Investigation into the hepatotoxicity of the novel anti-cancer drug ecteinascidin-743 (ET-743).
thesisposted on 19.11.2015, 09:15 by Sarah. Donald
Ecteinascidin-743 (ET-743) is a novel marine-derived anti-cancer drug with demonstrated anti-tumour activity in clinical trials against sarcoma, breast and ovarian carcinoma. Reversible transaminitis and subclinical cholangitis have frequently been described in patients who receive ET-743. To facilitate understanding of this adverse effect and help design suitable therapeutic rescue strategies, the hepatic effects of ET-743, administered as a single i.v. dose of 40 ?.g/kg, were characterised in female Wistar rats by histopathology, electron microscopy, hepatic and plasma biochemistry and DNA microarray analysis. Plasma levels of bilirubin were elevated up to 7-fold over those in untreated rats and activities of alkaline phosphatase and aspartate aminotransferase in plasma were slightly elevated. Livers displayed degeneration and necrosis of bile duct epithelia associated with mild inflammation followed by fibrosis. DNA microarray analysis of livers from ET-743-treated rats showed a significant increase in the expression of ATP binding cassette transport genes abcbla and abcblb and cell cycle genes cdc2a and ccndl. The cell cycle gene expression changes mirrored ET-743- induced increases in liver weight and Ki-67 labelling of liver nuclei. The results suggest that the toxicity exerted by ET-743 in the rat liver is a consequence of biliary damage and is accompanied by a wave of mitogenic activity. Pre-treatment with dexamethasone (10 mg/kg p.o.) 24 hours prior to ET-743 abrogated the biochemical and histopathological manifestations of ET-743-induced liver changes without interfering with the anti-tumour activity. Dexamethasone pre-treatment decreased hepatic levels of ET-743 dramatically compared to those obtained after administration of ET-743 alone. Pre-treatment with dexamethasone effectively protected against ET-743-mediated hepatic damage by decreasing hepatic exposure to ET-743, probably linked to induction of certain cytochrome P450 enzymes. Pre-treatment with cytochrome P450 inducers ?-naphthoflavone, phenobarbitone or indole-3-carbinol also reduced ET-743-mediated hepatotoxicity. In conclusion, the results strongly advocate the clinical evaluation of pretreatment with dexamethasone in patients who receive ET-743 to ameliorate its unwanted effects in the liver.