Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines

Abstract

Oxaliplatin ( l-OHP) is a new platinum analogue that has shown antitumour activity against colon cancer both in vitro and in vivo and is now used in the chemotherapeutic treatment of metastatic colon and rectal cancer. l-OHP like cisplatin (CDDP), is detoxified by glutathione (GSH)-related enzymes and forms platinum (Pt)–DNA adducts lesions that are repaired by the nucleotide excision repair system (NER). We investigated the cytotoxicity and the pharmacology of l-OHP and CDDP on a panel of six colon cell lines in vitro. We showed that GSH and glutathione S-transferase (GST) activity were not correlated to oxaliplatin cytotoxicity. Pt–DNA adducts formation and repair were correlated with CDDP, but not with l-OHP cytotoxicity. The determination of ERCC1 and XPA expression, two enzymes of the NER pathway, by reverse transcriptase-polymerase chain reaction (RT-PCR), demonstrated that ERCC1 expression was predictive of l-OHP sensitivity ( r 2=0.67, P=0.02) and XPA level after oxaliplatin exposure was also correlated to l-OHP IC 50 ( r 2=0.5; P=0.04). The knowledge of such correlations could help predict the sensitivity of patients with colon cancer to l-OHP.