity. Br J Haematol, 2000; 109: 427–9.CrossRefGoogle ScholarPubMed
Aslanian, A. M. & Kilberg, M. S.Multiple adaptive mechanisms affect asparagine synthetase substrate availability in asparaginase-resistant MOLT-4 human leukaemia cells. Biochem J, 2001; 358: 59–67.CrossRefGoogle ScholarPubMed
Iiboshi, Y., Papst, P. J., Hunger, S. P., et al.L-Asparaginase inhibits the rapamycin-targeted signaling pathway. Biochem Biophys Res Commun, 1999; 260: 534–9.CrossRefGoogle ScholarPubMed
Hu, Z. B., Minden, M. D., & McCulloch, E. A.Regulation of drug sensitivity by ribosomal protein S3a. Blood, 2000; 95: 1047–55.Google ScholarPubMed
Holleman, A., Cheok, M. H., Boer, M. L., et al.Gene expression patterns in drug resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med, 2004; 351: 533–42.CrossRefGoogle ScholarPubMed
Mandelkow, E. & Mandelkow, E. M.Microtubules and microtubule-associated proteins. Curr Opin Cell Biol, 1995; 7: 72–81.CrossRefGoogle ScholarPubMed
Kavallaris, M., Tait, A. S., Walsh, B. J., et al.Multiple microtubule alterations are associated with Vinca alkaloid resistance in human leukemia cells. Cancer Res, 2001; 61: 5803–9.Google ScholarPubMed
Giannakakou, P., Nakano, M., Nicolaou, K. C., et al.Enhanced microtubule-dependent trafficking and p53 nuclear accumulation by suppression of microtubule dynamics. Proc Natl Acad Sci U S A, 2002; 99: 10855–60.CrossRefGoogle ScholarPubMed
Boer, M. L., Pieters, R., Kazemier, K. M., 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: 2023–30.CrossRefGoogle Scholar
Boer, M. L., Pieters, R., Kazemier, K. M., et al.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: 912–20.CrossRefGoogle Scholar
Siva, A. C., Raval-Fernandes, S., Stephen, A. G., et al.Up-regulation of vaults may be necessary but not sufficient for multidrug resistance. Int J Cancer, 2001; 92: 195–202.3.0.CO;2-7>CrossRefGoogle Scholar
Legrand, O., Simonin, G., Beauchamp-Nicoud, A., et al.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: 1046–56.Google ScholarPubMed
Goasguen, J. E., 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: 567–76.CrossRefGoogle ScholarPubMed
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: 641–7.CrossRefGoogle Scholar
Borg, A. G., Burgess, R., Green, L. M., et al.P-glycoprotein 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.CrossRefGoogle Scholar
Tsuji, K., Motoji, T., 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: 370–8.CrossRefGoogle ScholarPubMed
Leith, C. P., Kopecky, K. J., Chen, I. M., 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: 1086–99.Google ScholarPubMed
Heuvel-Eibrink, M. M., 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.CrossRefGoogle ScholarPubMed
Bezombes, C., de Thonel, A., Apostolou, A., et al.Overexpression of protein kinase C zeta confers protection against antileukemic drugs by inhibiting the redox-dependent sphingomyelinase activation. Mol Pharmacol, 2002; 62: 1446–55.CrossRefGoogle ScholarPubMed
Batist, G., Schecter, R., Woo, A., et al.Glutathione depletion in human and in rat multi-drug resistant breast cancer cell lines. Biochem Pharmacol, 1991; 41: 631–5.CrossRefGoogle ScholarPubMed
Versantvoort, C. H. M., Broxterman, H. J., Bagrij, T., et al.Regulation of glutathione of drug transport in multidrug-resistant human lung tumour cell lines overexpressing multidrug resistance-associated protein. Br J Cancer, 1995; 72: 82–9.CrossRefGoogle ScholarPubMed
Kaufmann, S. H., Karp, J. E., Jones, R. J., et al.Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. Blood, 1994; 83: 517–30.Google ScholarPubMed
Klumper, E., Giaccone, G., Pieters, R., et al.Topoisomerase IIa gene expression in childhood acute lymphoblastic leukemia. Leukemia, 1995; 9: 1653–60.Google Scholar
