TOXICITY OF FOTEMUSTINE IN RAT HEPATOCYTES AND MECHANISM-BASED PROTECTION AGAINST IT

Folemustine is a relatively novel DNA-alkylating 2-chloroethyl-substit uted N-nitrosourea (CENU) drug, clinically used for the treatment of d isseminated malignant melanoma in different visceral and non-visceral tissues. Thrombocytopenia has been observed in patients treated with f otemustine and liver and renal toxicities as well. In this study. firs tly the metabolism of fotemustine was investigated in vitro and second ly the undesired cytotoxicity of fotemustine as well as different ways of protection against it. In rat hepatocytes, chosen as a model syste m, fotemustine was shown to cause lactate dehydrogenase (LDH) leakage, glutathione (GSH) depletion, GSSG-formation and lipid peroxidation (L PO). A reactive metabolite. DEP-isocyanate, is most likely responsible for these undesired cytotoxic effects. Based on the observed cytotoxi city mechanisms, chemoprotection with several sulfhydryl-containing nu cleophiles and antioxidants was investigated. The sulfhydryl nucleophi les, GSH, N-acetyl-L-cysteine (NAC) and glutathione isopropylester (GS H-IP) protected almost completely against fotemustine-induced LDH-leak age and LPO. NAC and GSH protected partly against fotemustine-induced GSH-depletion. The antioxidant, vitamin E protected completely against fotemustine-induced LPO, but only partly against fotemustine-induced LDH-leakage and not against GSH-depletion. Ebselen, a peroxidase-mimet ic organoselenium compound, did not show protective effects against th e cytotoxicity of fotemustine, possibly because GSH is required for th e bioactivation of ebselen. It is concluded that co-administration of sulfhydryl nucleophiles, in particular NAC and GSH-IP, possibly in com bination with antioxidants, such as vitamin E, are effective against t he toxicity of fotemustine in vitro. It might, therefore, be worthwhil e to investigate the cytoprotective potency of these agents against un desired toxicities of fotemustine in vivo as well. (C) 1998 Elsevier S cience Ireland Ltd. All rights reserved.