1. ¹EA 3035 Laboratoire de Pharmacologie Clinique et Expérimentale des Médicaments Anticancéreux, Université Paul Sabatier, Toulouse, France
2. ²Institut Claudius Regaud, 20-24, rue du Pont Saint Pierre, Toulouse Cedex 31052, France
3. ³équipe Instabilité génétique et cancer du département 'Mécanismes de surveillance du génome' Institut de Pharmacologie et de Biologie Structurale, CNRS UMR 5089 (IPBS) 205 route de Narbonne, Toulouse Cedex 31077, France

Correspondence: Drs JP Delord, Institut Claudius Regaud, 20-24, rue du Pont Saint Pierre, Toulouse Cedex 31052, France. E-mail: delord.jean-pierre@claudiusregaud.fr; BC Allal, E-mail: allal.cuider@claudiusregaud.fr

Revised 12 November 2007; Accepted 14 November 2007.

Abstract

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA–platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin–DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin–DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation.