Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy
| العنوان: | Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells: implications for efficacy of methotrexate therapy |
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| المؤلفون: | Godefridus J. Peters, Michal Stark, Ietje Kathmann, Jacek Gregorczyk, Gerrit Jansen, Lilah Rothem, Freidoun Albertioni, Kambiz Fotoohi, Yehuda G. Assaraf |
| المساهمون: | Rheumatology, Medical oncology |
| المصدر: | Fotoohi, K, Jansen, G, Assaraf, Y G, Rothem, L, Stark, M, Kathmann, I, Gregorczyk, J, Peters, G J & Albertioni, F 2004, ' Disparate mechanisms of antifolate resistance provoked by methotrexate and its metabolite 7-hydroxymethotrexate in leukemia cells : implications for efficacy of methotrexate therapy ', Blood, vol. 104, no. 13, pp. 4194-201 . https://doi.org/10.1182/blood-2004-04-1493 Blood, 104(13), 4194-201. American Society of Hematology |
| بيانات النشر: | American Society of Hematology, 2004. |
| سنة النشر: | 2004 |
| مصطلحات موضوعية: | musculoskeletal diseases, Drug, Antimetabolites, Antineoplastic, medicine.drug_class, Glutamine, Metabolite, media_common.quotation_subject, Immunology, Pharmacology, Biology, Biochemistry, Antimetabolite, chemistry.chemical_compound, immune system diseases, Cell Line, Tumor, medicine, Humans, Gene silencing, heterocyclic compounds, skin and connective tissue diseases, media_common, Leukemia, Biological Transport, Cell Biology, Hematology, medicine.disease, Methotrexate, chemistry, Drug Resistance, Neoplasm, Cell culture, Antifolate, medicine.drug |
| الوصف: | 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 anti-folate resistance that may further disrupt MTX efficacy. For this purpose, we developed resistance to 7-OHMTX as well as MTX in 2 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). 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 due solely to a marked decreased (> 95%) in folylpolyglutamate synthetase (FPGS) activity, which conferred more than 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 compared with the parent drug MTX. The implications of this finding for MTX efficacy and strategies to circumvent MTX resistance are discussed. |
| تدمد: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2004-04-1493 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::8f1cca09c9d8c47e5a1bd9bd1df01636 https://doi.org/10.1182/blood-2004-04-1493 |
| Rights: | RESTRICTED |
| رقم الانضمام: | edsair.doi.dedup.....8f1cca09c9d8c47e5a1bd9bd1df01636 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15280020 00064971 |
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| DOI: | 10.1182/blood-2004-04-1493 |