Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity

Sylvie M. Guichard, Janet S. Macpherson, Iain Mayer, Eilidh Reid, Morwenna Muir, Michael Dodds, Susan Alexander, Duncan I. Jodrell

Research output: Contribution to journalArticlepeer-review

Abstract

Capecitabine is converted into 5'-deoxy-5-fluorocytidine (5'DFCR), 5'-deoxy-5-fluorouridine (5'DFUR) and 5-fluorouracil (5-FU) by CES1 and 2, CDD, and TP, in both liver and tumour. 5-FU is catabolised by DPD. Gene expression analysis of these enzymes was undertaken in fresh human hepatocytes, mouse liver, colorectal cancer cell lines and xenografts. Cell lines with low CDD expression (<1.5) had 5'DFCR/5'DFUR cytotoxicity ratios >2 and cell lines with TP/DPD < 0.6 had 5'DFUR IC50 > 50 mu M (SRB assay). A pharmacokinetic/pharmacodynamic study in nude mice bearing HCT 116 xenografts and treated with capecitabine by oral gavage assessed pharmacokinetic, gene expression and antitumour activity. Low liver CDD correlated with high 5'DFCR plasma concentrations in mice. CDD expression was similar to 100-fold higher in fresh human hepatocytes than mouse liver, explaining the higher plasma 5'DFUR concentrations reported previously in humans. Tumour 5-FU concentration correlated with TP/DPD and with tumour response. These studies identify the potential utility of gene expression analysis and drug monitoring in tumour in patients. (c) 2007 Elsevier Ltd. All rights reserved

Original languageEnglish
Pages (from-to)310-317
Number of pages8
JournalEuropean Journal of Cancer
Volume44
Issue number2
DOIs
Publication statusPublished - Jan 2008

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