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  • 1.
    Coulthard, Sally
    et al.
    Newcastle University, UK.
    Redfern, Christopher
    Newcastle University, UK.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Lindqvist Appell, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Karin
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jakobsen Falk, Ingrid
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Hall, Andrew
    Newcastle University, UK.
    Taylor, Gordon
    Newcastle University, UK.
    Hogarth, Linda
    Newcastle University, UK.
    Increased sensitivity to thiopurines in methylthioadenosine phosphorylase-deleted cancers in PURINERGIC SIGNALLING, vol 6, issue , pp 33-332010Inngår i: PURINERGIC SIGNALLING, Springer Science Business Media , 2010, Vol. 6, s. 33-33Konferansepaper (Fagfellevurdert)
    Abstract [en]

    The thiopurines, 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used in the treatment of leukaemia. Incorporation of deoxythioguanosine nucleotides (dGs) 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. Since the growth of MTAP-deleted tumour 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 leukaemic cell line, Jurkat, transfected with MTAP cDNA under the control of a tetracycline-inducible promoter, and a lung cancer cell line (A549-MTAP-ve) transfected to express MTAP constitutively (A549-MTAP+ve). Sensitivity to 6-MP or methyl mercaptopurine riboside, which is converted intra-cellularly to MeTIMP, was markedly higher in both cell lines under MTAP-ve conditions. Measurement of thiopurine metabolites support the hypothesis that DNPS inhibition is a major cause of cell death with 6-MP, whereas dGs 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.

  • 2.
    Folkesson, Maggie
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Sadowska, Natalia
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Karlsson, Matts
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanisk värmeteori och strömningslära. Linköpings universitet, Tekniska fakulteten. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Carlhäll, Carl-Johan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Länne, Toste
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Hjärt- och Medicincentrum, Thorax-kärlkliniken i Östergötland.
    Wågsäter, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Jensen, Lasse
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för kardiovaskulär medicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Differences in cardiovascular toxicities associated with cigarette smoking and snuff use revealed using novel zebrafish models2016Inngår i: Biology Open, ISSN 2046-6390, Vol. 5, nr 7, s. 970-978Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Tobacco use is strongly associated with cardiovascular disease and the only avoidable risk factor associated with development of aortic aneurysm. While smoking is the most common form of tobacco use, snuff and other oral tobacco products are gaining popularity, but research on potentially toxic effects of oral tobacco use has not kept pace with the increase in its use. Here, we demonstrate that cigarette smoke and snuff extracts are highly toxic to developing zebrafish embryos. Exposure to such extracts led to a palette of toxic effects including early embryonic mortality, developmental delay, cerebral hemorrhages, defects in lymphatics development and ventricular function, and aneurysm development. Both cigarette smoke and snuff were more toxic than pure nicotine, indicating that other compounds in these products are also associated with toxicity. While some toxicities were found following exposure to both types of tobacco product, other toxicities, including developmental delay and aneurysm development, were specifically observed in the snuff extract group, whereas cerebral hemorrhages were only found in the group exposed to cigarette smoke extract. These findings deepen our understanding of the pathogenic effects of cigarette smoking and snuff use on the cardiovascular system and illustrate the benefits of using zebrafish to study mechanisms involved in aneurysm development.

  • 3.
    Gad, Helge
    et al.
    Karolinska Institute, Sweden .
    Koolmeister, Tobias
    Karolinska Institute, Sweden .
    Jemth, Ann-Sofie
    Karolinska Institute, Sweden .
    Eshtad, Saeed
    Karolinska Institute, Sweden .
    Jacques, Sylvain A.
    Karolinska Institute, Sweden .
    Ström, Cecilia E.
    Karolinska Institute, Sweden .
    Svensson, Linda M.
    Stockholm University, Sweden .
    Schultz, Niklas
    Karolinska Institute, Sweden .
    Lundbäck, Thomas
    Karolinska Institute, Sweden .
    Osk Einarsdottir, Berglind
    University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden .
    Saleh, Aljona
    Stockholm University, Sweden .
    Göktürk, Camilla
    Karolinska Institute, Sweden .
    Baranczewski, Pawel
    Karolinska Institute, Sweden Uppsala University, Sweden .
    Svensson, Richard
    Karolinska Institute, Sweden; Uppsala University, Sweden .
    Berntsson, Ronnie P. -A.
    Stockholm University, Sweden .
    Gustafsson, Robert
    Stockholm University, Sweden .
    Strömberg, Kia
    Karolinska Institute, Sweden .
    Sanjiv, Kumar
    Karolinska Institute, Sweden .
    Jacques-Cordonnier, Marie-Caroline
    Karolinska Institute, Sweden .
    Desroses, Matthieu
    Karolinska Institute, Sweden .
    Gustavsson, Anna-Lena
    Karolinska Institute, Sweden .
    Olofsson, Roger
    University of Gothenburg, Sweden; Sahlgrenska University Hospital, Sweden .
    Johansson, Fredrik
    Stockholm University, Sweden .
    Homan, Evert J.
    Karolinska Institute, Sweden .
    Loseva, Olga
    Karolinska Institute, Sweden .
    Bräutigam, Lars
    Karolinska Institute, Sweden .
    Johansson, Lars
    Karolinska Institute, Sweden .
    Höglund, Andreas
    Karolinska Institute, Sweden .
    Hagenkort, Anna
    Karolinska Institute, Sweden .
    Pham, Therese
    Karolinska Institute, Sweden .
    Altun, Mikael
    Karolinska Institute, Sweden .
    Gaugaz, Fabienne Z.
    Karolinska Institute, Sweden; Uppsala University, Sweden .
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Evers, Bastiaan
    Karolinska Institute, Sweden .
    Henriksson, Martin
    Karolinska Institute, Sweden .
    Vallin, Karl S. A.
    Karolinska Institute, Sweden .
    Wallner, Olov A.
    Karolinska Institute, Sweden .
    Hammarström, Lars G. J.
    Karolinska Institute, Sweden .
    Wiita, Elisee
    Karolinska Institute, Sweden .
    Almlöf, Ingrid
    Karolinska Institute, Sweden .
    Kalderén, Christina
    Karolinska Institute, Sweden .
    Axelsson, Hanna
    Karolinska Institute, Sweden .
    Djureinovic, Tatjana
    Stockholm University, Sweden .
    Carreras Puigvert, Jordi
    Karolinska Institute, Sweden .
    Häggblad, Maria
    Stockholm University, Sweden .
    Jeppsson, Fredrik
    Karolinska Institute, Sweden .
    Martens, Ulf
    Stockholm University, Sweden .
    Lundin, Cecilia
    Karolinska Institute, Sweden .
    Lundgren, Bo
    Stockholm University, Sweden .
    Granelli, Ingrid
    Stockholm University, Sweden .
    Jenmalm Jensen, Annika
    Karolinska Institute, Sweden .
    Artursson, Per
    Karolinska Institute, Sweden; Uppsala University, Sweden .
    Nilsson, Jonas A.
    University of Gothenburg, Sweden, Sahlgrens University Hospital, Sweden .
    Stenmark, Pål
    Stockholm University, Sweden .
    Scobie, Martin
    Karolinska Institute, Sweden .
    Warpman Berglund, Ulrika
    Karolinska Institute, Sweden .
    Helleday, Thomas
    Karolinska Institute, Sweden .
    MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool2014Inngår i: Nature, ISSN 0028-0836, E-ISSN 1476-4687, Vol. 508, nr 7495, s. 215-221Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.

