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J Clin Pharmacol. 2019 Jan;59(1):20-34. doi: 10.1002/jcph.1275. Epub 2018 Jul 27.

Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients.

Author information

1
Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.
2
Yale Cancer Center, Yale University School of Medicine, New Haven, CT, USA.

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.

KEYWORDS:

DNA double-strand break; irinotecan; metabolomics; mitochondrial dysfunction; oxidative stress; steatohepatitis

PMID:
30052267
DOI:
10.1002/jcph.1275

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