RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer
RRM1 modulated in vitro and in vivo efficacy of gemcitabine and platinum in non-small-cell lung cancer
复制标题
DOI：
10.1200/jco.2006.06.1101
复制
发表时间：
2006-10-10
影响因子：
45.3
通讯作者：
Simon, George
中科院分区：
文献类型：
--
作者：
Bepler, Gerold;Kusmartseva, Irina;Simon, George
目的RRM 1编码核糖核苷酸还原酶的调节亚基，是吉西他滨的分子靶点。先前的研究表明，在细胞系连续暴露于吉西他滨时，RRM 1表达增加，并表明当用含吉西他滨的化疗治疗时，与高肿瘤RRM 1表达相比，低肿瘤RRM 1表达的患者的生存率提高。然而，肿瘤内基因表达水平与疾病反应相关的主要假设尚未得到解决。患者和方法我们构建了RRM 1表达增加和减少的遗传修饰肺癌细胞系，以研究吉西他滨、顺铂和卡铂的体外50%抑制浓度（IC 50）。在局部晚期非小细胞肺癌患者中进行了一项前瞻性II期临床试验，通过实时逆转录聚合酶链反应测定RRM 1和ERCC 1的表达。基因表达水平与肿瘤反应后两个周期的吉西他滨和carboplat.ResultsIn基因工程的15倍RRM 1表达范围的细胞系，吉西他滨的IC 50有100倍的范围，顺铂和卡铂的IC 50有两倍的范围。它们在具有高RRM 1表达的构建体中最高。在前瞻性临床试验中，RRM 1表达与疾病反应显著（P = 0.002）和负相关（r =-0.498）。ERCC 1表达显示出类似的趋势（P = 0.099）。结论结果强烈表明，肿瘤RRM 1表达是疾病对吉西他滨/铂类化疗反应的主要预测因子。ERCC 1表达是反应的预测，尽管程度较低。
PurposeRRM1 encodes the regulatory subunit of ribonucleotide reductase and is a molecular target of gemcitabine. Previous studies showed increased RRM1 expression on continuous exposure of cell lines to gemcitabine and suggested improved survival for patients with low as opposed to high tumoral RRM1 expression when treated with gemcitabine-containing chemotherapy. However, the principal hypothesis that intratumoral levels of gene expression are associated with disease response has not been addressed.Patients and MethodsWe constructed genetically modified lung cancer cell lines with increased and decreased RRM1 expression to investigate the in vitro 50% inhibitory concentration (IC50) for gemcitabine, cisplatin, and carboplatin. A prospective phase II clinical trial in patients with locally advanced non-small-cell lung cancer was conducted with pretreatment tumor collection for determination of RRM1 and ERCC1 expression by real-time reverse transcriptase polymerase chain reaction. The levels of gene expression were correlated with tumor response after two cycles of gemcitabine and carboplatin.ResultsIn cell lines with a genetically engineered 15-fold RRM1 expression range, the gemcitabine IC50 had a 100-fold range, and the cisplatin and carboplatin IC50 had a two-fold range. They were highest in constructs with high RRM1 expression. In the prospective clinical trial, RRM1 expression was significantly ( P =.002) and inversely correlated ( r = - 0.498) with disease response. ERCC1 expression showed a similar trend ( P =.099).ConclusionThe results strongly suggest that tumoral RRM1 expression is a major predictor of disease response to gemcitabine/platinum chemotherapy. ERCC1 expression is predictive of response albeit to a lesser degree.