Dataset Information

Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients.

ABSTRACT: The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography-tandem mass spectrometry-based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre- and post-irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN-38 (an active metabolite of irinotecan). Intracellular reactive oxygen species (ROS) was detected by dihydroethidium assay. Irinotecan induced a global metabolic change in patient plasma, as represented by elevations of circulating purine/pyrimidine nucleobases, acylcarnitines, and specific amino acid metabolites. The plasma metabolic signature was well replicated in HepatoCells medium on SN-38 exposure, whereas in cancer cell medium SN-38 induced accumulation of pyrimidine/purine nucleosides and nucleobases while having no impact on acylcarnitines and amino acid metabolites. SN-38 induced ROS in HepatoCells, but not in cancer cells. Distinct metabolite signatures of SN-38 exposure in HepatoCells medium and cancer cell medium revealed different mechanisms of drug action on hepatocytes and cancer cells. Elevations in circulating purine/pyrimidine nucleobases may stem from nucleotide degradation following irinotecan-induced DNA double-strand breaks. Accumulations of circulating acylcarnitines and specific amino acid metabolites may reflect, at least in part, irinotecan-induced mitochondrial dysfunction and oxidative stress in the liver. The plasma metabolic signature of irinotecan exposure provides early insights into irinotecan mechanism of action in patients.

SUBMITTER: Bao X

PROVIDER: S-EPMC6857457 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients.

Bao Xun X Wu Jianmei J Kim Seongho S LoRusso Patricia P Li Jing J

Journal of clinical pharmacology 20180727 1

The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography-tandem mass spectrometry-based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre- and post-irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic ...[more]

PMID: 30052267

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Project description:The initial decades of the 21st century have witnessed striking technical advances that have made it possible to detect, identify and quantitatively measure large numbers of plasma or tissue metabolites. In parallel, similar advances have taken place in our ability to sequence DNA and RNA. Those advances have moved us beyond studies of single metabolites and single genetic polymorphisms to the study of hundreds or thousands of metabolites and millions of genomic variants in a single cell or subject. It is now possible to merge and integrate large data sets generated by the use of different "-omics" techniques to increase our understanding of the molecular basis for variation in disease risk and/or drug response phenotypes. This "Brief Review" will outline some of the challenges and opportunities associated with studies in which metabolomic data have been merged with genomics in an attempt to gain novel insight into mechanisms associated with variation in drug response phenotypes, with an emphasis on the application of a pharmacometabolomics-informed pharmacogenomic research strategy and with selected examples of the application of that strategy. Studies that used pharmacometabolomics to inform and guide pharmacogenomics were reviewed. Clinical studies that were used as the basis for pharmacometabolomics-informed pharmacogenomic studies, published in five independent manuscripts, are described briefly. Within these five manuscripts, both pharmacokinetic and pharmacodynamic metabolomics approaches were used. Candidate gene and genome-wide approaches that were used in concert with these metabolomic data identified novel metabolite-gene relationships that were associated with drug response phenotypes in these pharmacometabolomics-informed pharmacogenomics studies. This "Brief Review" outlines the emerging discipline of pharmacometabolomics-informed pharmacogenomics in which metabolic profiles are associated with both clinical phenotypes and genetic variants to identify novel genetic variants associated with drug response phenotypes based on metabolic profiles.

Dataset Information

Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients.

Publications

Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients.

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