Cellular determinants of oxaliplatin sensitivity in colon cancer cell lines

• Published in: European journal of cancer (1990) Vol. 39; no. 1; pp. 112 - 119
• Main Authors: Arnould, S, Hennebelle, I, Canal, P, Bugat, R, Guichard, S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 2003; Elsevier
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; DNA adducts; DNA Adducts - metabolism; DNA, Neoplasm - metabolism; Glutathione; Glutathione - metabolism; Glutathione Transferase - metabolism; Humans; Lethal Dose 50; Medical sciences; Nucleotide excision repair; Organoplatinum Compounds - therapeutic use; Oxaliplatin; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction - methods; RNA, Messenger - metabolism; Tumor Cells, Cultured - drug effects; Nucleotide excision repair; Oxaliplatin; Colon cancer; DNA adducts; Cisplatin; Glutathione; Antineoplastic agent; Human; Excision; Cytotoxicity; Pharmacology; Malignant tumor; Colonic disease; Chemotherapy; Sensitivity; Treatment; DNA; Established cell line; Nucleotide; Digestive diseases; Intestinal disease; Colon; Molecular biology; Predictive factor; Repair; Reverse transcription polymerase chain reaction; Adduct; Platinum II Complexes
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(02)00411-2

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.