  • 4.
    Green, Henrik
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Division of Gene Technology, Royal Institute of Technology, Solna, Sweden/ Royal Institute Technology, Sweden; National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Hasmats, Johanna
    Royal Institute Technology, Sweden.
    Kupershmidt, Ilya
    Royal Institute Technology, Sweden; NextBio, CA USA.
    Edsgard, Daniel
    Royal Institute Technology, Sweden.
    de Petris, Luigi
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Lewensohn, Rolf
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Blackhall, Fiona
    Christie Hospital, England; University of Manchester, England.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Besse, Benjamin
    University of Paris 11, France.
    Lindgren, Andrea
    Linköpings universitet, Institutionen för medicin och hälsa. Region Östergötland, Hjärt- och Medicincentrum, Fysiologiska kliniken US. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US. Linköpings universitet, Medicinska fakulteten.
    Branden, Eva
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Koyi, Hirsh
    Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lundeberg, Joakim
    Royal Institute Technology, Sweden.
    Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities2016Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 2, s. 366-373Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

  • 5.
    Haglund, Sofie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Söderman, Jan
    Division of Medical Diagnostics, Laboratory Medicine, Ryhov Hospital, Jönköping;.
    Hindorf, Ulf
    Department of Gastroenterology, Lund University Hospital, Lund.
    Grännö, Christer
    Department of Medicine, Ryhov Hospital, Jönköping.
    Danelius, Margareta
    Department of Internal Medicine, Ersta Hospital, Stockholm, Sweden.
    Coulthard, Sally
    Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease2011Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 33, nr 2, s. 200-208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated.

    METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities.

    RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001).

    CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.

  • 6.
    Haglund, Sofie
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet.
    Zimdahl Kahlin, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning.
    Almér, Stefan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Söderman, Jan
    Division of Medical Diagnostics, Ryhov County Hospital, Jönköping, Sweden.
    P658 Effects of allopurinol on thiopurine metabolism and gene expression levels in HepG2 cells2014Konferansepaper (Annet vitenskapelig)
  • 7.
    Lee, Mi-Young
    et al.
    Karolinska Institute, Sweden.
    Apellaniz-Ruiz, Maria
    Spanish National Cancer Research Centre CNIO, Spain.
    Johansson, Inger
    Karolinska Institute, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Bergmann, Troels K.
    University of Southern Denmark, Denmark.
    Brosen, Kim
    University of Southern Denmark, Denmark.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Rodriguez-Antona, Cristina
    Spanish National Cancer Research Centre CNIO, Spain; ISCIII Centre Biomed Research Rare Disease CIBERER, Spain.
    Ingelman-Sundberg, Magnus
    Karolinska Institute, Sweden.
    Role of cytochrome P450 2C8*3 (CYP2C8*3) in paclitaxel metabolism and paclitaxel-induced neurotoxicity2015Inngår i: Pharmacogenomics (London), ISSN 1462-2416, E-ISSN 1744-8042, Vol. 16, nr 9, s. 929-937Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: The CYP2C8*3 allele has been suggested as a risk factor for paclitaxel-induced neuropathy but the data hitherto published are conflicting. Materials and methods: In total 435 patients were investigated with respect to maximum neuropathy grade and accumulated paclitaxel dose. The enzymatic properties of CYP2C8.3 variant were analyzed using heterologous mammalian HEK293 cell expression system. Results: No significant association between CYP2C8*3 allele and neuropathy was found, although a trend was observed. The paclitaxel and amodiaquine metabolism by CYP2C8.3 were found similar to CYP2C8.1, whereas CYP2C8.3 was more efficient in the metabolism of rosiglitazone. Conclusion: These results indicate a difference in substrate specificity between CYP2C8.1 and CYP2C8.3; however, the CYP2C8*3 allele has no major impact on paclitaxel metabolism in vitro or of paclitaxel-induced neuropathy in vivo. Original submitted on 6 February 2015; revision submitted on 9 April 2015

