Molecular Determinants of the Cytotoxicity of Platinum Compounds

Abstract

Gene expression profiling of tumors allows the establishment of relationships between gene expression profiles and sensitivity to anticancer drugs. In an attempt to study the molecular determinants of the activity of platinum compounds, we explored the publicly available databases of the National Cancer Institute (NCI; http://dtp.nci.nih.gov), which allow access to the gene expression profiles of the 60 cell lines for which drug cytotoxicity patterns already existed. Using this database, we have conducted an in silico research to identify the genes the expression of which was positively or negatively correlated to the sensitivity to four platinum compounds (cisplatin, carboplatin, oxaliplatin and tetraplatin). Important similarities were noticed between cisplatin and carboplatin on one hand, and tetraplatin and oxaliplatin on the other hand. In the restricted panel of 1416 genes and molecular markers, we identified 204 markers, among which 120 corresponded to identified genes, that significantly correlated (P < 0.001) with the cytotoxicity of at least one platinum compound. For example, the functionality of the p53-activated pathway appeared positively correlated with the cytotoxicity of all platinum compounds. More specific are the positive correlations between RAS gene mutations and MYC expression and the cellular sensitivity to oxaliplatin. Among the parameters already known as related to the sensitivity to platinum compounds, we identified, in the complete set of 9400 genes, numerous significant relationships, such as the negative correlations between ERB-B2 and BCL-X L expressions and the cytotoxicity of the platinum compounds. Public databases mining, therefore, appears to be a valuable tool for the identification of determinants of anticancer drug activity in tumors.

Gene Expression Signature Predicting High-Grade Prostate Cancer Responses to Oxaliplatin

“…Our results also revealed the drug-specific nature of these correlations within a class of compounds, with the identification of gene signatures specific to classic platinum derivatives and to diaminocyclohexyl platins. These results are in accordance with a previous in silico study that used the same NCI database (Vekris et al, 2004). These data strongly suggested that drug-induced cytotoxicity triggered distinct molecular pathways when cells were treated with cisplatin or carboplatin, as opposed to oxaliplatin or tetraplatin.…”

Identification of Candidate Molecular Markers Predicting Sensitivity in Solid Tumors to Dasatinib: Rationale for Patient Selection

“…A study of the molecular markers associated with four anticancer platinum compounds (cisplatin, carboplatin, tetraplatin and oxaliplatin) in cancer cell lines indicated that the expression level of CAV2 and F3 are correlated with sensitivity to both tetraplatin and oxaliplatin, whereas CAV1, TGFBR2 and CALD1 only correlated with sensitivity to oxaliplatin (41). Another gene, MYO10 is elevated in both oxaliplatin and carboplatin chemosensitive cells (41,42). All these genes are also expressed at higher levels in dasatinib sensitive cell lines (Table 2).…”

RNA Interference against Human Papillomavirus Oncogenes in Cervical Cancer Cells Results in Increased Sensitivity to Cisplatin

“…The p53 protein is known to be the target of E6, and its presence has been shown to correlate with sensitivity to cisplatin in a recent study using the National Cancer Institute set of 60 cancer cell lines (Vekris et al, 2004). We therefore performed a p53 Western blot to measure protein levels.…”