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ABCB1 genetic polymorphism influences the pharmacology of the new pyrrolobenzodiazepine derivative SJG-136

The Pharmacogenomics Journal volume 8, pages 289–296 (2008)Cite this article

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.

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Acknowledgements

We thank Spirogen Ltd and Ipsen Ltd for their permission to use SJG–136 in these studies. The authors have no conflict of interest with Spirogen Ltd and Ipsen Ltd. MT was supported by a Programme Grant from CORE (www.corecharity.org.uk).

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Authors and Affiliations

  1. Cancer Research UK Pharmacology and Drug Development Group, University of Edinburgh Cancer Research Centre, Edinburgh, UK

    R E Aird, M Thomson, J S Macpherson, D I Jodrell & S M Guichard

  2. Cancer Research UK Gene Targeted Drug Design Research Group, The School of Pharmacy, University of London, London, UK

    D E Thurston

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  1. R E Aird
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  2. M Thomson
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  3. J S Macpherson
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  4. D E Thurston
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Correspondence to S M Guichard.

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Aird, R., Thomson, M., Macpherson, J. et al. ABCB1 genetic polymorphism influences the pharmacology of the new pyrrolobenzodiazepine derivative SJG-136. Pharmacogenomics J 8, 289–296 (2008). https://doi.org/10.1038/sj.tpj.6500465

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