title: A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.
abstract: XK469 (NSC 697887) is a selective topoisomerase II β inhibitor eliminated mainly by aldehyde oxidase I (AOX1). We performed a candidate gene study to investigate whether AOX1 genetic variation contributes to interindividual variability in XK469 clearance. Forty-one AOX1 single nucleotide polymorphisms (SNPs) and seven liver expression quantitative trait loci were genotyped in White patients with advanced refractory solid tumors (n=59) and leukemia (n=33). We found a significant decrease in clearance (τ=-0.32, P=0.003) in solid tumor patients with rs10931910, although it failed to replicate in the leukemia cohort (τ=0.18, P=0.20). Four other AOX1 SNPs were associated with clearance (P=0.01-0.02) in only one of the two cohorts. Our study provides a starting point for future investigations on the functionality of AOX1 SNPs. However, variability in XK469 clearance cannot be attributed to polymorphisms in AOX1.
authors.affiliation: aDepartment of Medicine, The University of Chicago, Chicago, Illinois bDepartment of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Ramírez
authors.forename: Tae Won
authors.initials: TW
authors.lastname: Kim
authors.forename: Wanqing
authors.initials: W
authors.lastname: Liu
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Myers
authors.forename: Snezana
authors.initials: S
authors.lastname: Mirkov
authors.forename: Kouros
authors.initials: K
authors.lastname: Owzar
authors.forename: Dorothy
authors.initials: D
authors.lastname: Watson
authors.forename: Flora
authors.initials: F
authors.lastname: Mulkey
authors.forename: Eric R
authors.initials: ER
authors.lastname: Gamazon
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
authors.forename: Samir
authors.initials: S
authors.lastname: Undevia
authors.forename: Federico
authors.initials: F
authors.lastname: Innocenti
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
mesh_terms: D042931:Aldehyde Oxidase / Q000235:genetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D015331:Cohort Studies; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics*; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D011810:Quinoxalines / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D011810:Quinoxalines; C118180:XK 469; C526436:AOX1 protein, human; D042931:Aldehyde Oxidase