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: 1177–80.Google Scholar
Hellin, A. C., 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: 870–8.Google ScholarPubMed
Holleman, A., Boer, M. L., Kazemier, K. M., et al.Resistance to different classes of drugs is associated with impaired apoptosis in childhood acute lymphoblastic leukemia. Blood, 2003; 102: 4541–6.CrossRefGoogle ScholarPubMed
Friesen, C., Herr, I., Krammer, P. H., et al.Involvement of the CD95 (APO-1/Fas) receptor/ligand system in drug-induced apoptosis in leukemia cells. Nat Med, 1996; 2: 574–7.CrossRefGoogle ScholarPubMed
Landowski, T. H., Gleason-Guzman, M. C., & Dalton, W. S.Selection for drug resistance results in resistance to Fas-mediated apoptosis. Blood, 1997; 89: 1854–61.Google ScholarPubMed
Labroille, G., Dumain, P., Lacombe, F., et al.Flow cytometric evaluation of Fas expression in relation to response and resistance to anthracyclines in leukemic cells. Cytometry, 2000; 39: 195–202.3.0.CO;2-A>CrossRefGoogle ScholarPubMed
Debatin, K. M. & Krammer, P. H.Resistance to APO-1 (CD95) induced apoptosis in T-ALL is determined by a bcl-2 independent anti-apoptotic program. Leukemia, 1995; 9: 815–20.Google ScholarPubMed
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: 1245–52.CrossRefGoogle Scholar
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: 154–60.CrossRefGoogle Scholar
Munker, R. & Andreeff, M.Induction of death (CD95/Fas), activation and adhesion (CD54) molecules on blast cells of acute myelogenous leukemias by TNF-α and IFN-gamma. Cytokines Mol Ther, 1996; 2: 147–60.Google ScholarPubMed
Iijima, N., Miyamura, K., Itou, T., et al.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: 4901–9.Google Scholar
Jaffrezou, J. P., Levade, T., Bettaieb, A., et al.Daunorubicin-induced apoptosis: triggering of ceramide generation through sphingomyelin hydrolysis. EMBO J, 1996; 15: 2417–24.Google ScholarPubMed
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: 415–23.Google ScholarPubMed
Chikamori, K., Grabowski, D. R., 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: 12 696–702.CrossRefGoogle ScholarPubMed
Bugg, B. Y., Danks, M. K., Beck, W. T., et al.Expression of a mutant DNA topoisomerase II in CCRF-CEM human leukemic cells selected for resistance to teniposide. Proc Natl Acad Sci U S A, 1991; 88: 7654–8.CrossRefGoogle ScholarPubMed
Danks, M. K., Warmoth, M. R., 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: 1373–9.Google Scholar
Rots, M. G., Pieters, R., Kaspers, G. J., et al.Classification of ex vivo methotrexate resistance in acute lymphoblastic and myeloid leukaemia. Br J Haematol, 2000; 110: 791–800.CrossRefGoogle ScholarPubMed
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: 1013–18.Google ScholarPubMed
Matherly, L. H., Taub, J. W., Wong, S. C., et al.Increased frequency of expression of elevated dihydrofolate reductase in T-cell versus B-precursor acute lymphoblastic leukemia in children. Blood, 1997; 90: 578–89.Google ScholarPubMed
Zhang, L., Taub, J. W., Williamson, M., et al.Reduced folate carrier gene expression in childhood acute lymphoblastic leukemia: relationship to immunophenotype and ploidy. Clin Cancer Res, 1998; 4: 2169–77.Google ScholarPubMed
Belkov, V. M., Krynetski, E. Y., Schuetz, J. D., et al.Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood, 1999; 93: 1643–50.Google Scholar
Laverdiere, C., Chiasson, S., Costea, I., et al.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: 3832–4.CrossRefGoogle ScholarPubMed