  • 8.
    Lopez-Contreras, Andres J.
    et al.
    Spanish National Cancer Research Centre CNIO, Spain.
    Specks, Julia
    Spanish National Cancer Research Centre CNIO, Spain.
    Barlow, Jacqueline H.
    NCI, MD 20892 USA.
    Ambrogio, Chiara
    Spanish National Cancer Research Centre CNIO, Spain.
    Desler, Claus
    University of Copenhagen, Denmark.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Rodrigo-Perez, Sara
    Spanish National Cancer Research Centre CNIO, Spain.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58185 Linkoping, Sweden.
    Juel Rasmussen, Lene
    University of Copenhagen, Denmark.
    Murga, Matilde
    Spanish National Cancer Research Centre CNIO, Spain.
    Nussenzweig, Andre
    NCI, MD 20892 USA.
    Fernandez-Capetillo, Oscar
    Spanish National Cancer Research Centre CNIO, Spain.
    Increased Rrm2 gene dosage reduces fragile site breakage and prolongs survival of ATR mutant mice2015Inngår i: Genes & Development, ISSN 0890-9369, E-ISSN 1549-5477, Vol. 29, nr 7, s. 690-695Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity. Supplemental material is available for this article.

  • 9.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Greén, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    A validated and rapid high-performance liquidchromatography method for the quantification ofconversion of radio-labelled sex steroids2010Inngår i: Hormone Molecular Biology and Clinical Investigation, ISSN 1868-1891, Vol. 3, nr 1, s. 375-381Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The 17b -hydroxysteroid dehydrogenase enzymes modify the availability of potent sex steroids and have thus attracted interest in the study of several steroid-dependent pathologies including breast, endometrial and prostate cancers. An increased awareness of the importance of steroidogenic enzymes has brought forth a demand for efficient assays to study the effects of individual enzymes on steroid levels. Methods used for assessing steroid conversion are often laborious and frequently involve hazardous sample preparation steps. We developed and validated an optimised simple method for sample preparation of sex steroids using protein precipitation by the addition of zinc sulphate/sodium hydroxide. The interconversion of radio-labelled oestrogens and androgens was quantified using high-performance liquid chromatography separation of oestrone, oestradiol, androstenedione and testosterone followed by online radiometric flow scintillation analysis. The method, which can be applied for assessing, e.g., the efficacy of inhibitors of steroidogenic enzymes, was successfully used for evaluating oestrogenic interconversion in breast cancer cell lines MCF7 and T-47D.

  • 10.
    Sivik, Tove
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Jansson, Agneta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Onkologi. Linköpings universitet, Hälsouniversitetet.
    Expression Patterns of 17β-Hydroxysteroid Dehydrogenase 14 in Human Tissues2012Inngår i: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 44, nr 13, s. 949-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    17βHSD enzymes catalyze the stereospecific oxidation/reduction at carbon 17β of androgens and estrogens, and are important players in intracrine sex hormone synthesis. The biological relevance of 17βHSD14, first named retSDR3, is largely unknown. We generated and validated an antibody targeting the 17βHSD14 antigen and used this for immunohistochemical evaluation of expression patterns in 33 healthy human tissues. Furthermore, sex steroid conversional activity in HSD17B14 overexpressing HEK293 and MCF10A cells was investigated by assessing interconversion products of estrone, estradiol, androstenedione, testosterone, and dehydroepiandrosterone. Immunohistochemical staining patterns of 17βHSD14 with the enzyme being primarily expressed in glandular epithelial tissue reveal an enzyme with possible implications in the secretion or conversion of externally derived compounds. A role for 17βHSD14 in sex steroid metabolism is supported by the finding that 17HSD14 oxidizes both estradiol and testosterone into less bioactive steroid metabolites estrone and androstenedione, respectively.

  • 11.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Boiso, Samuel
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Single-nucleotide polymorphisms of ABCG2 increase the efficacy of tyrosine kinase inhibitors in the K562 chronic myeloid leukemia cell line2014Inngår i: Pharmacogenetics & Genomics, ISSN 1744-6872, E-ISSN 1744-6880, Vol. 24, nr 1, s. 52-61Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    ObjectiveThe tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ATP-binding cassette subfamily G member 2 (ABCG2). Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single-nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in-vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs [imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib, and bosutinib].Materials and methodsABCG2 SNPs 34Ggreater thanA, 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, 1574Tgreater thanG, and 1582Ggreater thanA were constructed from ABCG2 wild-type cDNA and transduced to K562 cells by retroviral gene transfer. Variant ABCG2 expression in cell membranes was evaluated and the effects of ABCG2 SNPs on transport and efficacy of TKIs were measured as the ability of ABCG2 variants to protect against TKI cytotoxicity.ResultsWild-type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided better protection against CGP74588 than its parent compound, imatinib. ABCG2 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib, and nilotinib cytotoxicity.ConclusionThese findings show that the ABCG2 SNPs 421Cgreater thanA, 623Tgreater thanC, 886Ggreater thanC, and 1574Tgreater thanG increase the efficacy of investigated TKIs, indicating a reduced transport function that might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is influenced by ABCG2 expression to a greater extent than the parent compound.

