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Blood, 1 September 2005, Vol. 106, No. 5, pp. 1778-1785. Prepublished online as a Blood First Edition Paper on May 19, 2005; DOI 10.1182/blood-2005-01-0143. This Article Full Text (PDF) Supplemental Figures and Tables All Versions of this Article: 2005-01-0143v1 106/5/1778    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zaza, G. Articles by Evans, W. E Search for Related Content PubMed PubMed Citation Articles by Zaza, G. Articles by Evans, W. E Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 12, 2005 Accepted April 24, 2005 Gene expression and thioguanine nucleotide disposition in acute lymphoblastic leukemia after in vivo mercaptopurine treatment Gianluigi Zaza, Meyling Cheok, Wenjian Yang, John C Panetta, Ching-Hon Pui, Mary V Relling, and William E Evans* Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Bari, Bari, Italy Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennesee, Memphis, TN, USA Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA Hematological Malignancies Program, St. Jude Children's Research Hospital, Memphis, TN, USA; Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA; University of Tennesee, Memphis, TN, USA * Corresponding author; email: william.evans{at}stjude.org. To elucidate inter-patient variability in thioguanine nucleotide (TGN) concentrations in acute lymphoblastic leukemia (ALL) cells, we determined the TGN concentration in leukemic blasts from 82 children with newly diagnosed ALL after intravenous mercaptopurine (MP). Patients treated with MP alone, achieved higher TGN concentrations compared to those treated with the combination of methotrexate plus mercaptopurine (MTX+MP). Analysis of the expression of approximately 9,600 genes in ALL cells obtained at diagnosis identified 60 gene probes significantly associated with TGN accumulation in patients treated with MP alone and 75 gene probes in patients treated with MTX+MP, with no overlap between the two sets of genes. Genes significantly associated with intracellular TGN accumulation after MP alone, include those encoding MP metabolic enzymes and transporters (e.g., SLC29A1). Inhibition of SLC29A1 by nitrobenzylmercaptopurine ribonucleoside (NBMPR) caused a 33-45% reduction of TGN in ALL cells, in vitro (p< 0.006), consistent with the gene expression findings. Genes associated with TGN concentration, after combination therapy include genes involved in protein and ATP-biosynthesis. Together, these in vivo and in vitro data provide new insights into the genomic basis of inter-patient differences in intracellular TGN accumulation, and reveal significant differences between treatment with MP alone or in combination with MTX. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: More and more about less and less Bruce Matthew Camitta Blood 2005 106: 1512. [Full Text] [PDF] This article has been cited by other articles: A. D. ASKANASE, D. J. WALLACE, M. H. WEISMAN, C.-E TSENG, L. BERNSTEIN, H. M. BELMONT, E. SEIDMAN, M. ISHIMORI, P. M. IZMIRLY, and J. P. BUYON Use of Pharmacogenetics, Enzymatic Phenotyping, and Metabolite Monitoring to Guide Treatment with Azathioprine in Patients with Systemic Lupus Erythematosus J Rheumatol, January 1, 2009; 36(1): 89 - 95. [Abstract] [Full Text] [PDF] P. Krishnamurthy, M. Schwab, K. Takenaka, D. Nachagari, J. Morgan, M. Leslie, W. Du, K. Boyd, M. Cheok, H. Nakauchi, et al. Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity Cancer Res., July 1, 2008; 68(13): 4983 - 4989. [Abstract] [Full Text] [PDF] C. Flotho, E. Coustan-Smith, D. Pei, S. Iwamoto, G. Song, C. Cheng, C.-H. Pui, J. R. Downing, and D. Campana Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2 Blood, August 1, 2006; 108(3): 1050 - 1057. [Abstract] [Full Text] [PDF] C.-H. Pui and W. E. Evans Treatment of Acute Lymphoblastic Leukemia N. Engl. J. Med., January 12, 2006; 354(2): 166 - 178. [Full Text] [PDF]

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