Whetstine, J. R., Gifford, A. J., 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: 3416–22.Google ScholarPubMed
Gifford, A. J., Haber, M., Witt, T. L., et al.Role of the E45K-reduced folate carrier gene mutation in methotrexate resistance in human leukemia cells. Leukemia, 2002; 16: 2379–87.CrossRefGoogle ScholarPubMed
Mantadakis, E., Smith, A. K., & Kamen, B. A.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: 221–6.CrossRefGoogle ScholarPubMed
Zeng, H., Chen, Z. S., Belinsky, M. G., et al.Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res, 2001; 61: 7225–32.Google ScholarPubMed
Chen, Z. S., 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: 3144–50.Google ScholarPubMed
Assaraf, Y. G., Rothem, L., Hooijberg, J. H., 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: 6680–6.CrossRefGoogle Scholar
Whitehead, V. M., Rosenblatt, D. S., Vuchich, M. J., et al.Accumulation of methotrexate and methotrexate polyglutamates in lymphoblasts at diagnosis of childhood acute lymphoblastic leukemia: a pilot prognostic factor analysis. Blood, 1990; 76: 44–9.Google ScholarPubMed
Mantadakis, E., Smith, A. K., Hynan, L., et al.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: 636–42.CrossRefGoogle ScholarPubMed
Galpin, A. J., Schuetz, J. D., Masson, E., et al.Differences in folylpolyglutamate 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: 155–63.CrossRefGoogle ScholarPubMed
Barredo, J. C., Synold, T. W., Laver, J., et al.Differences in constitutive and post-methotrexate folylpolyglutamate synthetase activity in B-lineage and T-lineage leukemia. Blood, 1994; 84: 564–9.Google ScholarPubMed
Longo, G. S., Gorlick, R., Tong, W. P., et al.Disparate affinities of antifolates for folylpolyglutamate synthetase from human leukemia cells. Blood, 1997; 90: 1241–5.Google ScholarPubMed
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: 677–84.Google ScholarPubMed
Spencer, H. T., Sorrentino, B. P., Pui, C. H., et al.Mutations in the gene for human dihydrofolate reductase: an unlikely cause of clinical relapse in pediatric leukemia after therapy with methotrexate. Leukemia, 1996; 10: 439–46.Google ScholarPubMed
Krajinovic, M., Costea, I., & Chiasson, S.Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet, 2002; 359: 1033–4.CrossRefGoogle ScholarPubMed
Chiusolo, P., Reddiconto, G., Casorelli, I., et al.Preponderance of methylenetetrahydrofolate reductase C677T homozygosity among leukemia patients intolerant to methotrexate. Ann Oncol, 2002; 13: 1915–18.CrossRefGoogle ScholarPubMed
Taub, J. W., Matherly, L. H., Ravindranath, Y., et al.Polymorphisms in methylenetetrahydrofolate reductase and methotrexate sensitivity in childhood acute lymphoblastic leukemia. Leukemia, 2002; 16: 764–5.CrossRefGoogle ScholarPubMed
Dervieux, T., Blanco, J. G., Krynetski, E. Y., et al.Differing contribution of thiopurine methyltransferase to mercaptopurine versus thioguanine effects in human leukemic cells. Cancer Res, 2001; 61: 5810–6.Google ScholarPubMed
Coulthard, S. A., Hogarth, L. A., Little, M., et al.The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs. Mol Pharmacol, 2002; 62: 102–9.CrossRefGoogle ScholarPubMed
Davidson, J. D.Studies on the mechanism of action of 6-mercaptopurine in sensitive and resistant L1210 leukemia in vitro. Cancer Res, 1960; 20: 225.Google ScholarPubMed
Brockman, R. W.A mechanism of resistance to 6-mercaptopurine: metabolism of hypoxanthine and 6-mercaptopurine by sensitive and resistant neoplasms. Cancer Res, 1960; 20: 643.Google ScholarPubMed
Ellis, D. B. & LePage, G. A.Biochemical studies of resistance to 6-thioguanine. Cancer Res, 1963; 23: 436.Google Scholar