  • 12.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Moreno, Samuel Boiso
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för radiologiska vetenskaper. Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Centrum för medicinsk bildvetenskap och visualisering, CMIV.
    Jönsson, Jan-Ingvar
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för mikrobiologi och molekylär medicin. Linköpings universitet, Hälsouniversitetet.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Influence of variant ABCG2 on tyrosine kinase inhibitor transport and efficacy in the K562 chronic myeloid leukemia cell lineManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Objective: The tyrosine kinase inhibitors (TKIs) used in the treatment of chronic myeloid leukemia are substrates for the efflux transport protein ABCG2. Variations in ABCG2 activity might influence pharmacokinetics and therapeutic outcome of TKIs. The role of ABCG2 single nucleotide polymorphisms (SNPs) in TKI treatment is not clear and functional in vitro studies are lacking. The aim of this study was to investigate the consequences of ABCG2 SNPs for transport and efficacy of TKIs (imatinib, N-desmethyl imatinib (CGP74588), dasatinib, nilotinib and bosutinib). Methods: ABCG2 SNPs 34G>A, 421C>A, 623T>C, 886G>C, 1574T>G and 1582G>A were constructed from ABCG2 wild type cDNA and transduced to K562 cells by retroviral gene transfer. The ability of variant cells to express ABCG2 in the cell membrane and protect against TKI cytotoxicity was investigated. Results: Wild type ABCG2 had a protective effect against the cytotoxicity of all investigated compounds except bosutinib. It was found that ABCG2 expression provided a better protection against CGP74588 than its parent compound, imatinib. ABCG2 421C>A, 623T>C, 886G>C and 1574T>G reduced cell membrane expression of ABCG2 and the protective effect of ABCG2 against imatinib, CGP74588, dasatinib and nilotinib cytotoxicity. The most prominent effect was found for the 623T>C SNP which resulted in undetectable ABCG2 expression and low protection against TKI cytotoxicity. Conclusion: These findings show that the ABCG2 SNPs 421C>A, 623T>C, 886G>C and 1574T>G impair ABCG2 transport function and might influence TKI pharmacokinetics in vivo. Furthermore, the active imatinib metabolite CGP74588 is to a greater extent than the parent compound transported by ABCG2.

  • 13.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa. Linköpings universitet, Hälsouniversitetet.
    Richter, J.
    Department of Hematology and Coagulation, Skåne University Hospital, Lund, Sweden.
    Olsson-Strömberg, U.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Bergquist, J.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Aluthgedara, W.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Ubhayasekera, K.
    Analytical Chemistry, Department of Chemistry – Biomedical Center and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Svedberg, A.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Söderlund, S.
    Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital, Uppsala, Sweden.
    Sandstedt, Anna
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier. Linköpings universitet, Hälsouniversitetet.
    Johnsson, A.
    Department of Internal Medicine, Motala Hospital, Motala, Sweden.
    Aagesen, J.
    Department of Medicine, Ryhov County Hospital, Jönköping, Sweden.
    Alsenhed, J.
    Department of Internal Medicine, Västervik Hospital, Västervik, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patientsManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    Introduction: The hepatic enzymes CYP3A4 and CYP3A5 metabolize the tyrosine kinase inhibitor imatinib into a large number of metabolites including the pharmacologically active N-desmethyl imatinib (CGP74588). Because the metabolic activity of CYP3A varies considerably between individuals and a previous pilot study suggested an inverse association between in vivo CYP3A metabolic activity and therapeutic outcome of imatinib, the primary aim of this study was to investigate the influence of CYP3A metabolic activity on the outcome of imatinib therapy in chronic myeloid leukemia patients.

    Methods: Fifty-five patients were included and CYP3A activity was estimated in vivo using quinine as a probe drug. Imatinib and CGP74588 trough concentrations in the plasma were determined at steady state in 34 patients. Cytogenetic and molecular responses after 12 months of first-line imatinib were retrospectively collected from patients’ medical records.

    Results: Patients with optimal response to imatinib (complete cytogenetic response (CCgR) or molecular response of BCR-ABL <1%) did not have different levels of CYP3A activity compared to non-optimal responders. Similar results were found when analyzing the molecular response and CCgR separately. Neither the imatinib trough concentration nor the CGP74588/imatinib ratio were significantly associated with CYP3A activity.

    Conclusion: CYP3A enzyme activity, as measured by quinine metabolic ratio, does not correlate with the plasma concentrations of imatinib or CGP74588 and is not predictive of imatinib therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the   ratelimiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes such as plasma protein binding or transport protein activity to look for the major contributor to patient variability in imatinib plasma concentration.

  • 14.
    Skoglund, Karin
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Richter, Johan
    Skåne University Hospital, Sweden.
    Olsson-Stromberg, Ulla
    Uppsala University, Sweden.
    Bergquist, Jonas
    Uppsala University, Sweden.
    Aluthgedara, Warunika
    Uppsala University, Sweden.
    Ubhayasekera, S. J. Kumari A.
    Uppsala University, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Karolinska Institute, Sweden.
    Svedberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Söderlund, Stina
    Uppsala University, Sweden.
    Sandstedt, Anna
    Linköpings universitet, Institutionen för samhälls- och välfärdsstudier. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Johnsson, Anders
    Region Östergötland, Närsjukvården i västra Östergötland, Medicinska specialistkliniken.
    Aagesen, Jesper
    Ryhov County Hospital, Sweden.
    Alsenhed, Jonas
    Vastervik Hosp, Dept Internal Med, Västervik, Sweden.
    Hägg, Staffan
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Lotfi, Kourosh
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Hematologiska kliniken US.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia2016Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, nr 2, s. 230-238Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML. Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry. Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity. Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

  • 15.
    Svedberg, Anna
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. National Board Forens Med, Department Forens Genet and Forens Toxicol, SE-58758 Linkoping, Sweden; KTH Royal Institute Technology, Sweden.
    Vikström, Anders
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Lungmedicinska kliniken US.
    Lundeberg, Joakim
    KTH Royal Institute Technology, Sweden.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma2015Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 107, s. 186-195Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method was developed and validated for quantification of erlotinib and its metabolites in human plasma. The method is suitable for therapeutic drug monitoring and pharmacokinetic studies. The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 min. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites, respectively. Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL, respectively. Precision and accuracy was less than14% except for OSI-420 at LLOQ (17%). Extraction recovery was above 89%, 99% and 89% for erlotinib, OSI-420 and didesmethyl erlotinib, respectively. The human liver microsomes generated 14 metabolites, three of them not previously reported. Twelve metabolites were measured semi-quantitatively and validated with respect to selectivity, precision and stability. (C) 2014 Elsevier B.V. All rights reserved.

