[Background] In 2004 AACR annual meeting, we have reported a novel chemosensitivity test using quantification of mRNA, which is enhanced by cell injury evoked by chemotherapy. In the study, three molecules, gadd153, p21 and c-Jun is confirmed to be useful for the assay in our experimental model using gastric cancer cells. [Purpose] In the present study, we calculate receiver operating characteristic curve as a final result of in vitro and in vivo experiment. In addition, clinical usefulness of the assay is assessed, objecting stage IIIB or IV gastric cancer patients initially treated with 5-FU derivate and CDDP. [Materials and Methods] We have been quantifying the expression of gadd153, p21 and c-jun mRNA, which can distinguish at least 2 times change of mRNA. (In vitro and in vivo) Human gastric cancer cell lines, TMK-1, MKN-45, and MKN-74 were treated with 5FU or CDDP, examining both each gene expression and final outcome by the chemotherapy, calculating sensitivity, specificity, and cut-off value using ROC curve. (Clinical evaluation and patients) 11 patients with Stage IIIB or IV gastric cancer were treated with 5-FU derivate and CDDP. Endoscopic biopsied samples were obtained before and at 3-5 days after the therapy. Tumor responses were assessed around 1∼2months after therapy by gasrtography and CT. [Results] (in vitro) ROC curve of gadd153, p21 and c-Jun showed both high sensitivity and specificity; 94%, 96% and 88% in sensitivity and 79.4%, 74.3% and 72.7% in specificity, respectively, elucidating useful assay to predict chemosensitivity by mRNA quantification. Each cut-off value of gadd153, p21 and c-jun is settled as 1.3, 1.8 and 0.98 in each expression levels rated by GAPDH. (in vivo) ROC curve of gadd153, p21 and c-Jun showed both high sensitivity and specificity; 94%, 87% and 97% in sensitivity and 88.2%, 80% and 72.7% in specificity, respectively, elucidating useful assay to predict chemosensitivity by mRNA quantification even in in vivo system. Each cut-off value of gadd153, p21 and c-jun is settled as 1.8, 1.9 and 2.2 in each expression levels rated by GAPDH. (Clinical evaluation and patients) 2 of the 11 patients obtained partial response, of whom mRNA expressions of GADD153, p21 and c-Jun were ranged from 10-18-fold, 12-20-fold and 9-19-fold. 5 of the 11 patients, who achieved no change, showed moderate increase of each mRNA level, ranged from 8-12-fold, 10-15-fold and 2-7-fold. 6 of the 11 patients with progressive disease did not show significant increase of all molecules. [Conclusion] As well as our previous reports, clinical usefulness of the assay was elucidated after evaluating 11 patients with highly advanced gastric cancer, who is treated with chemotherapy. The assay will be useful to provide prediction of chemotherapeutic outcome as early as at 3-5 days after the initial administration of chemotherapeutic agent.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]