Zimm, S., Johnson, G. E., Chabner, B. A., et al.Cellular pharmacokinetics of mercaptopurine in human neoplastic cells and cell lines. Cancer Res, 1985; 45: 4156–61.Google ScholarPubMed
Brockman, R. W.Resistance to purine antagonists in experimental leukemia systems. Cancer Res, 1965; 25: 1596–605.Google ScholarPubMed
Curt, G. A., Clendeninn, N. J., & Chabner, B. A.Drug resistance in cancer. Cancer Treat Rep, 1984; 68: 87–99.Google Scholar
Pieters, R., Huismans, D. R., Loonen, A. H., et al.Hypoxanthine-guanine phosphoribosyltransferase in childhood leukemia: relation with immunophenotype, differentiation stage, in vitro drug resistance and clinical prognosis. Int J Cancer, 1992; 51: 213–17.CrossRefGoogle ScholarPubMed
Pieters, R., Huismans, D. R., Loonen, A. H., 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: 375–80.Google ScholarPubMed
Veerman, A. J. P., Hogeman, P. H. G., Zantwijk, C. H. Van., et al.Prognostic value of 5′ nucleotidase in acute lymphoblastic leukemia with the common-ALL phenotype. Leuk Res, 1985; 9: 1227–9.CrossRefGoogle ScholarPubMed
Pieters, R., Huismans, D. R., & Veerman, A. J.Are children with lymphoblastic leukaemia resistant to 6-mercaptopurine because of 5′-nucleotidase ?Lancet, 1987; 2: 1471.CrossRefGoogle ScholarPubMed
Pieters, R., Thompson, L. F., Broekema, G. J., et al.Expression of 5′-nucleotidase (CD73) related to other differentiation antigens in leukemias of B-cell lineage. Blood, 1991; 78: 488–92.Google ScholarPubMed
Pieters, R., Huismans, D. R., Loonen, A. H., et al.Relation of 5′-nucleotidase and phosphatase activities with immunophenotype, drug resistance and clinical prognosis in childhood leukemia. Leuk Res, 1992; 16: 873–80.CrossRefGoogle ScholarPubMed
Rosman, M., Lee, M. H., Creasey, W. A., et al.Mechanisms of resistance to 6-thiopurines in human leukemia. Cancer Res, 1974; 34: 1952–6.Google ScholarPubMed
Lennard, L. & Lilleyman, J. S.Variable mercaptopurine metabolism and treatment outcome in childhood lymphoblastic leukemia. J Clin Oncol, 1989; 7: 1816–23.CrossRefGoogle ScholarPubMed
Lilleyman, J. S. & Lennard, L.Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet, 1994; 343: 1188–90.CrossRefGoogle ScholarPubMed
McLeod, H. L., Relling, M. V., Liu, Q., et al.Polymorphic thiopurine methyltransferase in erythrocytes is indicative of activity in leukemic blasts from children with acute lymphoblastic leukemia. Blood, 1995; 85: 1897–902.Google ScholarPubMed
Lennard, L., Welch, J. C., & Lilleyman, J. S.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: 455–61.CrossRefGoogle ScholarPubMed
Krynetski, E. Y., Tai, H. L., Yates, C. R., et al.Genetic polymorphism of thiopurine S-methyltransferase: clinical importance and molecular mechanisms. Pharmacogenetics, 1996; 6: 279–90.CrossRefGoogle ScholarPubMed
Coulthard, S. A., Howell, C., Robson, J., et al.The relationship between thiopurine methyltransferase activity and genotype in blasts from patients with acute leukemia. Blood, 1998; 92: 2856–62.Google ScholarPubMed
McLeod, H. L., Krynetski, E. Y., Relling, M. V., et al.Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia, 2000; 14: 567–72.CrossRefGoogle ScholarPubMed
Relling, M. V., Hancock, M. L., Boyett, J. M., et al.Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood, 1999; 93: 2817–23.Google ScholarPubMed
Owens, J. K., Shewach, D. S., Ullman, B., et al.Resistance to 1-beta-D-arabinofuranosylcytosine in human T-lymphoblasts mediated by mutations within the deoxycytidine kinase gene. Cancer Res, 1992; 52: 2389–93.Google ScholarPubMed
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: 780–5.Google ScholarPubMed
