Abk�rzung zur Hauptnavigation Abk�rzung zu den Newsmeldungen Abk�rzung zu den Topstories  
  Barrierefreiheit    Kontakt MedUni Wien    Intranet    MedUni Wien - Shop    Universitätsbibliothek    Universitätsklinikum AKH Wien  
 
ccc_logo_en.gif
 
AKH Wien
 
 
Hauptnavigation
  • Livestream 2021
  • Home
  • Über das CCC
    • Allgemeines
    • Leitung der Organisationseinheit
    • CCC-Office Team
    • Kliniken und Partner
    • Qualitätsmanagement
    • Kontakt
  • PatientInnen
    • Covid-19
    • Allgemeines
    • Cancer School
    • Terminvereinbarung
    • Pflegeambulanz
    • PatientInnenvertretung
    • Links
  • Klinischer Bereich
    • Allgemeines
    • CCC Tumorboards
  • Wissenschaft & Forschung
    • Young CCC
    • CCC-ExpertInnenvideos
    • CCC Forschungscluster
    • CCC Units
    • CCC Platforms
    • Translationale Forschung
    • CCC Best Paper Award
    • CCC-TRIO Symposium
    • Kontakt/Links
  • Lehre
    • CCC Cancer School
    • Vienna International Summer School on Clinical and Experimental Oncology - VSSO
    • CCC Excellence Lecture
    • Interdisziplinäre onkologische Ausbildung
    • Klinisch-Praktisches Jahr (KPJ)
    • PhD Programme
    • Postgraduelle Fort- und Weiterbildung
    • Information/Contact
 
 
Subnavigation
    Inhaltsbereich


    Zurück zur Übersicht
    Thrombosis research. 2021 Jan 18. pii: S0049-3848(21)00015-3. doi: 10.1016/j.thromres.2021.01.006
    Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.
    Zaslavsky A1,  Adams M2,  Cao X3,  Yamaguchi A4,  Henderson J5,  Busch-Østergren P6,  Udager A7,  Pitchiaya S8,  Tourdot B9,  Kasputis T10,  Church SJ11,  Lee SK12,  Ohl S13,  Patel S14,  Morgan TM15,  Alva A16,  Wakefield TW17,  Reichert Z18,  Holinstat M19,  Palapattu GS20
    Author information
    1Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address: azaslavs@med.umich.edu.
    2Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    3Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    4Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
    5Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    6Department of Urology, Herlev and Gentofte Hospital, Herlev, Denmark.
    7Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
    8Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
    9Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
    10Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    11Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    12Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    13Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    14Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    15Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.
    16Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
    17Section of Vascular Surgery, Department of Surgery, Conrad Jobst Vascular Research Laboratories, University of Michigan Medical School, Ann Arbor, MI, USA.
    18Department of Internal Medicine-Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
    19Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
    20Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria. Electronic address: gpalapat@med.umich.edu.
    Abstract

    INTRODUCTION: Despite the great promise for therapies using antisense oligonucleotides (ASOs), their adverse effects, which include pro-inflammatory effects and thrombocytopenia, have limited their use. Previously, these effects have been linked to the phosphorothioate (PS) backbone necessary to prevent rapid ASO degradation in plasma. The main aim of this study was to assess the impact of the nucleic acid portion of an ASO-type drug on platelets and determine if it may contribute to thrombosis or thrombocytopenia.

    METHODS: Platelets were isolated from healthy donors and men with advanced prostate cancer. Effects of antisense oligonucleotides (ASO), oligonucleotides, gDNA, and microRNA on platelet activation and aggregation were evaluated. A mouse model of lung thrombosis was used to confirm the effects of PS-modified oligonucleotides in vivo.

    RESULTS: Platelet exposure to gDNA, miRNA, and oligonucleotides longer than 16-mer at a concentration above 8 mM resulted in the formation of hypersensitive platelets, characterized by an increased sensitivity to low-dose thrombin (0.1 nM) and increase in p-Selectin expression (6-8 fold greater than control; p < 0.001). The observed nucleic acid (NA) effects on platelets were toll-like receptor (TLR) -7 subfamily dependent. Injection of a p-Selectin inhibitor significantly (p = 0.02) reduced the formation of oligonucleotide-associated pulmonary microthrombosis in vivo.

    CONCLUSION: Our results suggest that platelet exposure to nucleic acids independent of the presence of a PS modification leads to a generation of hypersensitive platelets and requires TLR-7 subfamily receptors. ASO studies conducted in cancer patients may benefit from testing the ASO effects on platelets ex vivo before initiation of patient treatment.


    Copyright © 2021 Elsevier Ltd. All rights reserved.

    KEYWORDS: Antisense oligonucleotides, Platelets, Prostate Cancer, Toll-like receptors

    Publikations ID: 33540294
    Quelle: öffnen
     
    Drucken
     
    ccc_logo_en.gif
    ccc_logo_en.gif
    ccc_logo_en.gif

    Schnellinfo

     
    -- Initiative Krebsforschung / Krebsforschungslauf

    -- Cancer Care
    -- Kliniken und Partner
    -- CCC Cancer School
    -- Young CCC
    -- CCC Tumorboards
    -- CCC Forschungscluster
    -- CCC Units
    -- CCC Platforms
    -- SOPs / Leitlinien
    -- Kontakt
    Zuklappen
     
    Ausklappen
     
     

    Featured

     
     
     
     
     
     
     
     
     
     
     
     
     
    © MedUni Wien |
     Impressum | Nutzungsbedingungen | Kontakt