  • 16.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Development of new methodology for therapeutic drug monitoringof thiopurine treatment2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The three thiopurine drugs azathioprine (AZA), 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are used to treat several diseases, including inflammatory bowel disease (IBD). They are pro-drugs and are believed to act through the formation of thioguanine nucleotides (TGNs). Other important metabolites are the methylthioinosine nucleotides (meTINs). These metabolites are active in the white blood cells (WBCs).Most patients respond well to the thiopurine drugs but up to a third have to modify or discontinue their treatment due to adverse events or a lack of therapeutic effects. This could be caused by inter-patient variability in the metabolism of the drugs. Therapeutic drug monitoring (TDM) of thiopurine nucleotides in red blood cells (RBCs) is used to guide treatment. Current routine assays measure the nucleotides after hydrolysation to nucleic bases and are therefore unable to distinguish between mono-, di-, and triphosphates. Recently it was shown that these assays failed to predict the clinical outcome in about 40% of the patients. It has been suggested that measuring thioguanosine triphosphate (TGTP) (believed to be the most active of the TGNs) separately might increase the clinical value.An assay suitable for measuring thioguanosine mono- (TGMP) and diphosphate (TGDP) and TGTP, as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) separately in RBCs in clinical samples has been developed. In clinical studies of 82 IBD patients, we found no correlation between the thiopurine dose and metabolite levels in RBCs, thus illustrating the importance of metabolite measurements in the TDM of thiopurines.The TGN peak measured by the routine assay during TDM of patients treated with thiopurines consisted of TGTP and TGDP with a small contribution from TGMP. The meTIN also consisted of mono-, di- and triphosphates, but in different proportions, indicating differences in the formation. The inter-individual differences in nucleotide distribution were very small and a strong correlation between the different nucleotides and their respective sums was observed. As a consequence, measuring the mono-, di- and triphosphates separately was not beneficial in predicting remission, which was confirmed by the results from the clinical study.Further research into the metabolism and mode of action of thiopurine drugs is needed to understand the inter-patient variability in response and metabolite formation. An assay suitable for such studies, measuring TGNs and meTINs in cultured cells, has also been developed.

    Delarbeid
    1. Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?
    Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?
    2009 (engelsk)Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, nr 3, s. 345-50Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-18985 (URN)10.1097/FTD.0b013e3181a1ea58 (DOI)19363461 (PubMedID)
    Tilgjengelig fra: 2009-06-07 Laget: 2009-06-07 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical use
    Åpne denne publikasjonen i ny fane eller vindu >>Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical use
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84843 (URN)
    Tilgjengelig fra: 2012-10-24 Laget: 2012-10-24 Sist oppdatert: 2012-10-24bibliografisk kontrollert
    3. Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separately
    Åpne denne publikasjonen i ny fane eller vindu >>Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separately
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-84844 (URN)
    Tilgjengelig fra: 2012-10-24 Laget: 2012-10-24 Sist oppdatert: 2012-10-24bibliografisk kontrollert
    4. The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Åpne denne publikasjonen i ny fane eller vindu >>The Role of Inosine-5'-Monophosphate Dehydrogenase in Thiopurine Metabolism in Patients With Inflammatory Bowel Disease
    Vise andre…
    2011 (engelsk)Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 33, nr 2, s. 200-208Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    BACKGROUND:: There is a large interindividual variability in thiopurine metabolism. High concentrations of methylthioinosine-5'-monophosphate (meTIMP) and low concentrations of 6-thioguanine nucleotides (6-TGNs) have been associated with a lower response rate and an increased risk of adverse events. In this study, the role of inosine-5'-monophosphate dehydrogenase (IMPDH) for differences in metabolite patterns of thiopurines was investigated.

    METHODS:: IMPDH activity and thiopurine metabolite concentrations were determined in patients with inflammatory bowel disease and a normal thiopurine methyltransferase (TPMT) phenotype and meTIMP/6-TGN concentration ratio > 20 (n = 26), in patients with a metabolite ratio ≤20 (n = 21), in a subgroup with a metabolite ratio <4 (n = 6), and in 10 patients with reduced TPMT activity. In vitro studies were conducted on human embryonic kidney cells (HEK293) with genetically engineered IMPDH and TPMT activities.

    RESULTS:: Patients with metabolite ratios >20 had lower IMPDH activity than those with ratios ≤20 (P < 0.001). Metabolic ratios >20 were only observed in patients with normal TPMT activity. Downregulation of IMPDH activity in HEK293 cells was associated with an increase in the concentration of meTIMP (fold change: 17 up to 93, P < 0.001) but, unexpectedly, also of 6-thioguanosine monophosphate (fold change: 2.6 up to 5.0, P < 0.001).

    CONCLUSIONS:: These data question the general view of IMPDH as the rate-limiting enzyme in the phosphorylation of thiopurines. Investigations of other mechanisms are needed to more fully explain the various metabolite patterns and outcomes in patients under treatment.

    sted, utgiver, år, opplag, sider
    Lippincott Williams & Wilkins, 2011
    HSV kategori
    Identifikatorer
    urn:nbn:se:liu:diva-66431 (URN)10.1097/FTD.0b013e31820b42bb (DOI)000288498100010 ()21311411 (PubMedID)
    Tilgjengelig fra: 2011-03-15 Laget: 2011-03-15 Sist oppdatert: 2017-12-11bibliografisk kontrollert
  • 17.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use2013Inngår i: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, s. 145-152Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

  • 18.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi. Linköpings universitet, Tekniska högskolan.
    Monitoring of thiopurine metabolites: A high-performance liquid chromatography method for clinical useManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBC:s were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials in thiopurine therapy and proven valid by analysis of authentic patient samples.

    The method measured thioguanosine mono- (TGMP), di- (TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine).

    LOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8x10^8 RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 5 °C for 8 hours after sampling.

  • 19.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Andersson, David
    Skåne University Hospital, Sweden; Danderyd Hospital, Sweden.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Magtarmmedicinska kliniken. Karolinska Institute, Sweden; Karolinska University Hospital, Sweden.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hindorf, Ulf
    Skåne University Hospital, Sweden.
    Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease2014Inngår i: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, nr 12, s. 1702-1709Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background and aims: The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums. Methods: Samples from 79 patients with Crohns disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined. Results: TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p = 0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p = 0.01). When TGN was measured by the routine assay the correlation was not evident (p = 0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8 x 10less than^greater than8 RBCs were more likely to have active disease (p = 0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R-2 greater than 0.88). Conclusions: The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity. (C) 2014 European Crohns and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

  • 20.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, David
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Hindorf, Ulf
    Department of Gastroenterology, Skåne University Hospital, Lund, Sweden.
    Therapeutic drug monitoring of thiopurines in inflammatory bowel disease: Evaluating the benefit of measuring mono-, di-, and triphosphates separatelyManuskript (preprint) (Annet vitenskapelig)
    Abstract [en]

    The thiopurines are widely used in the treatment of inflammatory bowel diseases but are limited by poor dose-effect relationship and large interindividual variability in clinical effects. Many attempts have been made to predict response by therapeutic drug monitoring of phosphorylated and methylated metabolites grouped together as thioguanine nucleotides and methylthioinosine monophosphate. We have developed a method to determine the individual metabolites, thioguanosine mono-, di-, and triphosphates, as well as methylthioinosine mono-, di-, and triphosphates, separately in red blood cells.

    This aim of this study was to assess the ability of our novel method to predict clinical outcome compared to the routine method in 82 patients with inflammatory bowel diseases.

    TPMT wild-type patients with TGN levels below the cut-off level were more likely to have an active disease when TGN was measured by both the routine method (p < 0.05), the novel method (p<0.05), and when TGTP was measured separately (p < 0.01). TGN levels and TGTP were, however, not correlated to disease activity in TPMT defective patients. Patients with meTIN levels above 1500 pmol were more likely to have an active disease (39%, 18/46 vs. 17%, 5/30; p = 0.02). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R2 > 0.88) and the TGTP ratio (TGTP/(TGDP+TGTP)) was not different in patients with active disease or in clinical remission.

    Thiopurine metabolites should still be measured by the routine method, since the novel and technically more challenging method, including determination of TGTP and TGTP ratio, does not offer a clinical advantage compared to the routine method.

  • 21.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Almer, Sven H C
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    Monitoring of thiopurine metabolites in patients with inflammatory bowel disease-what is actually measured?2009Inngår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 31, nr 3, s. 345-50Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Azathioprine and 6-mercaptopurine are often used in the treatment of patients with inflammatory bowel disease (IBD). They are prodrugs and undergo a complex metabolism to active and inactive metabolites. Thiopurine treatment is monitored in many laboratories by measuring metabolite concentrations in erythrocytes (red blood cells). The metabolites of interest are not measured directly but as hydrolysis products, which can be produced from several metabolites. The aim of this study was to examine which metabolites are actually measured during routine monitoring. Samples from 18 patients treated with a thiopurine were analyzed by a typical routine high-performance liquid chromatography method for therapeutic drug monitoring and by a newly developed specific method measuring thioguanosine monophosphate (TGMP), thioguanosine diphosphate (TGDP), and thioguanosine triphosphate (TGTP), as well as methylthioinosine monophosphate (meTIMP), and the results were compared. 6-Thioguanine nucleotide (TGN) values detected by the routine method were 69% (range 40%-90%) of the sum of TGMP, TGDP, and TGTP measured by the specific method. TGTP and TGDP contributed 85% (range 78%-90%) and 14% (range 10%-21%) of the TGN total, respectively. Thioguanosine was not found in any patient sample. The concentration of meTIMP obtained by the routine method was 548% of the value obtained by the specific method (range 340%-718%). The difference in TGN measurements between the routine and specific methods can be explained by low hydrolysis efficiency in the routine method, although the most likely explanation for the difference in meTIMP values is that not yet identified metabolites are codetermined in the routine high-performance liquid chromatography method. Concentrations reported as TGN during therapeutic drug monitoring of thiopurine metabolites consist of TGDP and TGTP with a minor contribution of the TGMP. Concentrations reported as meTIMP or methyl mercaptopurine consist in part of meTIMP, but other not yet identified metabolites are codetermined.

  • 22.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk farmakologi.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Kirurgi- och onkologicentrum, Onkologiska kliniken US.
    How Should Thiopurine Treatment be Monitored? Methodological Aspects2010Inngår i: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 29, nr 04-Jun, s. 278-283Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Monitoring of thiopurine metabolites is important due to a complex metabolism with large interindividual variation, but the suitability of currently used methods has been questioned. The drawbacks include poor reproducibility, the inability to differentiate between the different analytes, as well as the use of a nontarget matrix. Further research should be directed toward measuring thiopurine metabolites in mononuclear cells, measuring the different nucleotides specifically, as well as measuring the incorporation of thioguanine into DNA. The studies should not be limited to thioguanosine nucleotides but include methylthioinosine nucleotides as well.

