title: ABCB1 genetic polymorphism influences the pharmacology of the new pyrrolobenzodiazepine derivative SJG-136.
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.
authors.affiliation: Cancer Research UK Pharmacology and Drug Development Group, University of Edinburgh Cancer Research Centre, Edinburgh, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Aird
authors.forename: M
authors.initials: M
authors.lastname: Thomson
authors.forename: J S
authors.initials: JS
authors.lastname: Macpherson
authors.forename: D E
authors.initials: DE
authors.lastname: Thurston
authors.forename: D I
authors.initials: DI
authors.lastname: Jodrell
authors.forename: S M
authors.initials: SM
authors.lastname: Guichard
mesh_terms: D016475:3T3 Cells; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D011110:Polymorphism, Genetic / Q000187:drug effects / Q000235:genetics*; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C423343:1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione); C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001570:Benzodiazepinones; D011758:Pyrroles; C438462:pyrrolo(2,1-c)(1,4)benzodiazepine; D001569:Benzodiazepines