In vitro-acquired resistance gene expression profile and in vivo response to oxaliplatin-based treatment

Abstract

e15041 Background: Resistance to oxaliplatin is one of the main problems of colorectal cancer (CRC) treatment success. It is not clear if intrinsic and acquired resistance processes are developed by related mechanisms. In a previous work (Martinez-Cardús et al. Mol Cancer Ther, January 2009), we determined a profile of oxaliplatin-acquired resistance related genes by using an in vitro model. In the present work, we analyzed this genetic profile in paraffin-embedded primary adenocarcinomas from CRC patients treated with oxaliplatin-fluoropyrimidine. mRNA expression data was correlated with response rate and time to progression (TTP) in order to determine the role of these genes as markers of resistance to oxaliplatin-based treatment. Material and Method: mRNA levels were analyzed by using Real Time PCR. β-actin and 18s were used as housekeeping genes and, as a reference sample, we used commercial pool of mRNA from different human tumours. Chi- square and Fisher test were used in order to value differences in response rate to treatment. TTP was studied by using Kaplan Meyer curves and Log rank test. Median and percentile 33 and 66 were used as threshold values to determine both high and low expression level groups for each gene analyzed. We considered statistically significant a two-sided p-value lower than 0.05. Results: Forty-four advanced CRC patients treated with fluoropyrimidine plus oxaliplatin were analyzed. 54.5% of them were males; primary tumour was localized in colon in a 65.9% of cases. According to qRT-PCR analysis, the in vitro oxaliplatin acquired resistance related genes could be detected in the tumours but the expression of any of them correlated significantly with in vivo resistance to oxaliplatin-based treatment by using the three different threshold values to define groups. Conclusions: According to our results, these genes could not be used as markers of resistance to oxaliplatin-based treatment in non-treated tumours. Thereby, oxaliplatin resistance acquisition genes seems not to be involved in intrinsic drug resistance probably due to the fact that acquired and intrinsic oxaliplatin resistance are not related mechanisms. Further studies to typify oxaliplatin intrinsic resistance potential markers are guaranteed. No significant financial relationships to disclose.