Gene expression predicts differential capecitabine metabolism, impacting on both pharmacokinetics and antitumour activity.
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.
Guichard
Sylvie M
SM
Cancer Research UK Pharmacology and Drug Development Group, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK. sylvie.guichard@astrazeneca.com
Macpherson
Janet S
JS
Mayer
Iain
I
Reid
Eilidh
E
Muir
Morwenna
M
Dodds
Michael
M
Alexander
Susan
S
Jodrell
Duncan I
DI
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
D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil