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  • 1
    Publication Date: 2014-04-04
    Description: 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 bind in 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gad, Helge -- Koolmeister, Tobias -- Jemth, Ann-Sofie -- Eshtad, Saeed -- Jacques, Sylvain A -- Strom, Cecilia E -- Svensson, Linda M -- Schultz, Niklas -- Lundback, Thomas -- Einarsdottir, Berglind Osk -- Saleh, Aljona -- Gokturk, Camilla -- Baranczewski, Pawel -- Svensson, Richard -- Berntsson, Ronnie P-A -- Gustafsson, Robert -- Stromberg, Kia -- Sanjiv, Kumar -- Jacques-Cordonnier, Marie-Caroline -- Desroses, Matthieu -- Gustavsson, Anna-Lena -- Olofsson, Roger -- Johansson, Fredrik -- Homan, Evert J -- Loseva, Olga -- Brautigam, Lars -- Johansson, Lars -- Hoglund, Andreas -- Hagenkort, Anna -- Pham, Therese -- Altun, Mikael -- Gaugaz, Fabienne Z -- Vikingsson, Svante -- Evers, Bastiaan -- Henriksson, Martin -- Vallin, Karl S A -- Wallner, Olov A -- Hammarstrom, Lars G J -- Wiita, Elisee -- Almlof, Ingrid -- Kalderen, Christina -- Axelsson, Hanna -- Djureinovic, Tatjana -- Puigvert, Jordi Carreras -- Haggblad, Maria -- Jeppsson, Fredrik -- Martens, Ulf -- Lundin, Cecilia -- Lundgren, Bo -- Granelli, Ingrid -- Jensen, Annika Jenmalm -- Artursson, Per -- Nilsson, Jonas A -- Stenmark, Pal -- Scobie, Martin -- Berglund, Ulrika Warpman -- Helleday, Thomas -- England -- Nature. 2014 Apr 10;508(7495):215-21. doi: 10.1038/nature13181. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2]. ; Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden. ; Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden. ; Sahlgrenska Translational Melanoma Group, Sahlgrenska Cancer Center, Department of Surgery, University of Gothenburg and Sahlgrenska University Hospital, S-405 30 Gothenburg, Sweden. ; Department of Analytical Chemistry, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; 1] Chemical Biology Consortium Sweden, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Uppsala University Drug Optimization and Pharmaceutical Profiling Platform, Department of Pharmacy, Uppsala University, S-751 23 Uppsala, Sweden. ; Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Clinical Pharmacology, Department of Medical and Health Sciences, Linkoping University, S-58185 Linkoping, Sweden. ; 1] Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 21 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; 1] Department of Genetics, Microbiology and Toxicology, Stockholm University, S-106 91 Stockholm, Sweden [2] Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1006 Amsterdam, The Netherlands (B.E.); Department of Immunology, Genetics, and Pathology, Uppsala University, S-751 23 Uppsala, Sweden (T.D.). ; Science for Life Laboratory, RNAi Cell Screening Facility, Department of Biochemistry and Biophysics, Stockholm University, S-106 91 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695224" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Cell Death/drug effects ; Cell Survival/drug effects ; Crystallization ; DNA Damage ; DNA Repair Enzymes/*antagonists & inhibitors/chemistry/metabolism ; Deoxyguanine Nucleotides/metabolism ; Enzyme Inhibitors/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Female ; Humans ; Male ; Mice ; Models, Molecular ; Molecular Conformation ; Molecular Targeted Therapy ; Neoplasms/*drug therapy/*metabolism/pathology ; Nucleotides/*metabolism ; Oxidation-Reduction/drug effects ; Phosphoric Monoester Hydrolases/*antagonists & inhibitors/chemistry/metabolism ; Pyrimidines/chemistry/pharmacokinetics/pharmacology/therapeutic use ; Pyrophosphatases/antagonists & inhibitors ; Reproducibility of Results ; Xenograft Model Antitumor Assays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Keywords: VIVO ; DISCOVERY ; ASSAY ; PERMEABILITY ; CYTOTOXICITY ; CULTURES ; ACUTE SYSTEMIC TOXICITY ; LD50 ; DRUG ABSORPTION
    Abstract: ACuteTox is a project within the 6th European Framework Programme which had as one of its goals to develop, optimise and prevalidate a non-animal testing strategy for predicting human acute oral toxicity. In its last 6months, a challenging exercise was conducted to assess the predictive capacity of the developed testing strategies and final identification of the most promising ones. Thirty-two chemicals were tested blind in the battery of in vitro and in silico methods selected during the first phase of the project. This paper describes the classification approaches studied: single step procedures and two step tiered testing strategies. In summary, four in vitro testing strategies were proposed as best performing in terms of predictive capacity with respect to the European acute oral toxicity classification. In addition, a heuristic testing strategy is suggested that combines the prediction results gained from the neutral red uptake assay performed in 3T3 cells, with information on neurotoxicity alerts identified by the primary rat brain aggregates test method. Octanol-water partition coefficients and in silico prediction of intestinal absorption and blood-brain barrier passage are also considered. This approach allows to reduce the number of chemicals wrongly predicted as not classified (LD50〉2000mg/kg b.w.).
