Guichard Sylvie M, Macpherson Janet S, Mayer Iain, Reid Eilidh, Muir Morwenna, Dodds Michael, Alexander Susan, Jodrell Duncan I
Cancer Research UK Pharmacology and Drug Development Group, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, UK.
Eur J Cancer. 2008 Jan;44(2):310-7. doi: 10.1016/j.ejca.2007.10.023.
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.
在肝脏和肿瘤中，卡培他滨通过羧酸酯酶1和2（CES1和2）、胞嘧啶脱氨酶（CDD）和胸苷磷酸化酶（TP）转化为5'-脱氧-5-氟胞苷（5'DFCR）、5'-脱氧-5-氟尿苷（5'DFUR）和5-氟尿嘧啶（5-FU）。5-FU由二氢嘧啶脱氢酶（DPD）分解代谢。对这些酶进行了基因表达分析，分析对象包括新鲜人肝细胞、小鼠肝脏、结肠癌细胞系和异种移植瘤。CDD表达低（<1.5）的细胞系的5'DFCR/5'DFUR细胞毒性比>2，而TP/DPD<0.6的细胞系的5'DFUR半数抑制浓度（IC50）>50微摩尔（磺酰罗丹明B法）。对荷HCT 116异种移植瘤的裸鼠进行了药代动力学/药效学研究，通过口服灌胃给予卡培他滨，评估了药代动力学、基因表达和抗肿瘤活性。小鼠肝脏中CDD低与血浆中高浓度的5'DFCR相关。新鲜人肝细胞中的CDD表达比小鼠肝脏高约100倍，这解释了先前报道的人类血浆中5'DFUR浓度较高的原因。肿瘤5-FU浓度与TP/DPD以及肿瘤反应相关。这些研究确定了基因表达分析和药物监测在患者肿瘤中的潜在用途。
