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Research Articles: Therapeutics

Repression of cell cycle–related proteins by oxaliplatin but not cisplatin in human colon cancer cells

¹ Oncology Department, Sanofi-Synthelabo Recherche, Montpellier, France and ² Hôpital Saint Louis (Assistance Publique Hospitaux de Paris), Paris, France

Requests for reprints: Pierre Casellas, Sanofi-Synthelabo Recherche, 371 rue du Professeur Joseph Blayac, F-34184 Montpellier Cedex 04, France. Phone: 33-4-67-10-62-90; Fax: 33-4-67-10-60-00. E-mail: pierre.casellas{at}sanofi-aventis.com

Oxaliplatin (Eloxatin) is a third-generation platinum derivative with an in vitro and in vivo spectrum of activity distinct from that of cisplatin, especially in colon cancer cells. Here, we studied the molecular basis of this difference on the HCT-116 human colon carcinoma cell line (mismatch repair-deficient, wild-type functional p53). Oxaliplatin inhibited HCT-116 cell proliferation with greater efficacy than cisplatin. At comparable concentrations, cisplatin slowed down the replication phase and activated the G₂-M checkpoint, whereas oxaliplatin activated the G₁-S checkpoint and completely blocked the G₂-M transition. With the aim of finding oxaliplatin-specific target genes and mechanisms differing from those of cisplatin, we established the transcriptional signatures of both products on HCT-116 cells using microarray technology. Based on hierarchical clustering, we found that (a) many more genes were modulated by oxaliplatin compared with cisplatin and (b) among the 117 modulated genes, 79 were regulated similarly by both drugs and, in sharp contrast, 38 genes were dose dependently down-regulated by oxaliplatin and, conversely, up-regulated or unaffected by cisplatin. Interestingly, several cell cycle–related genes encoding proteins involved in DNA replication and G₂-M progression belong to this latter group. RNA modulations, confirmed at the protein level, were in accordance with oxaliplatin- and cisplatin-induced cell cycle variations. Beyond the identification of genes affected by both drugs, the identified oxaliplatin-specific target genes could be useful as predictive markers for evaluating and comparing the efficacy and molecular pharmacology of platinum drugs. [Mol Cancer Ther 2006;5(9):2149–57]

Received 6/27/05; revised 6/30/06; accepted 7/12/06.

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