Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.
Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.
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DOI：
10.1038/sj.bjc.6603559
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发表时间：
2007-02-12
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
为了确定吉西他滨耐药的预测性分子标志物，我们研究了胰腺癌细胞系获得性吉西他滨耐药发展过程中与吉西他滨转运和代谢相关的四种基因表达的变化。在吉西他滨获得性耐药的发展过程中，通过实时光循环PCR分析了人平衡型核苷转运蛋白1（hENT 1）、脱氧胞苷激酶（dCK）、RRM 1和RRM 2 mRNA在各种亚克隆中的表达水平。实时光循环PCR显示，RRM 1或RRM 2的表达水平在吉西他滨耐药的发展过程中逐渐增加。在对较低浓度吉西他滨耐药的细胞中，dCK的表达略有增加，但在较高浓度耐药的亚克隆中，dCK的表达降低至不可检测的水平以下。hENT 1的表达在吉西他滨耐药的发展中增加。由于对吉西他滨的获得性耐药似乎与这四个因素的平衡相关，因此我们计算了吉西他滨耐药亚克隆中hENT 1 × dCK/RRM 1 × RRM 2基因表达的比率。在吉西他滨耐药亚克隆中，基因表达的比例随着获得性耐药的发展而逐渐降低。此外，在8个胰腺癌细胞系中，表达比率与吉西他滨敏感性显著相关，而没有单个基因表达水平与敏感性相关。这些结果表明，胰腺癌细胞对吉西他滨的敏感性是由参与吉西他滨转运和代谢的四个因素的比例决定的。四种基因表达水平的比率与胰腺癌细胞中获得性吉西他滨耐药相关，并且可以用作胰腺癌患者中吉西他滨治疗功效的预测标志物。
To identify predictive molecular markers for gemcitabine resistance, we investigated changes in the expression of four genes associated with gemcitabine transport and metabolism during the development of acquired gemcitabine resistance of pancreatic cancer cell lines. The expression levels of human equilibrative nucleoside transporter-1 (hENT1), deoxycytidine kinase (dCK), RRM1, and RRM2 mRNA were analysed by real-time light cycler-PCR in various subclones during the development of acquired resistance to gemcitabine. Real-time light cycler-PCR demonstrated that the expression levels of either RRM1 or RRM2 progressively increased during the development of gemcitabine resistance. Expression of dCK was slightly increased in cells resistant to lower concentrations of gemcitabine, but was decreased below the undetectable level in higher concentration-resistant subclones. Expression of hENT1 was increased in the development of gemcitabine resistance. As acquired resistance to gemcitabine seems to correlate with the balance of these four factors, we calculated the ratio of hENT1 × dCK/RRM1 × RRM2 gene expression in gemcitabine-resistant subclones. The ratio of gene expression decreased progressively with development of acquired resistance in gemcitabine-resistant subclones. Furthermore, the expression ratio significantly correlated with gemcitabine sensitivity in eight pancreatic cancer cell lines, whereas no single gene expression level correlated with the sensitivity. These results suggest that the sensitivity of pancreatic cancer cells to gemcitabine is determined by the ratio of four factors involved in gemcitabine transport and metabolism. The ratio of the four gene expression levels correlates with acquired gemcitabine-resistance in pancreatic cancer cells, and may be useful as a predictive marker for the efficacy of gemcitabine therapy in pancreatic cancer patients.
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影响因子：
11.5
作者：
Pellisé, M;Castells, A;Piqué, JM
通讯作者：
Piqué, JM
影响因子：
9.8
作者：
Agarwal, B;Abu-Hamda, E;Ho, L
通讯作者：
Ho, L
影响因子：
11.2
作者：
Arnold, NB;Ketterer, K;Korc, M
通讯作者：
Korc, M
影响因子：
10.3
作者：
Mackey, JR;Yao, SYM;Young, JD
通讯作者：
Young, JD
影响因子：
45.3
作者：
Burris, HA;Moore, MJ;VanHoff, DD
通讯作者：
VanHoff, DD