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Toxicological Sciences 58, 153-160 (2000)
Copyright © 2000 by the Society of Toxicology

Respiratory Toxicology

Efficient Protection of Human Bronchial Epithelial Cells against Sulfur and Nitrogen Mustard Cytotoxicity Using Drug Combinations

S. Rappeneau*,1, A. Baeza-Squiban*, F. Marano* and J.-H. Calvet{dagger}

* Laboratoire de Cytophysiologie et Toxicologie Cellulaire, Université Paris VII Denis-Diderot, Tour 53–54, E3 case 7073, 2 place Jussieu, 75251 Paris cedex 05, France; and {dagger} Centre d'Etudes du Bouchet (Defense Medical Research Center), 91710 Vert Le Petit, France

The aim of this study was to test the efficacy of several candidate molecules against sulfur mustard (SM) and nitrogen mustard (HN2) using a human bronchial-epithelial cell line (16HBE14o-). Candidate molecules were chosen on the basis of the known cytotoxicity mechanisms of mustards or their efficacy previously observed on other cellular models. It included the sulfhydryl-containing molecules N-acetyl-cysteine (NAC) and WR-1065, the nucleophile hexamethylenetetramine (HMT), the energy-level stabilizer niacinamide (NC), the antioxidant dimethylthiourea (DMTU), L-arginine analogues such as L-thiocitrulline (L-TC) and L-nitroarginine methyl ester (L-NAME), and the anti-gelatinase doxycycline (DOX). Their efficacy was determined using 2-(4-[3-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2Htetrazolium (WST-1) reduction by viable cells 24 h after initial exposure to 100 µM HN2 or SM. On individual immediate cotreatment, some molecules exhibited selective protection against only one mustard, such as DMTU and WR-1065 against HN2 and DOX against SM, whereas NAC and L-TC were effective against both SM and HN2 cytotoxicity. However, as the level of protection against SM was always weak compared to HN2, several combinations were investigated against SM to improve the protection. The effective combinations (L-TC + DOX, NAC + DOX, NAC + DMTU, NAC + HMT, NC + DOX) combined agents, reducing the bioavailability of the mustard with compounds possibly acting on the consequences of alkylation. One of these combinations, NAC + DOX, appeared to be the most interesting, as these agents are already used in human therapy. It exhibited good efficacy in delayed cotreatment (up to 90 min) against SM.

Key Words: sulfur mustard; nitrogen mustard; comparative protection; respiratory epithelium in culture.


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