  • 23.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Carlsson, Björn
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk farmakologi.
    Coulthard, S
    Newcastle University, Northern Institute for Cancer Research.
    Josefsson, Martin
    National Board of Forensic Medicine, Department of Forensic Genetics and Forensic Toxicology, Linkoping.
    Almer, Sven
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Gastroenterologi och hepatologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Hjärt- och Medicincentrum, Endokrin- och magtarmmedicinska kliniken US.
    Peterson, Curt
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Rapid Method to Measure Thioguanine Incorporation Into DNA2011Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, nr Supplement 1, s. S650-S650Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    Background: The thiopurine drugs, 6-mercaptopurine, azathioprine, and thioguanine, are used in the treatment of acute lymphoblastic leukaemia (ALL). During treatment the thioguanine nucleotides formed are incorporated into the DNA, causing apoptosis due to the cells inability to repair the resulting damage. This mechanism is believed to be important for the effects of thiopurine drugs. We have developed a novel method for the determination of thioguanine incorporation into DNA which is both faster and cheaper than earlier methods.

    Monitoring the effects of thiopurine treatment by measuring thiopurine metabolites in erythrocytes has proven to be elusive due to the lack of good correlation between measured concentrations and thiopurine effects. If the incorporation is the main mechanism of thiopurine action, a reliable method capable of measuring the incorporation in an ordinary blood sample, such as the method we have developed, should provide a significantly better correlation with treatment effect.

    Material and Methods: Briefly, DNA extracted from buffy coat is degraded using nuclease P1 and alkaline phosphatase to produce free nucleosides which are purified by filtration. Thioguanosine and thymidine are separated and detected using an LC-MS/MS system and the ratio between the bases provides a measurement of the extent of thioguanine incorporation in DNA. The method has been successfully applied to cell culture samples as well as samples from patients treated orally with thiopurines.

    Results: In 8 inflammatory bowel disease patients treated with azathioprine the measured incorporation ranged from 2.2 to 8.4 thioguanine bases for every 10 000 thymidine bases (median 5.2). This is in agreement with earlier reports on incorporation in childhood leukemia patients.

    Conclusions: With the presented method it is possible to determine the incorporation of thioguanine into DNA during thiopurine treatment in a cost effective manner, but further research is needed to determine if there is a place for this type of methods in the monitoring of thiopurine treatment.

    An ongoing study aims to compare the incorporation to treatment effects as well as conventional measurements of erythrocyte metabolite levels. By this study we hope to determine if incorporation is a more reliable measurement to predict treatment effect and if the erythrocyte metabolite levels correlate with the incorporation.

  • 24.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Editorial Material: Putting Designer Drugs Back in Pandoras Box: Analytical Challenges and Metabolite Identification in CLINICAL CHEMISTRY, vol 62, issue 1, pp2016Inngår i: Clinical Chemistry, ISSN 0009-9147, E-ISSN 1530-8561, Vol. 62, nr 1Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    n/a

  • 25.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping Sweden.
    Brinkhagen, Linda
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping Sweden.
    Mukhtar, Shahzabe
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping Sweden.
    Identification of AB-FUBINACA metabolites in authentic urine samples suitable as urinary markers of drug intake using liquid chromatography quadrupole tandem time of flight mass spectrometry.2016Inngår i: Drug Testing and Analysis, ISSN 1942-7603, E-ISSN 1942-7611, Vol. 8, nr 9, s. 950-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Synthetic cannabinoids are a group of psychoactive drugs presently widespread among drug users in Europe. Analytical methods to measure these compounds in urine are in demand as urine is a preferred matrix for drug testing. For most synthetic cannabinoids, the parent compounds are rarely detected in urine. Therefore urinary metabolites are needed as markers of drug intake. AB-FUBINACA was one of the top three synthetic cannabinoids most frequently found in seizures and toxicological drug screening in Sweden (2013-2014). Drug abuse is also reported from several other countries such as the USA and Japan. In this study, 28 authentic case samples were used to identify urinary markers of AB-FUBINACA intake using liquid chromatography quadrupole tandem time of flight mass spectrometry and human liver microsomes. Three metabolites suitable as markers of drug intake were identified and at least two of them were detected in all but one case. In total, 15 urinary metabolites of AB-FUBINACA were reported, including hydrolxylations on the indazole ring and the amino-oxobutane moiety, dealkylations and hydrolysis of the primary amide. No modifications on the fluorobenzyl side-chain were observed. The parent compound was detected in 54% of the case samples. Also, after three hours of incubation with human liver microsomes, 77% of the signal from the parent compound remained. Copyright © 2015 John Wiley & Sons, Ltd.

  • 26.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Josefsson, Martin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Green, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Identification of AKB-48 and 5F-AKB-48 Metabolites in Authentic Human Urine Samples Using Human Liver Microsomes and Time of Flight Mass Spectrometry2015Inngår i: Journal of Analytical Toxicology, ISSN 0146-4760, E-ISSN 1945-2403, Vol. 39, nr 6, s. 426-435Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The occurrence of structurally related synthetic cannabinoids makes the identification of unique markers of drug intake particularly challenging. The aim of this study was to identify unique and abundant metabolites of AKB-48 and 5F-AKB-48 for toxicological screening in urine. Investigations of authentic urine samples from forensic cases in combination with human liver microsome (HLM) experiments were used for identification of metabolites. HLM incubations of AKB-48 and 5F-AKB-48 along with 35 urine samples from authentic cases were analyzed with liquid chromatography quadrupole tandem time of flight mass spectrometry. Using HLMs 41 metabolites of AKB-48 and 37 metabolites of 5F-AKB-48 were identified, principally represented by hydroxylation but also ketone formation and dealkylation. Monohydroxylated metabolites were replaced by di- and trihydroxylated metabolites within 30 min. The metabolites from the HLM incubations accounted for on average 84% (range, 67-100) and 91% (range, 71-100) of the combined area in the case samples for AKB-48 and 5F-AKB-48, respectively. While defluorinated metabolites accounted for on average 74% of the combined area after a 5F-AKB-48 intake only a few identified metabolites were shared between AKB-48 and 5F-AKB-48, illustrating the need for a systematic approach to identify unique metabolites. HLMs in combination with case samples seem suitable for this purpose.

