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

Marlena M. Westcott, Ralph J. Abi-Habib, Kimberley A. Cohen, Mark C. Willingham, Shihui Liu, Thomas H. Bugge, Stephen H. Leppla, Arthur E. Frankel

Research output: Contribution to journalArticle

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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 DT390 mGMCSF 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.

Original languageEnglish (US)
Pages (from-to)1681-1689
Number of pages9
JournalMolecular Cancer Therapeutics
Volume3
Issue number12
StatePublished - Dec 2004

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Diphtheria Toxin
Kupffer Cells
Granulocyte-Macrophage Colony-Stimulating Factor
Liver
Hepatocytes
Rodentia
Interleukin-3 Receptors
Granulocyte-Macrophage Colony-Stimulating Factor Receptors
Poisons
Aspartate Aminotransferases
Transaminases
Serum
Alanine Transaminase
Acute Myeloid Leukemia
Monocytes
Necrosis
Endothelial Cells
Macrophages
Staining and Labeling
Wounds and Injuries

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology

Cite this

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.

Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. / Westcott, Marlena M.; Abi-Habib, Ralph J.; Cohen, Kimberley A.; Willingham, Mark C.; Liu, Shihui; Bugge, Thomas H.; Leppla, Stephen H.; Frankel, Arthur E.

In: Molecular Cancer Therapeutics, Vol. 3, No. 12, 12.2004, p. 1681-1689.

Research output: Contribution to journalArticle

Westcott, MM, Abi-Habib, RJ, Cohen, KA, Willingham, MC, Liu, S, Bugge, TH, Leppla, SH & Frankel, AE 2004, 'Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells', Molecular Cancer Therapeutics, vol. 3, no. 12, pp. 1681-1689.
Westcott MM, Abi-Habib RJ, Cohen KA, Willingham MC, Liu S, Bugge TH et al. Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. Molecular Cancer Therapeutics. 2004 Dec;3(12):1681-1689.
Westcott, Marlena M. ; Abi-Habib, Ralph J. ; Cohen, Kimberley A. ; Willingham, Mark C. ; Liu, Shihui ; Bugge, Thomas H. ; Leppla, Stephen H. ; Frankel, Arthur E. / Diphtheria toxin-murine granulocyte-macrophage colony-stimulating factor-induced hepatotoxicity is mediated by Kupffer cells. In: Molecular Cancer Therapeutics. 2004 ; Vol. 3, No. 12. pp. 1681-1689.
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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 DT390 mGMCSF 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.",
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AU - Willingham, Mark C.

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