Predictive value of GADD153, p21 and c-Jun for chemotherapy response in gastric cancer

We sought to determine whether changes in the expression of early response genes (GADD153, p21 and c-Jun) are indicators of chemotherapy response in gastric cancer. Three human gastric cancer cell lines were exposed to 5-fluorouracil or cisplatin in vitro. Xenografts of TMK-1 cells in nude mice were also treated with 5-fluorouracil or cisplatin in vivo. For each of these treatments, we tested for a correlation between early gene expression levels and inhibition ratios derived at a later time. A 5-fluorouracil derivative, S-1, and cisplatin were administered to 12 patients with advanced gastric cancer for 3 weeks. Gene expression levels were measured using biopsy specimens obtained by endoscopy soon after initiation of chemotherapy. There was a significant correlation between expression levels of these genes at 24 h and inhibition ratios at 72 h in vitro. Cut-off values determined from receiver-operating characteristic curves were 1.3 for GADD153, 1.8 for p21 and 2.1 for c-Jun There was also a significant correlation between gene expression levels at 2 days and inhibition ratios at 21 days in vivo. Cut-off values were 1.8 for GADD153, 1.9 for p21 and 2.2 for c-Jun. Levels of early response gene expression in patients showing progressive disease were significantly lower than those in patients with partial response. 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. (Cancer Sci 2007; 98: 707–715)