title: Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy.
abstract: ABCC2 (MRP2, cMOAT) expression has been implicated in cisplatin resistance in vitro. In mice, cisplatin disposition and toxicity were unaffected by Abcc2 knockout (Abcc2−/−). Moreover, in cancer patients (n = 237), cisplatin pharmacokinetics (P > 0.12) and efficacy (P > 0.41) were not associated with seven of the single-nucleotide polymorphisms (SNPs) in ABCC2. These SNPs were also not correlated with ABCC2 expression in the NCI60 panel (P > 0.26) or with cisplatin-induced cytotoxicity (P = 0.21). These findings highlight the importance of verifying drug-transporter interactions with in vitro tests in humans.
authors.affiliation: Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Sprowl
authors.forename: V
authors.initials: V
authors.lastname: Gregorc
authors.forename: C
authors.initials: C
authors.lastname: Lazzari
authors.forename: R H
authors.initials: RH
authors.lastname: Mathijssen
authors.forename: W J
authors.initials: WJ
authors.lastname: Loos
authors.forename: A
authors.initials: A
authors.lastname: Sparreboom
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015331:Cohort Studies; D004247:DNA / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D012313:RNA / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044465:White People; D051598:Whole Body Imaging
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D004247:DNA; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012313:RNA; C000715087:ABCC2 protein, human