Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis.
Purpose: Hepatic veno-occlusive disease (HVOD) is one of the major complications following hematopoietic stem cell transplantation (HSCT). Although high-dose busulfan is associated with the development of HVOD, the underlying molecular mechanisms are still unknown. Methods: Transcriptional gene regu...
| Published in: | European Journal of Clinical Pharmacology Vol. 68; no. 6; pp. 923 - 936 |
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| Main Authors: | , , , , , , , , |
| Format: | research tables/charts Journal Article |
| Published: |
Springer Nature
Jun2012
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104567757&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104567757 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jun2012 vid: 68 iid: 6 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 104567757 75178532 10.1007/s00228-011-1209-y NLM22286157 104567757 ppf: 923 ppct: 13 formats: fmt: @attributes: type: P tig: atl: Antineoplastic agent busulfan regulates a network of genes related to coagulation and fibrinolysis. aug: au: Reimer, Janka Bien, Sandra Ameling, Sabine Hammer, Elke Völker, Uwe Hempel, Georg Boos, Joachim Kroemer, Heyo Ritter, Christoph affil: Research Center of Pharmacology and Experimental Therapeutics, Department of Pharmacology, Ernst-Moritz-Arndt-University of Greifswald, Greifswald Germany sug: subj: Busulfan Administration and Dosage Blood Coagulation Drug Effects Fibrinolysis Drug Effects Hematopoietic Stem Cell Transplantation Adverse Effects Hepatic Veins Vascular Diseases Etiology Busulfan Pharmacokinetics Human Enzyme-Linked Immunosorbent Assay Plasminogen Activators Antagonists and Inhibitors Polymerase Chain Reaction Child In Vitro Studies Gene Expression Profiling Growth Substances Cell Culture Techniques RNA Analysis Busulfan Blood Descriptive Statistics Unpaired T-Tests Wilcoxon Rank Sum Test One-Way Analysis of Variance Blood Coagulation Factors Blood Time Factors Post Hoc Analysis Tumor Necrosis Factor Drug Effects Peptide Hormones Drug Effects Data Analysis Software Funding Source Antineoplastic Agents Neoplasms Surgery Neoplasms Drug Therapy Child: 6-12 years ab: Purpose: Hepatic veno-occlusive disease (HVOD) is one of the major complications following hematopoietic stem cell transplantation (HSCT). Although high-dose busulfan is associated with the development of HVOD, the underlying molecular mechanisms are still unknown. Methods: Transcriptional gene regulation by busulfan was profiled using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Messenger RNA (mRNA) expression of regulated genes was assessed by TaqMan real-time polymerase chain reaction (PCR), and protein expression and secretion was determined by enzyme-linked immunosorbent assay (ELISA) in cell supernatants, lysates, and patient plasma. Results: Plasma levels of plasminogen activator inhibitor (PAI)-1 significantly increased 48 h after starting busulfan treatment IV in children preconditioned for HSCT. In vitro, busulfan significantly induced plasminogen activator inhibitor-1 (PAI-1) expression in endothelium-like ECV304 cells in a concentration- and time-dependent manner. Comparative transcriptional profiling of busulfan-treated and control ECV304 cells identified differential expression of genes related to coagulation and fibrinolysis, including tissue factor, tissue factor pathway inhibitor-1, protein S, thrombospondin-1, urokinase receptor, and PAI-1, as well as activin A and transforming growth factor beta 1 (TGF-β1). Ingenuity pathway analysis (IPA) suggested TGF-β1 as a central modulator of gene regulation by busulfan. Consequently, expression of tissue factor, urokinase receptor, and PAI-1 mRNA and PAI-1 protein secretion induced by busulfan were significantly reduced by the activin A/TGF-β1 inhibitor SB 431542 in ECV304 and primary endothelial cells. Conclusions: This is the first report that directly relates busulfan exposure to antifibrinolytic activity by PAI-1 and hypercoagulation possibly mediated by members of the TGF-β1 family. This suggests further research to evaluate activin A and TGF-β1 as potential targets for HVOD treatment. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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