A pharmacogenetic study of aldehyde oxidase I in patients treated with XK469.
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.
Ramírez, J; Kim, TW; Liu, W; Myers, JL; Mirkov, S; Owzar, K; Watson, D; Mulkey, F; Gamazon, ER; Stock, W; Undevia, S; Innocenti, F; Ratain, MJ
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