| 1. |
- Coulthard, Sally A, et al.
(författare)
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Increased Sensitivity to Thiopurines in Methylthioadenosine Phosphorylase-Deleted Cancers
- 2011
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Ingår i: MOLECULAR CANCER THERAPEUTICS. - : AMER ASSOC CANCER RESEARCH, 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA. - 1535-7163. ; 10:3, s. 495-504
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Tidskriftsartikel (refereegranskat)abstract
- The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG), are used in the treatment of leukemia. Incorporation of deoxythioguanosine nucleotides (dG(s)) into the DNA of thiopurine-treated cells causes cell death, but there is also evidence that thiopurine metabolites, particularly the 6-MP metabolite methylthioinosine monophosphate (MeTIMP), inhibit de novo purine synthesis (DNPS). The toxicity of DNPS inhibitors is influenced by methylthioadenosine phosphorylase (MTAP), a gene frequently deleted in cancers. Because the growth of MTAP-deleted tumor cells is dependent on DNPS or hypoxanthine salvage, we would predict such cells to show differential sensitivity to 6-MP and 6-TG. To test this hypothesis, sensitivity to 6-MP and 6-TG was compared in relation to MTAP status using cytotoxicity assays in two MTAP-deficient cell lines transfected to express MTAP: the T-cell acute lymphoblastic leukemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP(-)) transfected to express MTAP constitutively (A549-MTAP(+)). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intracellularly to MeTIMP, was markedly higher in both cell lines under MTAP(-) conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dG(s) incorporation is the main cause of cytotoxicity with 6-TG. These data suggest that thiopurines, particularly 6-MP, may be more effective in patients with deleted MTAP.
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| 2. |
- Lindqvist Appell, Malin, et al.
(författare)
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Nomenclature for alleles of the thiopurine methyltransferase gene
- 2013
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Ingår i: Pharmacogenetics & Genomics. - : Lippincott, Williams and Wilkins. - 1744-6872 .- 1744-6880. ; 23:4, s. 242-248
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Forskningsöversikt (refereegranskat)abstract
- The drug-metabolizing enzyme thiopurine methyltransferase (TPMT) has become one of the best examples of pharmacogenomics to be translated into routine clinical practice. TPMT metabolizes the thiopurines 6-mercaptopurine, 6-thioguanine, and azathioprine, drugs that are widely used for treatment of acute leukemias, inflammatory bowel diseases, and other disorders of immune regulation. Since the discovery of genetic polymorphisms in the TPMT gene, many sequence variants that cause a decreased enzyme activity have been identified and characterized. Increasingly, to optimize dose, pretreatment determination of TPMT status before commencing thiopurine therapy is now routine in many countries. Novel TPMT sequence variants are currently numbered sequentially using PubMed as a source of information; however, this has caused some problems as exemplified by two instances in which authors articles appeared on PubMed at the same time, resulting in the same allele numbers given to different polymorphisms. Hence, there is an urgent need to establish an order and consensus to the numbering of known and novel TPMT sequence variants. To address this problem, a TPMT nomenclature committee was formed in 2010, to define the nomenclature and numbering of novel variants for the TPMT gene. A website (http://www.imh.liu.se/tpmtalleles) serves as a platform for this work. Researchers are encouraged to submit novel TPMT alleles to the committee for designation and reservation of unique allele numbers. The committee has decided to renumber two alleles: nucleotide position 106 (Gandgt;A) from TPMT*24 to TPMT*30 and position 611 (Tandgt;C, rs79901429) from TPMT*28 to TPMT*31. Nomenclature for all other known alleles remains unchanged. Pharmacogenetics and Genomics 23: 242-248
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| 3. |
- Kambiz Fotoohi, Alan, et al.
(författare)
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Thiopurines: Factors influencing toxicity and response
- 2010
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Ingår i: BIOCHEMICAL PHARMACOLOGY. - : Elsevier BV. - 0006-2952 .- 1873-2968. ; 79:9, s. 1211-1220
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Tidskriftsartikel (refereegranskat)abstract
- Thiopurines are the backbone of current anti-leukemia regimens and have also been effective immunosuppressive agents for the past half a century. Extensive research on their mechanism of action has been undertaken, yet many issues remain to be addressed to resolve unexplained cases of thiopurine toxicity or treatment failure. The aim of this review is to summarize current knowledge of the mechanism of thiopurine action in experimental models and put into context with clinical observations. Clear understanding of their metabolism will contribute to maximizing efficacy and minimizing toxicity by individually tailoring therapy according to the expression profile of relevant factors involved in thiopurine activation pathway.
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| 4. |
- Richards, David A, et al.
(författare)
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The state of European nursing research : dead, alive, or chronically diseased? A systematic literature review
- 2014
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Ingår i: Worldviews on Evidence-Based Nursing. - : Alpha Beta Sigma. - 1545-102X .- 1741-6787. ; 11:3, s. 147-55
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Forskningsöversikt (refereegranskat)abstract
- Background: Reviews of nursing research have suggested that most is descriptive; with no more than 15% providing strong evidence for practice. No studies have examined this from the perspective of nursing research conducted in Europe. Objective: The aim of this study was to review reports of European clinical nursing research in the top 20 nursing journals in 2010 to establish a baseline of nursing research activity in the year immediately prior to the launch of a European Science Foundation network to increase the proportion of intervention research in Europe. Methods: We identified eligible reports that were then data‐extracted by two independent reviewers. Disagreements were resolved through pair discussion and independent arbitration. We appraised and synthesized topics, methods, and the extent to which studies were programmatic. We synthesized data as proportions of study reports meeting our a priori categorization criteria. Results: We identified 1995 published reports and included 223 from 21 European countries, of which 193 (86.6%) reported studies of primary research only, 30 (13.5%) secondary research, and three (1.4%) a mix of primary and secondary. Methodological description was often poor, misleading, or even absent. One hundred (44.8%) articles reported observational studies, 87 (39.0%) qualitative studies. We found 26 (11.7%) articles reporting experimental studies, 10 (4.5%) of which were randomized controlled trials. We found 29 (13.0%) reports located within a larger program of research. Seventy‐six (34.1%) articles reported studies of nursing interventions. Linking Evidence to Action: European research in nursing reported in the leading nursing journals remains descriptive and poorly described. Only a third of research reports concerned nursing interventions, and a tiny proportion were part of a programmatic endeavor. Researchers in nursing must become better educated and skilled in developing, testing, evaluating, and reporting complex nursing interventions. Editors of nursing journals should insist on systematic reporting of research designs and methods in published articles.
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