In vitro synergistic cytotoxicity of gemcitabine and pemetrexed and pharmacogenetic evaluation of response to gemcitabine in bladder cancer patients

被引:43
作者
Mey, V.
Giovannetti, E.
De Braud, F.
Nannizzi, S.
Curigliano, G.
Verweij, F.
De Cobelli, O.
Pece, S.
Del Tacca, M.
Danesi, R.
机构
[1] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56100 Pisa, Italy
[2] Univ Pisa, Dept Internal Med, Div Pharmacol & Chemotherapy, I-56126 Pisa, Italy
[3] European Inst Oncol, Dept Med Oncol, I-20141 Milan, Italy
[4] European Inst Oncol, Div Urol, I-20141 Milan, Italy
关键词
bladder cancer; antifolates; gemcitabine; drug combination; inducible gene expression;
D O I
10.1038/sj.bjc.6603242
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-I (hENTI), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENTI had better response. Moreover, human nucleoside concentrative transporter-I was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.
引用
收藏
页码:289 / 297
页数:9
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