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The causes discussed include the detachment of thrombogenic particles from tumor cells or the adverse effects of chemotherapeutic agents. Cytostatic agents can either act directly on their targets or, in the case of a prodrug approach, require metabolization for their action. Cyclophosphamide (CPA) is a widely used cytostatic drug that requires prodrug activation by cytochrome P450 enzymes (CYP) in the liver. We hypothesize that CPA could induce thrombosis in one of the following ways: (1) damage to endothelial cells (EC) after intra-endothelial metabolization; or (2) direct damage to EC without prior metabolization. In order to investigate this hypothesis, endothelial cells (HUVEC) were treated with CPA in clinically relevant concentrations for up to 8 days. HUVECs were chosen as a model representing the first place of action after intravenous CPA administration. No expression of CYP2B6, CYP3A4, CYP2C9 and CYP2C19 was found in HUVEC, but a weak expression of CYP2C18 was observed. CPA treatment of HUVEC induced DNA damage and a reduced formation of an EC monolayer and caused an increased release of prostacyclin (PGI2) and thromboxane (TXA) associated with a shift of the PGI2\/TXA balance to a prothrombotic state. In an in vivo scenario, such processes would promote the risk of thrombus formation.<\/jats:p>","DOI":"10.3390\/cells12151965","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T01:39:32Z","timestamp":1690767572000},"page":"1965","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Anti-Cancer Prodrug Cyclophosphamide Exerts Thrombogenic Effects on Human Venous Endothelial Cells Independent of CYP450 Activation\u2014Relevance to Thrombosis"],"prefix":"10.3390","volume":"12","author":[{"given":"Anne","family":"Kr\u00fcger-Genge","sequence":"first","affiliation":[{"name":"Department of Healthcare, Biomaterials and Cosmeceuticals, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"K\u00f6hler","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4916-3794","authenticated-orcid":false,"given":"Markus","family":"Laube","sequence":"additional","affiliation":[{"name":"Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Haileka","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6763-5957","authenticated-orcid":false,"given":"Sandy","family":"Lemm","sequence":"additional","affiliation":[{"name":"Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany"},{"name":"Faculty of Chemistry and Food Chemistry, School of Science, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karolina","family":"Majchrzak","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9284-2242","authenticated-orcid":false,"given":"Sarah","family":"Kammerer","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Schulz","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"},{"name":"Brandenburg University of Technology Cottbus-Senftenberg, Fraunhofer Project Group PZ-Syn of the Fraunhofer Institute for Cell Therapy and Immunology, Branch Bioanalytics and Bioprocesses (IZI-BB), 14476 Potsdam, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joachim","family":"Storsberg","sequence":"additional","affiliation":[{"name":"Department of Healthcare, Biomaterials and Cosmeceuticals, Fraunhofer Institute for Applied Polymer Research (IAP), 14476 Potsdam, Germany"},{"name":"Faculty of Medicine, Private University in the Principality of Liechtenstein (UFL), 9495 Triesen, Liechtenstein"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1610-1493","authenticated-orcid":false,"given":"Jens","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, 01328 Dresden, Germany"},{"name":"Faculty of Chemistry and Food Chemistry, School of Science, Technische Universit\u00e4t Dresden, 01069 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan-Heiner","family":"K\u00fcpper","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friedrich","family":"Jung","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, Molecular Cell Biology, Brandenburg University of Technology Cottbus-Senftenberg, 01968 Senftenberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Abdol Razak, N.B., Jones, G., Bhandari, M., Berndt, M.C., and Metharom, P. 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