1. ¹Cancer Research UK Pharmacology and Drug Development Group, University of Edinburgh Cancer Research Centre, Edinburgh, UK
2. ²Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, London, UK

Correspondence: Dr SM Guichard, Cancer Research UK Pharmacology and Drug Development Group, University of Edinburgh Cancer Research Centre, Crewe Road, Edinburgh EH4 2XR, UK. E-mail: Sylvie.guichard@ed.ac.uk

Received 18 January 2007; Revised 8 May 2007; Accepted 9 May 2007; Published online 12 June 2007.

Abstract

ATP-binding cassette transporter P-glycoprotein (ABCB1) is responsible for the multidrug resistance (MDR1) phenotype observed in cancer cells. SJG-136, a new pyrrolobenzodiazepine dimer, is a sequence-dependent DNA crosslinking agent and substrate of ABCB1. We previously showed that colon cancer cell lines expressing high levels of ABCB1 showed a lower sensitivity to SJG-136. Here, we show that in 3T3 isogenic fibroblasts, ABCB1 genetic polymorphism differentially affects ABCB1 gene expression and transport function. However, this genotype–phenotype relationship was not observed in immortalized lymphocytes, which expressed 10- to 1000-fold less ABCB1 than colon cancer cell lines. Consistent with this, the cytotoxicity of SJG-136 in 3T3 fibroblasts was affected by ABCB1 genetic polymorphism but not in immortalized lymphocytes. ABCB1 genetic polymorphism is therefore likely to affect drug sensitivity in tissues expressing high levels of the transporter and in which significant variability is observed.