ATP-binding cassette B1 gene polymorphisms, mRNA expression and chemosensitivity to paclitaxel in non-small cell lung...

The adenosine triphosphate (ATP)-binding cassette, sub-family B, member 1 (ABCB1) gene encodes P-glycoprotein (Pgp), which plays an important role in drug disposition by limiting intracellular uptake of paclitaxel. ABCB1 gene polymorphisms may alter the expression and function of Pgp, thereby influencing the response to chemotherapy. A panel of 17 non-small cell lung cancer (NSCLC) cell lines was used to investigate whether alterations in the ABCB1 gene or its mRNA expression correlated with in vitro chemosensitivity to paclitaxel.

Polymorphisms in the ABCB1 gene were evaluated by direct sequencing. mRNA expression levels were assessed by quantitative real-time reverse transcription PCR. In vitro chemosensitivity to paclitaxel was expressed as half-maximal inhibitory concentration values, using a tetrazolium (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide)-based colorimetric assay.

The variant allele frequencies for four ABCB1 gene polymorphisms were 14.71% for 2677G>T/A, 32.35% for 2734T>C, 23.53% for 3396C>T and 76.47% for 3435C>T. There was a significant positive correlation between ABCB1 mRNA expression and half-maximal inhibitory concentration values for paclitaxel (r=0.5322, P=0.0279). None of the four ABCB1 gene polymorphisms were associated with paclitaxel chemosensitivity or ABCB1 mRNA expression in the 17 cell lines.

These in vitro results suggest that high ABCB1 mRNA expression may be a predictive biomarker for poor chemosensitivity to paclitaxel. The panel of NSCLC cell lines may provide clues and indications for establishing clinically useful relationships between a given polymorphism or level of gene expression and chemosensitivity to an anti-cancer agent.