Novel chmosensitivity testing using molecular dynamics responding to anticancer drugs

目的：探讨胃癌早期反应基因（GADD153、p21、c-Jun）的表达变化是否能提示化疗反应。实验设计：将3株人胃癌细胞株TMK-1、MKN-45和MKN-74体外暴露于5-氟尿嘧啶（5-FU）或顺铂（CDDP）。裸鼠移植的TMK-1也在体内用5-FU或CDDP处理。对于每一种治疗方法，我们都测试了早期基因表达水平与后期获得的抑制比（IR）之间的相关性。最后对12例晚期胃癌患者给予S-1和CDDP治疗3周。在不同反应组的患者中，使用化疗开始后不久内窥镜获得的活检标本比较GADD153， p21和c-Jun的表达水平。结果：这些基因在体外培养24小时（实时荧光定量PCR）的表达量与体外培养72小时的IRs有显著的相关性…More （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，GADD153、p21和c-Jun的截止值（计算用于预测化疗的有效性）分别为1.3、1.8和2.1。2天的基因表达水平与体内21天的IRs也存在显著相关性（GADD153, r = 0.77， P<0.001, p21, r = 0.85， P<0.001, c-Jun, r = 0.87， P<0.001）。ROC曲线定义GADD153的临界值为1.8，p21为1.9，c-Jun为2.2。在临床基因表达和反应预测研究中，进展性疾病（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（GADD153， P=0.002, P21， P= 0.003, c-Jun， P=0.033）。结论：这些结果表明，在给药后不久，三种早期反应基因的表达变化可以提高对胃癌化疗最终结果的预测。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