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  1. Article ; Online: Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.

    Johnson, Timothy I / Costa, Ana S H / Ferguson, Ashley N / Frezza, Christian

    Cell death & disease

    2018  Volume 9, Issue 9, Page(s) 913

    Abstract: An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production ... ...

    Abstract An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of fumarate. Recent data indicate that, in FH-deficient cells, fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by ionising radiation (IR), and promotes early mitotic entry after IR in a fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.
    MeSH term(s) Carcinoma, Renal Cell/genetics ; Cell Line, Tumor ; DNA Damage/genetics ; DNA Repair/genetics ; Fumarate Hydratase/genetics ; G2 Phase/genetics ; Genomic Instability/genetics ; Germ-Line Mutation/genetics ; Humans ; Kidney Neoplasms/genetics ; Leiomyomatosis/genetics ; Mitosis/genetics ; Neoplastic Syndromes, Hereditary/genetics ; Radiation, Ionizing ; Skin Neoplasms/genetics ; Uterine Neoplasms/genetics
    Chemical Substances Fumarate Hydratase (EC 4.2.1.2)
    Language English
    Publishing date 2018-09-06
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2541626-1
    ISSN 2041-4889 ; 2041-4889
    ISSN (online) 2041-4889
    ISSN 2041-4889
    DOI 10.1038/s41419-018-0912-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Quantifying cell cycle-dependent drug sensitivities in cancer using a high throughput synchronisation and screening approach.

    Johnson, Timothy I / Minteer, Christopher J / Kottmann, Daniel / Dunlop, Charles R / Fernández, Sandra Bernaldo de Quirós / Carnevalli, Larissa S / Wallez, Yann / Lau, Alan / Richards, Frances M / Jodrell, Duncan I

    EBioMedicine

    2021  Volume 68, Page(s) 103396

    Abstract: Background: Chemotherapy and targeted agent anti-cancer efficacy is largely dependent on the proliferative state of tumours, as exemplified by agents that target DNA synthesis/replication or mitosis. As a result, cell cycle specificities of a number of ... ...

    Abstract Background: Chemotherapy and targeted agent anti-cancer efficacy is largely dependent on the proliferative state of tumours, as exemplified by agents that target DNA synthesis/replication or mitosis. As a result, cell cycle specificities of a number of cancer drugs are well known. However, they are yet to be described in a quantifiable manner.
    Methods: A scalable cell synchronisation protocol used to screen a library of 235 anti-cancer compounds exposed over six hours in G1 or S/G2 accumulated AsPC-1 cells to generate a cell cycle specificity (CCS) score.
    Findings: The synchronisation method was associated with reduced method-related cytotoxicity compared to nocodazole, delivering sufficient cell cycle purity and cell numbers to run high-throughput drug library screens. Compounds were identified with G1 and S/G2-associated specificities that, overall, functionally matched with a compound's target/mechanism of action. This annotation was used to describe a synergistic schedule using the CDK4/6 inhibitor, palbociclib, prior to gemcitabine/AZD6738 as well as describe the correlation between the CCS score and published synergistic/antagonistic drug schedules.
    Interpretation: This is the first highly quantitative description of cell cycle-dependent drug sensitivities that utilised a tractable and tolerated method with potential uses outside the present study. Drug treatments such as those shown to be G1 or S/G2 associated may benefit from scheduling considerations such as after CDK4/6 inhibitors and being first in drug sequences respectively.
    Funding: Cancer Research UK (CRUK) Institute core grants C14303/A17197 and C9545/A29580. The Li Ka Shing Centre where this work was performed was generously funded by CK Hutchison Holdings Limited, the University of Cambridge, CRUK, The Atlantic Philanthropies and others.
    MeSH term(s) Cell Culture Techniques ; Cell Cycle/drug effects ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Drug Screening Assays, Antitumor ; Drug Synergism ; HeLa Cells ; High-Throughput Screening Assays ; Humans ; MCF-7 Cells ; Neoplasms/drug therapy ; Neoplasms/metabolism ; Nocodazole/pharmacology ; Piperazines/pharmacology ; Pyridines/pharmacology ; Small Molecule Libraries/pharmacology ; Time Factors ; Tubulin Modulators/pharmacology ; Gemcitabine
    Chemical Substances Piperazines ; Pyridines ; Small Molecule Libraries ; Tubulin Modulators ; Deoxycytidine (0W860991D6) ; palbociclib (G9ZF61LE7G) ; Nocodazole (SH1WY3R615) ; Gemcitabine
    Language English
    Publishing date 2021-05-25
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2851331-9
    ISSN 2352-3964
    ISSN (online) 2352-3964
    DOI 10.1016/j.ebiom.2021.103396
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 7090: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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  3. Article ; Online: Ataxia-Telangiectasia Mutated (ATM) loss of function displays variant and tissue-specific differences across tumor types.

