Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells
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 rep...
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| مؤلفون آخرون: | , , , , , , |
| التنسيق: | article |
| منشور في: |
2004
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| الوصول للمادة أونلاين: | http://hdl.handle.net/10725/2736 http://mct.aacrjournals.org/content/3/12/1681.short |
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| _version_ | 1864513459125747712 |
|---|---|
| author | Abi-Habib, Ralph J. |
| author2 | Westcott, Marlena Cohen, Kimberley Willingham, Mark Lui, Shihui Bugge, Thomas Leppla, Stephen H. Frankel, Arthur |
| author2_role | author author author author author author author |
| author_facet | Abi-Habib, Ralph J. Westcott, Marlena Cohen, Kimberley Willingham, Mark Lui, Shihui Bugge, Thomas Leppla, Stephen H. Frankel, Arthur |
| author_role | author |
| dc.creator.none.fl_str_mv | Abi-Habib, Ralph J. Westcott, Marlena Cohen, Kimberley Willingham, Mark Lui, Shihui Bugge, Thomas Leppla, Stephen H. Frankel, Arthur |
| dc.date.none.fl_str_mv | 2004 2015-11-30T11:50:11Z 2015-11-30T11:50:11Z 2016-05-10 |
| dc.identifier.none.fl_str_mv | 1535-7163 http://hdl.handle.net/10725/2736 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. http://mct.aacrjournals.org/content/3/12/1681.short |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Molecular cancer therapeutics |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_41bd7d4cba6f9a0bcb57363467939f2e |
| identifier_str_mv | 1535-7163 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. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/2736 |
| publishDate | 2004 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cellsAbi-Habib, Ralph J.Westcott, MarlenaCohen, KimberleyWillingham, MarkLui, ShihuiBugge, ThomasLeppla, Stephen H.Frankel, ArthurDT388GMCSF, 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.PublishedN/A2015-11-30T11:50:11Z2015-11-30T11:50:11Z20042016-05-10Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1535-7163http://hdl.handle.net/10725/2736Westcott, 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.http://mct.aacrjournals.org/content/3/12/1681.shortenMolecular cancer therapeuticsinfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/27362021-03-19T09:59:49Z |
| spellingShingle | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells Abi-Habib, Ralph J. |
| status_str | publishedVersion |
| title | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| title_full | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| title_fullStr | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| title_full_unstemmed | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| title_short | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| title_sort | Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor–induced hepatotoxicity is mediated by Kupffer cells |
| url | http://hdl.handle.net/10725/2736 http://mct.aacrjournals.org/content/3/12/1681.short |