1. Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity.
- Author
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Guichard SM, Macpherson JS, Mayer I, Reid E, Muir M, Dodds M, Alexander S, and Jodrell DI
- Subjects
- Analysis of Variance, Animals, Antimetabolites, Antineoplastic pharmacokinetics, Antimetabolites, Antineoplastic therapeutic use, Capecitabine, Cell Line, Tumor, Colonic Neoplasms metabolism, Deoxycytidine metabolism, Deoxycytidine pharmacokinetics, Deoxycytidine therapeutic use, Fluorouracil metabolism, Fluorouracil pharmacokinetics, Fluorouracil therapeutic use, Gene Expression, Hepatocytes metabolism, Mice, Mice, Inbred C57BL, Mice, Nude, Neoplasm Transplantation, Reverse Transcriptase Polymerase Chain Reaction, Transplantation, Heterologous, Antimetabolites, Antineoplastic metabolism, Colonic Neoplasms drug therapy, Deoxycytidine analogs & derivatives, Fluorouracil analogs & derivatives, Liver metabolism
- 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 microM (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 approximately 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.
- Published
- 2008
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