    Pilie, Patrick G / Giuliani, Virginia / Wang, Wei-Lien / McGrail, Daniel J / Bristow, Christopher A / Ngoi, Natalie Y L / Kyewalabye, Keith / Wani, Khalida M / Le, Hung / Campbell, Erick / Sánchez, Nora S / Yang, Dong / Gheeya, Jinesh S / Goswamy, Rohit Vivek / Holla, Vijaykumar / Shaw, Kenna Rael / Meric-Bernstam, Funda / Liu, Chiu-Yi / Ma, XiaoYan /
    Feng, Ningping / Machado, Annette A / Bardenhagen, Jennifer P / Vellano, Christopher P / Marszalek, Joseph R / Rajendra, Eeson / Piscitello, Desiree / Johnson, Timothy I / Likhatcheva, Maria / Elinati, Elias / Majithiya, Jayesh / Neves, Joana / Grinkevich, Vera / Ranzani, Marco / Roy-Luzarraga, Marina / Boursier, Marie / Armstrong, Lucy / Geo, Lerin / Lillo, Giorgia / Tse, Wai Yiu / Lazar, Alexander J / Kopetz, Scott E / Geck Do, Mary K / Lively, Sarah / Johnson, Michael G / Robinson, Helen M R / Smith, Graeme C M / Carroll, Christopher L / Di Francesco, M Emilia / Jones, Philip / Heffernan, Timothy P / Yap, Timothy A

    Clinical cancer research : an official journal of the American Association for Cancer Research

    2024  

    Abstract: Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently ... ...

    Abstract Purpose: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.
    Experimental design: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors, and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF biomarker approach in retrospective clinical datasets of patients treated with platinum-based chemotherapy or ATR inhibition.
    Results: ART0380 had potent, selective anti-tumor activity in a range of preclinical cancer models with differing degrees of ATM LOF. Pan-cancer analysis identified 10609 ATM variants in 8587 patient tumors. Cancer-lineage specific differences were seen in: the prevalence of deleterious (Tier 1) versus unknown/benign (Tier 2) variants, selective pressure for loss of heterozygosity, and concordance between a deleterious variant and ATM loss of protein (LOP). A novel ATM LOF biomarker approach that accounts for variant classification, relationship to ATM LOP, and tissue-specific penetrance significantly enriched for patients who benefited from platinum-based chemotherapy or ATR inhibition.
    Conclusions: These data help to better define ATM LOF across tumor types in order to optimize patient selection and improve molecularly targeted therapeutic approaches for patients with ATM LOF cancers.
    Language English
    Publishing date 2024-02-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1225457-5
    ISSN 1557-3265 ; 1078-0432
    ISSN (online) 1557-3265
    ISSN 1078-0432
    DOI 10.1158/1078-0432.CCR-23-1763
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4223: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  4. Article: Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging

    Strittmatter, Nicole / Richards, Frances M. / Race, Alan M. / Ling, Stephanie / Sutton, Daniel / Nilsson, Anna / Wallez, Yann / Barnes, Jennifer / Maglennon, Gareth / Gopinathan, Aarthi / Brais, Rebecca / Wong, Edmond / Serra, Maria Paola / Atkinson, James / Smith, Aaron / Wilson, Joanne / Hamm, Gregory / Johnson, Timothy I. / Dunlop, Charles R. /
    Kaistha, Brajesh P. / Bunch, Josephine / Sansom, Owen J. / Takats, Zoltan / Andrén, Per E. / Lau, Alan / Barry, Simon T. / Goodwin, Richard J. A. / Jodrell, Duncan I.

