Dihydrofolate reductase activity in adriamycin and methotrexate sensitive and resistant P388 leukemia cells |
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| Authors: | F Mandelbaum-Shavit A Ramu |
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| Affiliation: | 1. Department of Bacteriology, Hebrew University-Hadassah Medical School Jerusalem, Israel;2. Department of Radiation and Clinical Oncology, Hadassah University Hospital, Jerusalem, Israel;1. Department of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, PR China;2. National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China;3. Health Science Center, Shenzhen University, Shenzhen 518060, PR China;4. College of Chemistry and Chemical Engineering, Shenzhen University, Shenzhen 518060, PR China;5. Department of Pharmacy, Faculty of Science, National University of Singapore, 117543, Singapore;6. Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, PR China;1. Mass Spectrometry Centre, Organic Chemistry and Natural Products Unit, Dep. of Chemistry, Universidade de Aveiro, Campus de Santiago, 3810-193, Aveiro, Portugal;2. Cancer Biology and Epigenetics Group, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal;3. Institute for Biomedicine -iBiMED, Department of Medical Sciences, University of Aveiro, Portugal;4. Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signalling, University of Houston, Houston, TX 77204, USA;5. Department of Pathology, Portuguese Oncology Institute of Porto, 4200-072 Porto, Portugal;6. Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS) – University of Porto, 4050-313 Porto, Portugal;7. Science for Life Laboratory, Division of Proteomics, School of Biotechnology, KTH - Royal Institute of Technology, 171 21 Solna, Sweden;8. Department of Biosciences, Karolinska Institutet, Huddinge, Sweden;1. Université de Paris, NF-κB, Différenciation et Cancer, Paris, France;2. Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 7276, Université de Limoges, France, and CHU Dupuytren, Laboratoire d''Hématologie, Limoges, France;3. Equipe Labellisée Ligue contre le Cancer, entre de Recherche des Cordeliers, INSERM Unité 1138, Université de Paris, Sorbonne Université, Paris, France;4. Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France;5. Bio-informatic Plateform, Université de Paris, INSERM US24/CNRS, Unité Mixte de Service (UMS) 3633, Paris, France;6. Department of Pathology, Curie Institute, Paris, France;7. Université de Paris, INSERM/CNRS UMR 944/7212, Paris, France;8. Institut Carnot CALYM, Pierre-Bénite, France;9. Department of Hematology, Center for Applied Medical Research, University of Navarra, IDISNA, CIBERONC, Pamplona, Spain;10. INSERM, Unité 955, Créteil, France;11. Unité Hémopathies Lymphoides, Groupe Hospitalier Henri Mondor, APHP, INSERM U955, Université Paris-Est, Creteil, France;12. INSERM U1245, UNIROUEN, University of Normandie, Rouen, France; Department of Clinical Hematology, Centre Henri Becquerel, Rouen, France;13. Department of Pathology, Hôpital Ambroise Paré, Assistance Publique–Hôpitaux de Paris (AP-HP), Boulogne, France;14. Department of Diagnostic and Theranostic Medicine, Institut Curie Hospital Group, Paris Cedex, France;15. Hematology Department, Centre Henri Becquerel, Rouen, France;16. Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, Paris, France;17. AP-HP Centre, Université de Paris, Paris, France;18. Suzhou Institute for Systems Medicine, Chinese Academy of Sciences, Suzhou, China;19. Department of Women''s and Children''s Health, Karolinska Institute, Stockholm, Sweden;20. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France;21. Pathology, AP-HP, Centre–Université de Paris, Necker-Enfants Malades Paris, France;1. Department of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;2. Department of Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;3. Department of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;4. Department of Micro Array Lab, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;5. Department of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;6. Department of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;7. Department of Technology, Proteomics & Biological Resources, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA;8. Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA |
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| Abstract: | P388 murine leukemia cells 18.4-fold more resistant to methotrexate (MTX) than the parent, drug susceptible line, were shown to possess a 1.5-fold higher dihydrofolate reductase (EC1.5.1.3) (DHFR) activity. This is in contrast to a MTX-resistant line, obtained from adriamycin-resistant cells, which is 27.9-fold more resistant to MTX and exhibits a 22.4-fold higher DHFR activity than that of the parent. The susceptibility of the enzyme to inhibition by MTX does not markedly change with the acquired drug resistance of the cell lines studied. Thus MTX-resistant cells obtained from an adriamycin-resistant line acquired resistance due to increased activity of the target enzyme, whereas other mechanisms are responsible for the resistance of cells derived from the adriamycin-sensitive parent. |
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