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

被引：8

作者：

Aird, R. E. ^{[1
]}

Thomson, M. ^{[1
]}

Macpherson, J. S. ^{[1
]}

Thurston, D. E. ^{[2
]}

Jodrell, D. I. ^{[1
]}

Guichard, S. M. ^{[1
]}

机构：

[1] Univ Edinburgh, Canc Res Ctr, Canc Res UK Pharmacol & Drug Dev Grp, Edinburgh EH4 2XR, Midlothian, Scotland

[2] Univ London, Sch Pharm, Canc Res UK Gene Targeted Drug Design Res Grp, London WC1N 1AX, England

来源：

PHARMACOGENOMICS JOURNAL | 2008年 / 8卷 / 04期

关键词：

SJG-136; ABCB1; pyrrolobenzodiazepine; genetic polymorphism; colon cancer;

D O I：

10.1038/sj.tpj.6500465

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学]; 090102 [作物遗传育种];

摘要：

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.

引用

页码：289 / 296

页数：8

共 34 条

[1]

Expression of the drug transporters MDR1/ABCB1, MRP1/ABCC1, MRP2/ABCC2, BCRP/ABCG2, and PXR in peripheral blood mononuclear cells and their relationship with the expression in intestine and liver [J].