Novel chmosensitivity testing using molecular dynamics responding to anticancer drugs

目的：评价早期反应基因（GADD 153、p21和c-Jun）表达的变化是否可以指示胃癌的化疗反应。实验设计：将三种人胃癌细胞系（TMK-1、MKN-45和MKN-74）体外暴露于5-FU或顺铂（CDDP）。裸鼠TMK-1异种移植物也用5-FU或CDDP体内处理。对于这些治疗中的每一种，我们测试了早期基因表达水平与稍后得出的抑制率（IR）之间的相关性。最后，对12例晚期胃癌患者给予替吉奥和顺铂治疗3周。在不同反应组的患者中，GADD 153、p21和c-Jun的表达水平使用在开始化疗后不久通过内窥镜获得的活检标本进行比较。结果：这些基因在24小时的表达水平（通过实时PCR测量）与体外72小时的IR之间存在显著相关性 ...更多信息 GADD153;r=0.89，P<0.001，p21;r=0.93，P<0.001，c-Jun; r=0.80，P<0.001）。受试者工作特征（ROC）曲线显示，GADD 153、p21和c-Jun的截断值（计算以预测化疗的有效性）分别为1.3、1.8和2.1。在体内，2天的基因表达水平与21天的IR之间也存在显著相关性（GADD 153;r = 0.77，P<0.001，p21;r = 0.85，P<0.001，和c-Jun ; r = 0.87，P<0.001）。ROC曲线将GADD 153、p21和c-Jun的截断值分别定义为1.8、1.9和2.2。在临床基因表达和反应预测研究中，疾病进展（PD）患者3-7天的早期反应基因表达水平显著低于部分反应（PR）患者。GADD 153;P=0.002; P21;P = 0.003; c-Jun ; P=0.033）。结论：胃癌化疗后3种早期反应基因表达的变化可提高对化疗疗效的预测。少

Purpose : To evaluate whether changes in the expression of early-response genes (GADD153, p21, and c-Jun) can indicate chemotherapy response in gastric cancer.Experimental Design : Three human gastric cancer cell lines (TMK-1,MKN-45, and MKN-74) were exposed to 5-fluorouracil (5-FU) or cisplatin (CDDP) in vitro. Xenografts of TMK-1 in nude mice were also treated with 5-FU or CDDP in vivo. For each of these treatments, we tested for a correlation between early gene expression levels and inhibition ratios (IR) derived at a later time. Finally, S-1 and CDDP were administered to 12 patients with advanced gastric cancer for three weeks. Among patients in different response groups, expression levels of GADD153, p21, and c-Jun were compared using biopsy specimens that were obtained by endoscopy soon after initiation of chemotherapy.Results : There was a significant correlation between the expression levels of these genes at 24 hours (as measured by real-time PCR) and IRs at 72 hours in vitro … More (GADD153;r=0.89, P<0.001, p21;r=0.93, P<0.001, and c-Jun; r=0.80, P<0.001). Receiver-operating characteristic (ROC) curves revealed that the cut-off values (calculated to predict the effectiveness of chemotherapy) for GADD153, p21, and c-Jun were 1.3, 1.8, and 2.1, respectively. There was also a significant correlation between gene expression levels at 2 days and IRs at 21 days in vivo (GADD153;r = 0.77, P<0.001, p21;r = 0.85, P<0.001, and c-Jun ; r = 0.87, P<0.001). ROC curves defined the cut-off values as 1.8 for GADD153, 1.9 for p21, and 2.2 for c-Jun. In clinical Gene Expression and Response Prediction studies, levels of early-response gene expressions at 3-7 days in patients showing progressive disease (PD) were significant lower than those in patients with partial response (PR) (GADD153;P=0.002, P21;P = 0.003, and c-Jun ; P=0.033).Conclusions : These results suggest that changes in the expression of the three early response genes soon after drug administration could improve predictions of the final outcome of chemotherapy in gastric cancer. Less