title: Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach.
abstract: Cisplatin has been one of the most widely used anticancer agents, but its nephrotoxicity remains a dose-limiting complication. Here, we evaluated the idiopathic nature and the predose prediction of cisplatin-induced nephrotoxicity using a nuclear magnetic resonance (NMR)-based pharmacometabonomic approach. Cisplatin produced serious toxic responses in some animals (toxic group), but had little effect in others (nontoxic group), as judged by hematological and histological results. The individual metabolic profiles, assessed by urine NMR spectra, showed large differences between the post-administration profiles of the two groups, indicating the relevance of the NMR approach. Importantly, multivariate analysis of the NMR data showed that the toxic and nontoxic groups can be differentiated based on the pretreatment metabolite profiles. Leave-one-out analysis, performed to evaluate the practical performance of our approach, gave a 66% accuracy rate in predicting toxic responses based on the pretreatment metabolite profiles. Hence, we provide a working model that can explain the idiopathic toxicity mechanism based on marker metabolites found by NMR analysis consistent with tissue NADH measurements. Thus, a pharmacometabonomic approach using pretreatment metabolite profiles may help expedite personalized chemotherapy of anticancer drugs.
authors.affiliation: Department of Biochemistry, Inha University Hospital and Center for Advanced Medical Education by BK21 project, College of Medicine, Inha University, Shinheung-dong 3ga, Chung-gu, Incheon, Korea.
authors.forename: Hyuk Nam
authors.initials: HN
authors.lastname: Kwon
authors.forename: Mina
authors.initials: M
authors.lastname: Kim
authors.forename: He
authors.initials: H
authors.lastname: Wen
authors.forename: Sunmi
authors.initials: S
authors.lastname: Kang
authors.forename: Hye-Ji
authors.initials: HJ
authors.lastname: Yang
authors.forename: Myung-Joo
authors.initials: MJ
authors.lastname: Choi
authors.forename: Hee Seung
authors.initials: HS
authors.lastname: Lee
authors.forename: DalWoong
authors.initials: D
authors.lastname: Choi
authors.forename: In Suh
authors.initials: IS
authors.lastname: Park
authors.forename: Young Ju
authors.initials: YJ
authors.lastname: Suh
authors.forename: Soon-Sun
authors.initials: SS
authors.lastname: Hong
authors.forename: Sunghyouk
authors.initials: S
authors.lastname: Park
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002945:Cisplatin / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D015999:Multivariate Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D002945:Cisplatin