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Blood, 15 December 2004, Vol. 104, No. 13, pp. 4194-4201. Prepublished online as a Blood First Edition Paper on August 12, 2004; DOI 10.1182/blood-2004-04-1493. This Article Full Text (PDF) All Versions of this Article: 2004-04-1493v1 104/13/4194    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 Fotoohi, K. Articles by Albertioni, F. Search for Related Content PubMed PubMed Citation Articles by Fotoohi, K. Articles by Albertioni, F. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted April 19, 2004 Accepted July 23, 2004 Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy Kambiz Fotoohi, Gerrit Jansen, Yehuda G Assaraf, Lilah Rothem, Michal Stark, Ietje Kathmann, Jacek Gregorczyk, Godefridus J Peters, and Freidoun Albertioni* Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden Department of Rheumatology, University Hospital Vrije Universteit, Amsterdam, The Netherlands Department of Biology, The Technion-Israel Institute of Technology, Haifa, Israel Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands Department of Medicine and Care, Division of Clinical Pharmacology, Faculty of Health Sciences, Linkoping, Sweden * Corresponding author; email: freidoun.albertioni{at}ks.se. Methotrexate (MTX) is one of the leading drugs in the treatment of leukemia, but extensive metabolism to 7-hydroxymethotrexate (7-OHMTX) can limit its therapeutic efficacy. In this study we investigated whether 7-OHMTX itself can provoke antifolate resistance that may further disrupt MTX efficacy. For this purpose we developed resistance to 7-OHMTX as well as MTX in two human leukemia cell lines (CCRF-CEM and MOLT-4) by stepwise exposure to increasing concentrations of 7-OHMTX and MTX. Consequently, both leukemia cell lines displayed marked levels of resistance to 7-OHMTX (>10 fold) and MTX (>75 fold), respectively. The underlying mechanism of resistance in the MTX-exposed cells was a marked decrease (>10-fold) in reduced folate carrier (RFC)-mediated cellular uptake of MTX. This was associated with transcriptional silencing of the RFC gene in MTX-resistant CCRF-CEM cells. In contrast, the molecular basis for the resistance to 7-OHMTX was solely due to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity which conferred >100-fold MTX resistance upon a short term exposure to this drug. This is the first demonstration that 7-OHMTX can provoke distinct modalities of antifolate resistance as compared to the parent drug MTX. The implications of this finding for MTX efficacy and strategies to circumvent MTX resistance are discussed. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Stark, C. Wichman, I. Avivi, and Y. G. Assaraf Aberrant splicing of folylpolyglutamate synthetase as a novel mechanism of antifolate resistance in leukemia Blood, April 30, 2009; 113(18): 4362 - 4369. [Abstract] [Full Text] [PDF] W.-L. Zhao, Y.-Y. Liu, Q.-L. Zhang, L. Wang, C. Leboeuf, Y.-W. Zhang, J. Ma, J.-F. Garcia, Y.-P. Song, J.-M. Li, et al. PRDM1 is involved in chemoresistance of T-cell lymphoma and down-regulated by the proteasome inhibitor Blood, April 1, 2008; 111(7): 3867 - 3871. [Abstract] [Full Text] [PDF]

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