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

Brandon, Esther F. A.^a; Meijerman, Irma^a; Klijn, Joyce S.^a; Arend, Dineke den^a; Sparidans, Rolf W.^a; Lázaro, Louis López^b; Beijnen, Jos H.^{a c}; Schellens, Jan H. M.^{a d}

Author Information

^aDivision of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

^bPharmaMar SA, Colmenor, Viejo, Spain

^cSlotervaart Hospital, Amsterdam, The Netherlands

^dThe Netherlands Cancer Institute, Amsterdam, The Netherlands

Sponsorship: This work was financially supported by a grant from the Nijbakker-Morra Foundation, The Netherlands.

Correspondence to I. Meijerman, Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands

Tel: +31 30-2537590; fax +31 30-2535180;

e-mail:[email protected]

Received 6 May 2005 Revised form accepted 8 July 2005

Anti-Cancer Drugs16(9):p 935-943, October 2005. |DOI:10.1097/01.cad.0000180121.16407.38

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 investigatedin 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.