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

被引：16

作者：

Guichard, Sylvie M. ^{[1
]}

Macpherson, Janet S. ^{[1
]}

Mayer, Iain ^{[1
]}

Reid, Eilidh ^{[1
]}

Muir, Morwenna ^{[1
]}

Dodds, Michael ^{[1
]}

Alexander, Susan ^{[1
]}

Jodrell, Duncan I. ^{[1
]}

机构：

[1] Univ Edinburgh, Edinburgh Canc Res Ctr, Canc Res UK Pharmacol & Drug Dev Grp, Edinburgh, Midlothian, Scotland

来源：

EUROPEAN JOURNAL OF CANCER | 2008年 / 44卷 / 02期

关键词：

colorectal cancer; capecitabine; metabolism; gene expression; pharmacokinetics;

D O I：

10.1016/j.ejca.2007.10.023

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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

引用

页码：310 / 317

页数：8

共 29 条

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