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- Löfgren, C, et al.
(author)
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Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells
- 2004
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 320:3, s. 825-832
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Journal article (peer-reviewed)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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