title: In-vitro cytotoxicity of ET-743 (Trabectedin, Yondelis), a marine anti-cancer drug, in the Hep G2 cell line: influence of cytochrome P450 and phase II inhibition, and cytochrome P450 induction.
abstract: ET-743 is a marine anti-cancer drug and is currently in phase I trials in which the effect of combination therapies will be investigated. Its dose-limiting toxicity in patients is hepatotoxicity. In-vitro studies have shown that ET-743 is mainly metabolized by cytochrome P450 (CYP) 3A4, but also by 2C9, 2C19, 2D6 and 2E1, and the phase II enzymes uridine diphosphoglucuronosyl transferase and glutathione-S-transferase. Based on this metabolic profile, there is a risk of drug-drug interactions possibly influencing the hepatotoxicity of ET-743. Therefore, the effect of CYP and phase II activity on the cytotoxicity of ET-743 was investigated in vitro in a human cell line model system. The effect of different CYP and phase II inhibitors and CYP inducers on ET-743 cytotoxicity was studied after 48 and 120 h of treatment in Hep G2 cells using different assays. Furthermore, the toxicity of ET-743 metabolites was investigated. Potent cytotoxic activity of ET-743 after 120 h treatment was observed, which could be increased in combination with the CYP inhibitors metyrapone (3A4), phenanthrene (substrate for 2E1, 3A4), piperonyl butoxide (3A), proadifen (2C9, 2E1, 3A4), ritonavir (3A4), and warfarin (2C9, 2C19). No effect on the cytotoxicity of ET-743 was observed in combination with phase II enzyme inhibition and CYP induction. CYP metabolites of ET-743 were less toxic compared with ET-743. These findings indicate that combination therapy of ET-743 with CYP inhibitors, e.g. other anti-cancer drugs, could lead to changes in the hepatotoxicity of ET-743 and are therefore of clinical importance.
authors.affiliation: Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Esther F A
authors.initials: EF
authors.lastname: Brandon
authors.forename: Irma
authors.initials: I
authors.lastname: Meijerman
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Klijn
authors.forename: Dineke
authors.initials: D
authors.lastname: den Arend
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Sparidans
authors.forename: Louis López
authors.initials: LL
authors.lastname: Lázaro
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000494:pharmacology*; D001711:Biotransformation / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004149:Dioxoles / Q000378:metabolism / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007546:Isoquinolines / Q000378:metabolism / Q000494:pharmacology*; D050217:Metabolic Detoxication, Phase II; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin
chemical_list: D018906:Antineoplastic Agents, Alkylating; D065607:Cytochrome P-450 Enzyme Inhibitors; D004149:Dioxoles; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; D003577:Cytochrome P-450 Enzyme System; D000077606:Trabectedin