Heuvel-Eibrink, M. M., Wiemer, E. A., Kuijpers, M., et al.Absence of mutations in the deoxycytidine kinase (dCK) gene in patients with relapsed and/or refractory acute myeloid leukemia (AML). Leukemia, 2001; 15: 855–6.CrossRefGoogle Scholar
Taub, J. W., Huang, X., Matherly, L. H., 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: 1393–400.Google ScholarPubMed
Veuger, M. J., Honders, M. W., Landegent, J. E., et al.High incidence of alternatively spliced forms of deoxycytidine kinase in patients with resistant acute myeloid leukemia. Blood, 2000; 96: 1517–24.Google ScholarPubMed
Veuger, M. J., Heemskerk, M. H., Honders, M. W., et al.Functional role of alternatively spliced deoxycytidine kinase in sensitivity to cytarabine of acute myeloid leukemic cells. Blood, 2002; 99: 1373–80.CrossRefGoogle ScholarPubMed
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: 397–404.3.0.CO;2-C>CrossRefGoogle ScholarPubMed
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. Br J Haematol, 1999; 105: 388–93.CrossRefGoogle ScholarPubMed
Galmarini, C. M., Thomas, X., Calvo, F., et al.In vivo mechanisms of resistance to cytarabine in acute myeloid leukaemia. Br J Haematol, 2002; 117: 860–8.CrossRefGoogle ScholarPubMed
Verschuur, A. C., Gennip, A. H.Leen, R., et al.In vitro inhibition of cytidine triphosphate synthetase activity by cyclopentenyl cytosine in paediatric acute lymphocytic leukaemia. Br J Haematol, 2000; 110: 161–9.CrossRefGoogle ScholarPubMed
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; 102: 4493–8.CrossRefGoogle ScholarPubMed
Steinbach, D., Lengemann, J., Voigt, A., et al.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: 1083–6.Google ScholarPubMed
Kolk, D. M., De Vries, E. G., Noordhoek, L., et al.Activity and expression of the multidrug resistance proteins P-glycoprotein, MRP1, MRP2, MRP3 and MRP5 in de novo and relapsed acute myeloid leukemia. Leukemia, 2001; 15: 1544–53.CrossRefGoogle ScholarPubMed
Heuvel-Eibrink, M. M., Wiemer, E. A., & Prins, A., et al.Increased expression of the breast cancer resistance protein (BCRP) in relapsed or refractory acute myeloid leukemia (AML). Leukemia, 2002; 16: 833–9.CrossRefGoogle Scholar
Steinbach, D., Sell, W., Voigt, A., et al.BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia. Leukemia, 2002; 16: 1443–7.CrossRefGoogle ScholarPubMed
Sargent, J. M., Williamson, C. J., Maliepaard, M., et al.Breast cancer resistance protein expression and resistance to daunorubicin in blasts from patients with acute myeloid leukemia. Br J Haematol, 2001; 115: 257–62.CrossRefGoogle Scholar
Stam, R. W., Heuvel-Eibrink, M. M., Boer, M. L., et al.Multidrug resistance genes in infant acute lymphoblastic leukemia; Ara-C is not a substrate for the breast cancer resistance protein (BCRP). Leukemia, 2004; 18: 78–83.CrossRefGoogle Scholar
Sauerbrey, A., Sell, W., Steinbach, D., et al.Expression of the BCRP gene (ABCG2/MXR/ABCP) in childhood acute lymphoblastic leukaemia. Br J Haematol, 2002; 118: 147–50.CrossRefGoogle Scholar
Kumagai, M., Manabe, A., Pui, C. H., et al.Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest, 1996; 97: 755–60.CrossRefGoogle ScholarPubMed
Schimmer, A. D., Pedersen, I. M., 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: 1242–8.Google ScholarPubMed
Salomons, G. S., Smets, L. A., 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: 1574–80.CrossRefGoogle ScholarPubMed
Coustan-Smith, E., Kitanaka, A., Pui, C. H., et al.Clinical relevance of bcl-2 overexpression in childhood acute lymphoblastic leukemia. Blood, 1996; 87: 1140–6.Google ScholarPubMed
Wuchter, C., Ruppert, V., Schrappe, M., et al.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: 4109–15.CrossRefGoogle ScholarPubMed