    Type of Publication: Journal article published
    PubMed ID: 22922246
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  • 3
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    ISSN: 0920-5632
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 0165-4608
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Pentobarbital drug-stimulus ; Exteroceptive-interoceptive stimulus control ; Interaction ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Rats were trained in a spatial T-maze discrimination either in a drugged (D=pentobarbital, 17.5 mg/kg) or in a non-drugged (N=saline) state (drug discrimination learning). Either of two external discriminative stimulus sets (light vs complete darkness) was consistently associated with the D or N state. When tested in the presence of the external stimulus previously associated with training in the D state, the animals made more drug-appropriate choices when tested with low pentobarbital doses as compared to testing in the external stimulus condition previously associated with the N state. This was reflected both in the ED50 values and the slopes of the dose-generalization gradients. The gradients of the controls were intermediate to those of the experimental rats. The present data suggest a new approach for studying interactions between controlling features in environmental events and the internal state.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1439-0973
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Zur Bewertung der Wirksamkeit und Sicherheit von Aztreonam bei stationären Patienten mit Infektionen der oberen Harnwege wurde eine klinische Vergleichsstudie mit Cefuroxim durchgeführt. Ein komplizierender Faktor, meist eine Harnwegsobstruktion, lag bei 62% der mit Aztreonam und 60% der mit Cefuroxim behandelten Patienten vor. Aztreonam wurde in einer Dosis von 1 g und Cefuroxim in einer Dosis von 1,5 g dreimal täglich als i.v. Bolus injiziert. Die mittlere Therapiedauer betrug 8,2 Tage (Bereich fünf bis 14 Tage); Patienten mit Bakteriämie wurden im Mittel 10,3 Tage (Bereich sieben bis 13 Tage) lang behandelt. Die klinische Heilungsrate betrug bei den mit Aztreonam behandelten Patienten 89%, in der Cefuroxim-Gruppe 87%. Bakteriologische Befunde, die eine Woche nach Therapieende erhoben wurden, zeigten in den entsprechenden Gruppen Erregereradikationsraten von 70 bzw. 73%. Die Rate an Rezidiven oder Reinfektionen war mit beiden Medikamenten hoch. Einen Monat nach Therapieende war die bakteriologische Heilungsrate in der mit Aztreonam behandelten Gruppe auf 43% und in der Cefuroxim-Gruppe auf 40% zurückgegangen. Daraus ist zu schließen, daß bei diesen Infektionen eine längere Therapiedauer erforderlich ist. Superinfektionen, bei denen es sich meist um eine asymptomatische Besiedelung der Harnwege handelte, traten nach Aztreonamtherapie in 7%, nach Cefuroxim in 3% der Fälle auf; zu unerwünschten Nebenwirkungen war es unter Aztreonam in 23% und unter Cefuroxim in 12% der Fälle gekommen. In den meisten Fällen waren die Nebenwirkungen leicht und reversibel, ein Abbruch der Therapie war in 3% bzw. 3% der Fälle nötig. Die Bestimmung der Aztreonam-Halbwertzeit ergab bei sechs Patienten mit einer Kreatinin-Clearance von mehr als 80 ml/min nach einer i.v. Bolusinjektion von 1 g 2,0 h, bei sieben Patienten mit einer Kreatinin-Clearance zwischen 35 und 75 ml/min betrug die Halbwertzeit t 1/2 3,0 h.
