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 via 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 Caucasian 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.

Systematic exploration of predicted destabilizing nonsynonymous single nucleotide polymorphisms (nsSNPs) of human aldehyde oxidase: A Bio‐informatics study

“…To the best of our knowledge, the only reported pharmacogenetic study related with hAOX1 was that of patients treated with a synthetic derivative of quinoxaline phenoxypropionic acid (XK469), which is a selective topoisomerase II β inhibitor, eliminated mainly via hAOX1 metabolism. 17 A gene study was performed to investigate whether the genetic variation of hAOX1 contributed to interindividual variability observed in XK469 clearance. The study evaluated whether 41 hAOX1 nsSNPs and seven liver expression quantitative trait loci (eQTLs) were associated with XK469 plasma clearance, but the study was inconclusive and variability in XK469 clearance could not be attributed to polymorphisms in the AOX1 gene.…”

“…To the best of our knowledge, the only reported pharmacogenetic study related with hAOX1 was that of patients treated with a synthetic derivative of quinoxaline phenoxypropionic acid (XK469), which is a selective topoisomerase II β inhibitor, eliminated mainly via hAOX1 metabolism. 17 In this work, we utilized a collection of computational tools with concordance analysis approaches to predict putative phenotypic effects-deleterious or nondeleterious-and protein stability changesstabilizing, destabilizing, or neutral-of all validated hAOX1 nsSNPs deposited in the dbSNP. The corresponding amino acid substitutions were grouped according to their location in the crystal structure, and possible structural implications were also discussed.…”

Discovery of Novel Topoisomerase II Inhibitors by Medicinal Chemistry Approaches

“…Figure presents the chemical structures of some representative compounds that have been approved for the treatment of varied malignancies or which have entered into clinical trials. Among them, the imidazoacridinone derivative C-1311 ( 13 , Symadex) was recommended for phase II a few years ago. , The quinolone derivative vosaroxin ( 12 , SNS-595), which is considered as a first-in-class antineoplastic drug, has entered phase III trials for the treatment of relapsed and refractory acute myeloid leukemia (AML). − The quinoxaline derivative XK469 ( 9 , NSC697887), as a selective topo IIβ inhibitor, has entered phase I evaluation . The third generation synthetic topo II inhibitor 9-aminoanthracycline derivative amrubicin ( 10 , SM-5887) has been shown to have comparable efficacy to doxorubicin in adult soft tissue sarcoma (STS) without obvious cardiac toxicity in a phase II study .…”

“…26−28 The quinoxaline derivative XK469 (9, NSC697887), as a selective topo IIβ inhibitor, has entered phase I evaluation. 29 The third generation synthetic topo II inhibitor 9-aminoanthracycline derivative amrubicin (10, SM-5887) has been shown to have comparable efficacy to doxorubicin in adult soft tissue sarcoma (STS) without obvious cardiac toxicity in a phase II study. 30 derivatives, amonafide (11, AS1413) and mitonafide (14, NSC 300288), have been studied in phase III and phase II clinical trials, respectively.…”

“…Compounds containing fused aryl phenazine skeletons, including but not limited to benzo[a]phenazine, pyrido[a]phenazine, benzo[a]phenazine diones, and tetrahydropyrido[a]phenazine, are capable of interfering with DNA metabolism by intercalating between DNA base pairs; therefore, these skeletons are typically used in the design of topo inhibitors. For example, the benzophenazine derivatives XR11576 (27), , and NC-182 (29) have entered clinical studies based on their broad antitumor activity that is not affected by MDR. Among these, the NC series exhibited selective and superior topo II inhibition upon induction of topo II-dependent DNA fragmentation, whereas XR11576 works as a topo I/II poison.…”