Predicting idiopathic toxicity of cisplatin by a pharmacometabonomic approach.
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.
Kwon
Hyuk Nam
HN
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.
Kim
Mina
M
Wen
He
H
Kang
Sunmi
S
Yang
Hye-Ji
HJ
Choi
Myung-Joo
MJ
Lee
Hee Seung
HS
Choi
DalWoong
D
Park
In Suh
IS
Suh
Young Ju
YJ
Hong
Soon-Sun
SS
Park
Sunghyouk
S
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
D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D002945:Cisplatin