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Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells

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dc.contributor.author Abi-Habib, Ralph J.
dc.contributor.author Westcott, Marlena
dc.contributor.author Cohen, Kimberley
dc.contributor.author Willingham, Mark
dc.contributor.author Lui, Shihui
dc.contributor.author Bugge, Thomas
dc.contributor.author Leppla, Stephen H.
dc.contributor.author Frankel, Arthur
dc.date.accessioned 2015-11-30T11:50:11Z
dc.date.available 2015-11-30T11:50:11Z
dc.date.copyright 2004
dc.date.issued 2015-11-30
dc.identifier.issn 1535-7163 en_US
dc.identifier.uri http://hdl.handle.net/10725/2736
dc.description.abstract DT388GMCSF, a fusion toxin composed of the NH2-terminal region of diphtheria toxin (DT) fused to human granulocyte-macrophage colony-stimulating factor (GMCSF) has shown efficacy in the treatment of acute myeloid leukemia. However, the primary dose-limiting side effect is liver toxicity. We have reproduced liver toxicity in rats using the rodent cell-tropic DT-murine GMCSF (DT390mGMCSF). Serum aspartate aminotransferase and alanine aminotransferase were elevated 15- and 4-fold, respectively, in DT390mGMCSF-treated rats relative to controls. Histologic analysis revealed hepatocyte swelling; however, this did not lead to hepatic necrosis or overt histopathologic changes in the liver. Immunohistochemical staining showed apoptotic cells in the sinusoids, and depletion of cells expressing the monocyte/macrophage markers, ED1 and ED2, indicating that Kupffer cells (KC) are targets of DT390mGMCSF. In contrast, sinusoidal endothelial cells seemed intact. In vitro, DT390mGMCSF was directly cytotoxic to primary KC but not hepatocytes. Two related fusion toxins, DT388GMCSF, which targets the human GMCSF receptor, and DT390mIL-3, which targets the rodent IL-3 receptor, induced a less than 2-fold elevation in serum transaminases and did not deplete KC in vivo. In addition, DTU2mGMCSF, a modified form of DT390mGMCSF with enhanced tumor cell specificity, was not hepatotoxic and was significantly less toxic to KC in vivo and in vitro. These results show that DT390mGMCSF causes liver toxicity by targeting KC, and establish a model for studying how this leads to hepatocyte injury. Furthermore, alternative fusion toxins with potentially reduced hepatotoxicity are presented. en_US
dc.language.iso en en_US
dc.title Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells en_US
dc.type Article en_US
dc.description.version Published en_US
dc.author.school SAS en_US
dc.author.idnumber 200901419 en_US
dc.author.woa N/A en_US
dc.author.department Natural Sciences en_US
dc.description.embargo N/A en_US
dc.relation.journal Molecular cancer therapeutics en_US
dc.journal.volume 3 en_US
dc.journal.issue 12 en_US
dc.article.pages 1681-1689 en_US
dc.keywords Diphtheria toxin en_US
dc.keywords GMCSF receptor en_US
dc.keywords Fusion toxin en_US
dc.keywords Kupffer cell en_US
dc.keywords Hepatotoxicity en_US
dc.identifier.ctation Westcott, M. M., Abi-Habib, R. J., Cohen, K. A., Willingham, M. C., Liu, S., Bugge, T. H., ... & Frankel, A. E. (2004). Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells. Molecular cancer therapeutics, 3(12), 1681-1689. en_US
dc.author.email ralph.abihabib@lau.edu.lb
dc.identifier.url http://mct.aacrjournals.org/content/3/12/1681.short


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