    Notes: Summary In order to evaluate the efficacy and safety of aztreonam in hospitalized patients with upper urinary tract infections (UTI), a comparative clinical study with cefuroxime was performed. 62/60% (aztreonam/cefuroxime) of the patients had a complicating factor, mostly obstructive uropathy. I.v. bolus injections were used at a dose of 1 g aztreonam or 1.5 g cefuroxime t.i.d., for a mean of 8.2 days (range: five to 14 days) except in patients with bacteraemia, who received a mean of 10.3 days (range: seven to 13 days) of therapy. 89% of the patients treated with aztreonam and 87% of those who received cefuroxime showed clinical cure and the bacteriological cure rate at one week post-therapy was 70% and 73% in the respective groups. The relapse/reinfection rate was high with both drugs; bacteriological cure at one month post-therapy was only 43% after aztreonam and 40% after cefuroxime. This suggests that these infections may need longer treatment times. Superinfections, mostly asymptomatic urinary colonization, occurred in 7% and 3%, respectively, and adverse reactions in 23% and 12%, respectively, of the patients treated with aztreonam or cefuroxime, the majority being mild and reversible and only 3% and 3%, respectively, requiring discontinuation of the therapy. The t 1/2 for aztreonam following a 1 g i.v. bolus was 2.0 h in six patients with creatinine clearance above 80 ml/min and 3.0 h in seven patients with creatinine clearance between 35–75 ml/min.
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Infection 5 (1977), S. 204-206 
    ISSN: 1439-0973
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Eine Listerien-Epidemie bei immunologisch intakten Erwachsenen trat vor einiger Zeit im westlichen Teil Schwedens auf. Alle zehn Patienten überlebten. Die Prognose der Listerien-Meningitis bei immunologisch nicht beeinträchtigten Patienten scheint beträchtlich besser zu sein als bei vorgeschädigten. Eine rasche Anwendung von Ampicillin (10–20 mg/kg/KG täglich) innerhalb der ersten 48 Stunden nach Einsetzen der klinischen Symptome mögen zu dem ausgezeichneten Ergebnis bei den beobachteten Fällen beigetragen haben, möglicherweise deswegen, weil ein gut funktionierender intrazellulärer Abtötungsmechanismus dieser Bakterien bei Listerien-Infektionen von größter Bedeutung sein kann.
    Notes: Summary A small epidemic of listeric infection among non-compromised adults recently occurred in the western part of Sweden. All ten patients survived and the prognosis of listeric meningitis in non-compromised patients would seem to be considerably better than in the compromised host. A rapid initiation of ampicillin treatment (10–20 mg/kg of body weight daily) within 48 hours after onset of symptoms may have contributed to the excellent outcome in the present series besides a well-functioning intracellular killing mechanism which seems to be of the greatest importance in listeric infection.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1572-8943
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Mittels einem simultanen TG-DSC Verfahren wurde die Löslichkeit von Polyäthylenglykolen in Äthanol-Wasser-Gemischen untersucht. Zum Vergleich wurde die Präzipitation in Reagenzgläsern beim Abkühlen auf 15 order 20°C und auch das Auflösen beim Erhitzen auf 25 und 60°C untersucht. Die Ergebnisse sind für Polyäthylenglykole mit einer Molekülmasse von 1500 bis 35000 in Dreiecksphasendiagrammen dargestellt.
    Abstract: Резюме Совмещенный метод ТГ и ДСК был использован для определения растворимости полие тиленгликолей в водн о-спиртовых смесях. Для сравнения было изучено осажден ие зтих растворов в испытательных труб ках при охлаждении до 15 или 20°, наряду с растворением полиэ тиленгликолей при на гревании до температуры 25–60°. Результаты предст авлены в виде тройных диаграмм для полизтиленглико лей с молекулярным ве сом от 1500 до 35000.
    Notes: Abstract A simultaneous TG-DSC method has been used for the determination of the solubility of polyethylene glycols in ethanol-water solutions. As a comparison precipitation was studied in test tubes at cooling to 15 or 20°C as well as dissolution at heating to temperatures between 25 and 60°C. The results are shown in ternary diagrams for polyethylene glycols with molecular weights from 1500 to 35000.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Surface Science 269-270 (1992), S. 695-699 
    ISSN: 0039-6028
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0003-2670
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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