| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Abdallah, Qasem M. A., et al.
(författare)
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Minor structural modifications to alchemix influence mechanism of action and pharmacological activity
- 2012
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Ingår i: Biochemical Pharmacology. - : Elsevier BV. - 0006-2952 .- 1356-1839 .- 1873-2968. ; 83:11, s. 1514-1522
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Tidskriftsartikel (refereegranskat)abstract
- Alchemix is an exemplar of a class of anthraquinone with efficacy against multidrug resistant tumours. We have explored further the mechanism of action of alchemix and investigated the effect of extending its side arm bearing the alkylating functionality with regard to DNA binding and activity against multidrug resistant cancer cells. Increasing the distance between the intercalating chromophore and the alkylating functionality of ICT2901 (propyl), ICT2902 (butyl) and ICT2903 (pentyl), led to a higher number of DNA alkylation sites, more potent topoisomerase II inhibition and generated more apoptotic and necrotic cells when analysed in p53-proficient HCT116 cells. Intriguingly, alchemix, the compound with the shortest distance between its intercalative chromophore and alkylating functionality (ethyl), did not conform to this SAR. A different toxicity pattern against DNA repair defective CHO cell lines as well as arrest of cells in Cl supports a somewhat distinct mode of action by alchemix compared with its analogues. Importantly, both alchemix and ICT2901 demonstrated greater cytotoxic activity against anthraquinone-resistant MCF-7/adr cells than wild-type MCF-7 cells. Subtle synthetic modification in this anthraquinone series has led to significant changes to the stability of DNA-compound complexes and cellular activity. Given that the failure of chemotherapy in the clinic is often associated with MDR, the results of both alchemix and ICT2901 represent important advances towards improved therapies.
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| 3. |
- Sadiktsis, Ioannis, et al.
(författare)
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Automobile Tires-A Potential Source of Highly Carcinogenic Dibenzopyrenes to the Environment
- 2012
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Ingår i: Environmental Science and Technology. - : American Chemical Society (ACS). - 0013-936X .- 1520-5851. ; 46:6, s. 3326-3334
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Tidskriftsartikel (refereegranskat)abstract
- Eight tires were analyzed for 15 high molecular weight (HMW) polycyclic aromatic hydrocarbons (PAH), using pressurized fluid extraction. The variability of the PAH concentrations determined between different tires was large; a factor of 22.6 between the lowest and the highest. The relative abundance of the analytes was quite similar regardless of tire. Almost all (92.3%) of the total extractable PAH content was attributed to five PAHs: benzo[ghi]perylene, coronene, indeno[1,2,3-cd]pyrene, benzo[e]pyrene, and benzo[a]pyrene. The difference in the measured PAH content between summer and winter tires varied substantially across manufacturers, making estimates of total vehicle fleet emissions very uncertain. However, when comparing different types of tires from the same manufacturer they had significantly (p = 0.05) different PAH content. Previously, there have been no data available for carcinogenic dibenzopyrene isomers in automobile tires. In this study, the four dibenzopyrene isomers dibenzo[a,l]pyrene, dibenzo[a,e]pyrene, dibenzo[a,i]pyrene, and dibenzo[a,h]pyrene constituted <2% of the sum of the 15 analyzed HMW PAHs. These findings show that automobile tires may be a potential previously unknown source of carcinogenic dibenzopyrenes to the environment.
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| 4. |
- Skorodko, T., et al.
(författare)
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Delta Delta excitation in proton-proton induced pi(0)pi(0) production
- 2011
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Ingår i: Physics Letters B. - : Elsevier BV. - 0370-2693 .- 1873-2445. ; 695:1-4, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Exclusive measurements of the pp -> pp pi(0)pi(0) reaction have been performed at CELSIUS/WASA at energies from threshold up to T-p = 1.3 GeV. Total and differential cross sections have been obtained. Here we concentrate on energies T-p >= GeV. where the Delta Delta excitation becomes the leading process. No evidence is found for a significant ABC effect beyond that given by the conventional t-channel Delta Delta excitation. This holds also for the double-pionic fusion to the quasibound He-2. The data are compared to model predictions, which are based on both pi- and rho-exchange. Total and differential cross sections are at variance with these predictions and call for a profound modification of the rho-exchange. A phenomenological modification allowing only a small rho-exchange contribution leads to a quantitative description of the data.
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| 5. |
- Skorodko, T., et al.
(författare)
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THE pp -> pp pi(0)pi(0) REACTION AND ITS LIMITING CASE, FUSION TO QUASI-BOUND He-2, IN SEARCH OF THE ABC EFFECT
- 2011
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Ingår i: International Journal of Modern Physics A. - 0217-751X .- 1793-656X. ; 26:3-4, s. 702-704
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Tidskriftsartikel (refereegranskat)abstract
- The pi(0)pi(0) production in pp-collisions has been investigated in exclusive and kinematically complete measurements from threshold up to T-p = 1.4 GeV. For incident energies T-p > 1 GeV, i.e. in the region beyond the Roper excitation, the Delta Delta excitation process takes over. The data are well explained by the t-channel Delta Delta process dominated by pion exchange. There is no low-mass enhancement (ABC effect) in the pi(0)pi(0)-invariant mass distribution beyond that given by the conventional t-channel Delta Delta process. This is also true for the limiting case, where the protons are in the quasi-bound He-2 state.
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| 6. |
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