Novel chmosensitivity testing using molecular dynamics responding to anticancer drugs

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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