Prokop, A., Wieder, T., Sturm, I., et al.Relapse in childhood acute lymphoblastic leukemia is associated with a decrease of the Bax/Bcl-2 ratio and loss of spontaneous caspase-3 processing in vivo. Leukemia, 2000; 14: 1606–13.CrossRefGoogle ScholarPubMed
Cheok, M. H., & Boer, M. L.. Identification of genes associated crossresistance and treatment response in childhood acute leukemia. Cancer Cell, 2005; 7: 375–86.Google Scholar
Cheok, M. H., Yang, W., Pui, C. H., et al.Treatment-specific changes in gene expression discriminate in vivo drug response in human leukemia cells. Nat Genet, 2003; 34: 85–90.CrossRefGoogle ScholarPubMed
Yeoh, E. J., Ross, M. E., Shurtleff, S. A., et al.Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell, 2002; 1: 133–43.CrossRefGoogle ScholarPubMed
Armstrong, S. A., Staunton, J. E., Silverman, L. B., et al.MLL translocations specify a distinct gene expression profile that distinguishes a unique leukemia. Nat Genet, 2002; 30: 41–7.CrossRefGoogle ScholarPubMed
Ross, M. E., Zhou, X., Song, G., et al.Classification of pediatric acute lymphoblastic leukemia by gene expression profiling. Blood, 2003; 102: 2951–9.CrossRefGoogle ScholarPubMed
Yagi, T., Morimoto, A., Eguchi, M., et al.Identification of a gene expression signature associated with pediatric AML prognosis. Blood, 2003; 102: 1849–56.CrossRefGoogle ScholarPubMed
Armstrong, S. A., Kung, A. L., Mabon, M. E., et al.Inhibition of FLT3 in MLL. Validation of a therapeutic target identified by gene expression based classification. Cancer Cell, 2003; 3: 173–83.CrossRefGoogle ScholarPubMed

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  • Assays and molecular determinants of cellular drug resistance
    • By Monique L. den Boer, Associate Professor, Molecular Pediatric Oncology Head, Research Laboratory Pediatric Oncology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Department of Pediatric Oncology and Hematology, Rotterdam, the Netherlands, Rob Pieters, Professor and Head, Department of Pediatric Oncology and Hematology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands
  • Edited by Ching-Hon Pui
  • Book: Childhood Leukemias
  • Online publication: 01 July 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511471001.016
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  • Assays and molecular determinants of cellular drug resistance
    • By Monique L. den Boer, Associate Professor, Molecular Pediatric Oncology Head, Research Laboratory Pediatric Oncology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Department of Pediatric Oncology and Hematology, Rotterdam, the Netherlands, Rob Pieters, Professor and Head, Department of Pediatric Oncology and Hematology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands
  • Edited by Ching-Hon Pui
  • Book: Childhood Leukemias
  • Online publication: 01 July 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511471001.016
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  • Assays and molecular determinants of cellular drug resistance
    • By Monique L. den Boer, Associate Professor, Molecular Pediatric Oncology Head, Research Laboratory Pediatric Oncology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Department of Pediatric Oncology and Hematology, Rotterdam, the Netherlands, Rob Pieters, Professor and Head, Department of Pediatric Oncology and Hematology, Erasmus MC–Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, the Netherlands
  • Edited by Ching-Hon Pui
  • Book: Childhood Leukemias
  • Online publication: 01 July 2010
  • Chapter DOI: https://doi.org/10.1017/CBO9780511471001.016
Available formats
×