Jing Li
Wayne State University School of Medicine, USA
Title: Pharmacometabolomics reveals mechanisms of action underlying the antitumor activity and toxicity of irinotecan
Biography
Biography: Jing Li
Abstract
Irinotecan, atopoisomerase I inhibitor, inhibits DNA replication and transcription. Irinotecanis widely used for treating various solid tumors. Its major toxicities include neutropenia, diarrhea, and steatohepatitis. This study investigatedthe metabolic changes induced by irinotecan in cancer patient and cell lines, which may provide mechanistic insights into the antitumor activity and toxicity of irinotecan.Plasma samples were collected at pretreatment, 1.5, 5.5, 28, and 48 h following 1.5-h irinotecan infusion (100 mg/m2) in 11 cancer patients. ~250 metaboliteswere quantitatively determined in patient plasma using a LC-MS/MS based targeted metabolomicsplatform. Additionally, metabolomic profiling was performed for human primary liver cells and two breast cancer cell lines (MDA-MB-231 and T47D) treated with SN-38 (an active metabolite of irinotecan) at 50 and 500 nM for 1, 6, and 24 h.Irinotecan causedtime-dependent changesofmetabolites including nucleosides, nucleobases, amino acids, acylcarnitines, andaminoadipic acid in patient plasma. SN-38 inducedtime- and concentration-dependent increases of nucleosides and nucleobases in culture medium of both human liver cells and cancer cells, while aminoadipic acid (an oxidative stress marker) was elevated in liver cell medium only.SN-38 induced formation of reactive oxygen species in liver cells but not in cancer cells.In conclusion: Elevated circulating levels of nucleosides and nucleobases seem associated with irinotecan-induced inhibition of DNA replication. Oxidative stress appears to be implicated in irinotecan toxicities especially steatohepatitis. Further studies are needed to investigate whether these circulating metabolite changes could serve as mechanistic biomarkers for predicting irinotecan efficacy and toxicity.