title: Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity.
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.
authors: Cancer Research UK Pharmacology and Drug Development Group, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK. sylvie.guichard@astrazeneca.com
authors: Sylvie M
authors: SM
authors: Guichard
authors: Janet S
authors: JS
authors: Macpherson
authors: Iain
authors: I
authors: Mayer
authors: Eilidh
authors: E
authors: Reid
authors: Morwenna
authors: M
authors: Muir
authors: Michael
authors: M
authors: Dodds
authors: Susan
authors: S
authors: Alexander
authors: Duncan I
authors: DI
authors: Jodrell
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000069287:Capecitabine; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D005472:Fluorouracil / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D015870:Gene Expression; D022781:Hepatocytes / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil