Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells |
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Authors: | Löfgren Christina Hjortsberg Linn Blennow Malin Lotfi Kourosh Paul Christer Eriksson Staffan Albertioni Freidoun |
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Affiliation: | Department of Hematology, Huddinge University Hospital, Stockholm, Sweden. christina.lofgren@hematol.hs.sll.se |
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Abstract: | The aim of this study was to clarify the biochemical and molecular mechanisms behind the cross-resistance to nucleoside analogues (NAs) in four erythroleukemic cell lines with acquired resistance to the anthracycline daunorubicin and to the vinca alkaloid vincristine, expressing high levels of p-glycoprotein (P-gp, MDR1). All resistant strains exhibited cross-resistance to NA (cladribine and cytosine arabinoside)-induced apoptosis, assessed by caspase-3-like activation and were less sensitive to NA cytotoxicity in MTT assay. Real-time PCR and enzyme activity analysis showed reduced amounts of deoxycytidine kinase (35-80%) and elevated levels of 5'-nucleotidases (50-100%). The ratio 5'-nucleotidase to deoxycytidine kinase increased between 2.5- and 7.5-folds in resistant cells. This is in agreement with the observation that 5'-nucleotidase/deoxycytidine kinase ratio might be an important factor in predicting resistance to NAs. Implications of this finding for combining anthracyclines or vinca alkaloids with NAs toward leukemic cells are discussed. |
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Keywords: | Cytosine arabinoside Anthracycline p-Glycoprotein Deoxycytidine kinase 5′-Nucleotidase Cladribine |
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