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- Eriksson, Staffan, et al.
(författare)
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Differences in cytosolic and mitochondrial 5 '-nucleotidase and deoxynucleoside kinase activities in Sprague-Dawley rat and CD-1 mouse tissues: Implication for the toxicity of nucleoside analogs in animal models
- 2010
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Ingår i: Toxicology. - : Elsevier BV. - 0300-483X .- 1879-3185. ; 267, s. 159-164
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Tidskriftsartikel (refereegranskat)abstract
- Cytosolic and mitochondrial deoxynucleoside kinases (dNKs), as well as 5'deoxynucleotidases (5'-dNTs), control intracellular and intramitochondrial phosphorylation of natural nucleotides and nucleoside analogs used in antiviral and cancer chemotherapy. The balance in the activities of these two groups of enzymes to a large extent determines both the efficacy and side effects of these drugs. Because of the broad and overlapping substrate specificities of the nucleoside kinases and 5'-NTs, their tissue distribution and roles in the metabolism of both natural nucleosides and their analogs are still not fully elucidated. Here, the activity of dNKs: dCK and TK (TK1 and TK2) as well as 5'-dNTs: CN1, CN2 and dNT (dNT1 and dNT2) were determined in 14 different adult mouse and rat tissues. In most cases tissue activities of TK1, TK2 and dCK were 2-3-fold higher in the mouse, a similar pattern was found with CN1 and dNTs although with several exceptions, e.g., TK2 activities in muscle extracts from rats were 2-10-fold higher than in the mouse. Furthermore CN1 activities in hepatic, renal and adipose extracts were 2-3-fold higher in the rat. CN2 had higher levels in the testis, spleen, pancreas and diaphragm and lower level in the lung of mouse compared to rat tissues. The result suggests that a major difference in these activity profiles between mouse and rat may account for discrepancies in pharmacological response of the two animals to certain nucleoside compounds, and may help to improve the usefulness of animal models in future efforts of drug discovery. (C) 2009 Elsevier Ireland Ltd. All rights reserved.
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- Fotoohi, A K, et al.
(författare)
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Molecular mechanisms underlying the enhanced sensitivity of thiopurine-resistant T-lymphoblastic cell lines to methyl mercaptopurineriboside
- 2006
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839. ; 72:7, s. 816-823
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Tidskriftsartikel (refereegranskat)abstract
- Methylmercaptopurine riboside (meMPR), a cellular metabolite of 6-mercaptopurine (6-MP), is a potent inhibitor of de novo purine synthesis (DNPS). Human MOLT4 T-lymphoblastic leukaemia cells that have acquired resistance to 6-MP or 6-thioguanine (6-TG) as a consequence of defective transport exhibit enhanced sensitivity to meMPR. HPLC-based analysis of the transport of meMPR revealed normal uptake of this compound by our thiopurine-resistant cell sublines, suggesting a route of transport distinct from that for 6-MP and 6-TG. Studies on the wild-type parental leukemic cells showed that adenosine, dipyridamole and nitrobenzylthioinosine inhibit uptake of meMPR to a significant extent, whereas Na+ ions have no influence on this process. Transfection of these leukemic cells with small interference RNA molecules targeting the gene encoding the first member of the family of equiliberative nucleoside transporters (ENT1) strongly reduced the initial rate of meMPR transport. Our resistant cell lines exhibited 30-52% reductions (p < 0.005) in their levels of mRNA encoding several proteins involved in de novo purine synthesis, i.e., aminoimidazole carboxamide ribonucleotide formyltransferase, glycinamide ribonucleotide transformylase and guanine monophosphate synthetase. Consequently, the rate of de novo purine synthesis in these resistant sublines was decreased by 50%. Furthermore, the levels of ribonucleoside triphosphates in these cells were significantly lower than in the non-resistant parental cells. In combination, a reduced rate of de novo purine synthesis together with low levels of ribonucleoside triphosphates can explain the enhanced sensitivity of our thiopurine-resistant cell lines to meMPR. In this manner, meMPR bypasses the mechanisms of resistance to thiopurines and is even more cytotoxic towards resistant than towards wild-type cells. © 2006.
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- Löfgren, C, et al.
(författare)
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Mechanisms of cross-resistance between nucleoside analogues and vincristine or daunorubicin in leukemic cells
- 2004
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Ingår i: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 320:3, s. 825-832
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Tidskriftsartikel (refereegranskat)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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- Pettersson, B, et al.
(författare)
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Differences between children and adults in thiopurine methyltransferase activity and metabolite formation during thiopurine therapy : Possible role of concomitant methotrexate
- 2002
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Ingår i: Therapeutic Drug Monitoring. - : Ovid Technologies (Wolters Kluwer Health). - 0163-4356 .- 1536-3694. ; 24:3, s. 351-358
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Tidskriftsartikel (refereegranskat)abstract
- This study examined the role of thiopurine methyltransferase (TPMT) polymorphism in the metabolism and clinical effects of azathioprine and 6-mercaptopurine in the treatment of inflammatory bowel disease and childhood leukemia. The current hypothesis is that the cytotoxic effects of thiopurines are caused by the incorporation of thioguanine nucleotides into DNA. In this context, S-methylation catalyzed by TPMT can be regarded as a competing metabolic pathway. The authors assayed the TPMT activity in red blood cells from 122 patients treated with azathioprine or 6-mercaptopurine (83 adults with inflammatory bowel disease and 39 children with acute lymphoblastic leukemia) and in 290 untreated controls (219 adult blood donors and 71 children). The concentrations of thioguanine nucleotides and methylthioinosine monophosphate were also assayed in red blood cells from the patients. The TPMT activity and the concentrations of methylthioinosine monophosphate and thioguanine nucleotides were higher in children than in adults. All children but no adult patient received concomitant methotrexate. Interaction between methotrexate and 6-mercaptopurine has been described, and may explain the results. Low TPMT activity in adult patients with inflammatory bowel disease correlated to an increased incidence of adverse drug reactions. However, there was no correlation between TPMT activity and the red blood cell concentrations of methylthioinosine monophosphate or thioguanine nucleotides, or between the concentrations of these metabolites and the occurrence of adverse effects. The results show that the role of thiopurine metabolism for drug effects is complex.
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