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1-(3-C-Ethynyl-beta-D-ribo-pentofuranosyl)cytosine (ECyd, TAS106) is a newly developed anti-tumor agent that targets RNA synthesis. We report here that a low dose of ECyd induces radiosensitization of caspase-dependent apoptosis and reproductive cell death in cells of the gastric tumor cell lines MKN45 and MKN28 and murine rectum adenocarcinoma Colon26. Flow cytometry demonstrated that TAS106 induced the abrogation of the X-ray-induced G(2)/M checkpoint. Western blot analysis showed that X rays increased the expression of cyclin B1, phospho-Cdc2 and Wee1, whereas co-treatment with X rays and TAS106 decreased the expression of these cell cycle proteins associated with the G(2)/M checkpoint. Furthermore, TAS106 was shown to decrease the radiation-induced expression of survivin but not Bcl2 and BclX(L) regardless of TP53 status and cell type. Overexpression of wild-type survivin in MKN45 cells inhibited the induction of apoptosis induced by co-treatment with X rays and TAS106. These results suggest that TAS106 enhances X-ray-induced cell death through down-regulation of survivin and abrogation of the cell cycle machinery.

Aberrant glycosylation occurs during development of gastric carcinomas. The initiation of mucin-type O-glycosylation is regulated by GalNAc-T3 (UDP-N-acetylgalactosamine:polypeptide N-acetylgalactosaminyltransferase-3). However, the clinical significance of GalNAc-T3 expression in human gastric carcinoma has not yet been demonstrated. In the present study, we investigated the relationship between immunohistochemical GalNAc-T3 expression and various clinicopathologic factors, including prognosis, in 117 gastric carcinoma patients. Of 117 gastric carcinomas examined, 59 (50.4%) showed strong expression of GalNAc-T3. Strong expression was detected in 38 of 59 (64.4%) differentiated type and in 21 of 58 (36.2%) undifferentiated gastric carcinomas, indicating that the expression of GalNAc-T3 correlated significantly with tumor differentiation (P=0.0023, chi2 test). Overall 5-year survival rate in patients with strong GalNAc-T3 expression (71.0%) was significantly better than that of patients with weak expression (49.3%) (P=0.0197, log-rank test). Multivariate analysis identified GalNAc-T3 expression as an independent prognostic factor (P=0.0158, Cox proportional hazards model). Our data suggest that GalNAc-T3 expression may be a useful marker for prognosis and differentiation of gastric carcinomas.