    Analytical chemistry. 2022 Jan. 10, v. 94, no. 3

    2022  

    Abstract: Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; ... ...

    Abstract Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
    Keywords DNA damage ; adenocarcinoma ; analytical chemistry ; drugs ; eosin ; fluorescence microscopy ; genetic engineering ; mass spectrometry ; metabolism ; metabolites ; mice ; neoplasm cells ; pancreatic neoplasms
    Language English
    Dates of publication 2022-0110
    Size p. 1795-1803.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.1c04579
    Database NAL-Catalogue (AGRICOLA)

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  5. Article ; Online: Method To Visualize the Intratumor Distribution and Impact of Gemcitabine in Pancreatic Ductal Adenocarcinoma by Multimodal Imaging.

    Strittmatter, Nicole / Richards, Frances M / Race, Alan M / Ling, Stephanie / Sutton, Daniel / Nilsson, Anna / Wallez, Yann / Barnes, Jennifer / Maglennon, Gareth / Gopinathan, Aarthi / Brais, Rebecca / Wong, Edmond / Serra, Maria Paola / Atkinson, James / Smith, Aaron / Wilson, Joanne / Hamm, Gregory / Johnson, Timothy I / Dunlop, Charles R /
    Kaistha, Brajesh P / Bunch, Josephine / Sansom, Owen J / Takats, Zoltan / Andrén, Per E / Lau, Alan / Barry, Simon T / Goodwin, Richard J A / Jodrell, Duncan I

    Analytical chemistry

    2022  Volume 94, Issue 3, Page(s) 1795–1803

    Abstract: Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; ... ...

    Abstract Gemcitabine (dFdC) is a common treatment for pancreatic cancer; however, it is thought that treatment may fail because tumor stroma prevents drug distribution to tumor cells. Gemcitabine is a pro-drug with active metabolites generated intracellularly; therefore, visualizing the distribution of parent drug as well as its metabolites is important. A multimodal imaging approach was developed using spatially coregistered mass spectrometry imaging (MSI), imaging mass cytometry (IMC), multiplex immunofluorescence microscopy (mIF), and hematoxylin and eosin (H&E) staining to assess the local distribution and metabolism of gemcitabine in tumors from a genetically engineered mouse model of pancreatic cancer (KPC) allowing for comparisons between effects in the tumor tissue and its microenvironment. Mass spectrometry imaging (MSI) enabled the visualization of the distribution of gemcitabine (100 mg/kg), its phosphorylated metabolites dFdCMP, dFdCDP and dFdCTP, and the inactive metabolite dFdU. Distribution was compared to small-molecule ATR inhibitor AZD6738 (25 mg/kg), which was codosed. Gemcitabine metabolites showed heterogeneous distribution within the tumor, which was different from the parent compound. The highest abundance of dFdCMP, dFdCDP, and dFdCTP correlated with distribution of endogenous AMP, ADP, and ATP in viable tumor cell regions, showing that gemcitabine active metabolites are reaching the tumor cell compartment, while AZD6738 was located to nonviable tumor regions. The method revealed that the generation of active, phosphorylated dFdC metabolites as well as treatment-induced DNA damage primarily correlated with sites of high proliferation in KPC PDAC tumor tissue, rather than sites of high parent drug abundance.
    MeSH term(s) Animals ; Carcinoma, Pancreatic Ductal/diagnostic imaging ; Carcinoma, Pancreatic Ductal/drug therapy ; Cell Line, Tumor ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Deoxycytidine/therapeutic use ; Mice ; Multimodal Imaging ; Pancreatic Neoplasms/diagnostic imaging ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/metabolism ; Tumor Microenvironment ; Gemcitabine
    Chemical Substances Deoxycytidine (0W860991D6) ; Gemcitabine
    Language English
    Publishing date 2022-01-10
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1508-8
    ISSN 1520-6882 ; 0003-2700
    ISSN (online) 1520-6882
    ISSN 0003-2700
    DOI 10.1021/acs.analchem.1c04579
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 4033: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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