  • 27.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Klinisk farmakologi. Linköpings universitet, Hälsouniversitetet.
    Kronstrand, Robert
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Hälsouniversitetet.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, SE-581 33 Linköping, Sweden.
    Retention of opioids and their glucuronides on a combined zwitterion and hydrophilic interaction stationary phase2008Inngår i: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1187, nr 01-Feb, s. 46-52Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A stationary phase combining zwitterionic ion chromatography and hydrophilic interaction chromatography (ZIC-HILIC) from SeQuant was evaluated for the chromatography of some opiates and their polar metabolites. The effects of mobile phase constitution on retention and resolution were extensively evaluated. Different aspects of mobile phase constitution such as ion strength and type of buffer, type and amount of organic modifier and pH were examined. The selectivity and retention of the opiates compared to their glucuronides could be substantially altered with small changes of the mobile phase, especially when the type of buffer, i.e., formate, or acetate and organic modifier, i.e., acetonitrile or methanol were changed. The retention on the ZIC-HILIC was dominated by hydrophilic interaction chromatography (HILIC) but considerable effects on the selectivity was observed, possibly caused by an ion exchange mechanism due to interactions with the charges on the stationary phase.

  • 28.
    Vikingsson, Svante
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Strömqvist, Malin
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Svedberg, Anna
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Hansson, Johan
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
    Höiom, Veronica
    Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
    Gréen, Henrik
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Novel rapid liquid chromatography tandem masspectrometry method for vemurafenib and metabolites in human plasma, including metabolite concentrations at steady-state.2016Inngår i: BMC Biomedical chromotography, ISSN 0269-3879, E-ISSN 1099-0801, Vol. 30, nr 8, s. 1234-1239Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A novel, rapid and sensitive liquid chromatography tandem-mass spectrometry method for quantification of vemurafenib in human plasma, that also for the first time allows for metabolite semi-quantification, was developed and validated to support clinical trials and therapeutic drug monitoring. Vemurafenib was analysed by precipitation with methanol followed by a 1.9 min isocratic liquid chromatography tandem masspectrometry analysis using an Acquity BEH C18 column with methanol and formic acid using isotope labelled internal standards. Analytes were detected in multi reaction monitoring mode on a Xevo TQ. Semi-quantification of vemurafenib metabolites was performed using the same analytical system and sample preparation with gradient elution. The vemurafenib method was successfully validated in the range 0.5-100 µg/mL according to international guidelines. The metabolite method was partially validated due to the lack of commercially available reference materials. For the first time concentration levels at steady-state for melanoma patients treated with vemurafenib is presented. The low abundance of vemurafenib metabolites suggests that they lack clinical significance. This article is protected by copyright. All rights reserved.

  • 29.
    Vorkapic, Emina
    et al.
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Dugic, Elma
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Vikingsson, Svante
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Roy, Joy
    Vascular Surgery, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mäyränpää, Mikko I.
    Department of Pathology, University of Helsinki, Helsinki, Finland / HUSLAB, Division of Pathology, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland.
    Eriksson, Per
    Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
    Wågsäter, Dick
    Linköpings universitet, Institutionen för medicin och hälsa, Avdelningen för läkemedelsforskning. Linköpings universitet, Medicinska fakulteten.
    Imatinib treatment attenuates growth and inflammation of angiotensin II induced abdominal aortic aneurysm2016Inngår i: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 249, s. 101-109Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AbstractBackground Abdominal aortic aneurysm (AAA) is characterized by vascular remodeling with increased infiltration of inflammatory cells and apoptosis/modulation of vascular smooth muscle cells (SMCs). Imatinib is a selective inhibitor of several tyrosine kinases, including PDGF receptors, Abl, and c-kit. The objective of this study was to characterize the potential protective role of imatinib on AAA development and the molecular mechanisms involved. Methods Male ApoE−/− mice were infused with angiotensin (Ang) II (1000 ng/kg/min) for 4 weeks to induce AAA or saline as controls. Daily treatment with 10 mg/kg imatinib, or tap water as control, was provided via gavage for 4 weeks. Results Treatment with imatinib was found to decrease the aortic diameter and vessel wall thickness, mediated by multiple effects. Imatinib treatment in AngII infused mice resulted in a reduced cellular infiltration of CD3ε positive T lymphocytes by 86% and reduced gene expression of mast cell chymase by 50% compared with AngII infused mice lacking imatinib. Gene expression analysis of SMC marker SM22α demonstrated an increase by 48% together with a more intact medial layer after treatment with imatinib as evaluated with SM22α immunostaining. Conclusion Present findings highlight the importance of tyrosine kinase pathways in the development of AAA. Our results show, that imatinib treatment inhibits essential mast cell, T lymphocyte and SMC mediated processes in experimental AAA. Thus, our results support the idea that tyrosine kinase inhibitors may be useful in the treatment of pathological vascular inflammation and remodeling in conditions like AAA.

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