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S-1, a novel oral fluoropyrimidine, is increasingly used for the treatment of human cancer including gastrointestinal carcinomas. Using the 5-FU resistant DLD-1/FU human colon cancer cell xenografts, the present study investigated whether S-1 enhances the therapeutic efficacy of radiation and if so what are the underlying mechanisms. Nude mice bearing tumor xenografts were treated with radiation, S-1, or both. Tumor growth delay was the treatments' endpoint. To determine whether S-1 enhances intrinsic cell radiosensitivity, we performed clonogenic cell survival assay. Also we assessed the expression of thymidylate synthase (TS) using immunohistochemistry assay. While S-1 or 5 Gy were only slightly effective as single agents in delaying tumor growth, the combined treatment was highly effective. Clonogenic cell survival showed that S-1 strongly enhanced cell radiosensitivity. Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation. Combined S-1 plus radiation treatment resulted in a synergistic effect in the therapy of 5-FU resistant human colon carcinoma xenografts (EF = 2.06). The effect could be attributed to the ability of S-1 to increase cell radiosensitivity (EF = 1.9) and to the down-regulation of TS involved in cellular processes leading to radio- and (or) chemo-resistance.

The purpose of this study was to determine the role of TP and VEGF in angiogenesis and its clinical significance in prognosis of patients with esophageal carcinoma. Expressions of TP and VEGF, microvascular density and cell proliferation activity were evaluated by using 40 immunohistochemically stained resected esophageal carcinoma tissues, and the survival rate of the patients was analyzed. Significant positive correlation and regression were found between the VEGF expression level of tumor and microvascular density (r=0.73, p<0.0001). Not statistically strong but significant positive correlation and regression were found between the TP expression level of tumor and microvascular density (r=0.32, p=0.046). No significant relationships were found between TP and VEGF expressions. Pathological T-factor and pathological N-factor were significant prognostic factors. Tumor length, site of lesion, gender, age, and Ki67 labeling index were not significant prognostic factors. The VEGF expression level was one of the unfavorable prognostic factors (risk ratio =1.035, 95% CI=1.007-1.065, p=0.01). The patients with high TP expression showed a tendency for unfavorable prognosis, but it was not statistically significant (RR=1.017, 95% CI=0.996-1.042, p=0.1). The prognosis of patients in the TP/VEGF[+/+] group was significantly poorer than that of the patients in the TP/VEGF[-/-] group and TP/VEGF[+/- or -/+] group (RR=0.488 for TP/VEGF[-/-] group, =0.717 for TP/VEGF[+/- or -/+] group, p=0.005). In conclusion, VEGF and TP expression seems to have a relationship with tumor angiogenesis, and co-expression of TP and VEGF seemed to be one of the unfavorable prognostic factors.

Several studies have shown that macroscopically infiltrative type of esophageal carcinoma generally has a poorer local response to radiation therapy than that of localized type. The aim of this study was to determine the role of metallothionein (MT) as a radioprotective agent in the difference of clinical radiosensitivities in esophageal carcinoma. A total of 45 surgically resected esophageal carcinoma tissues [20 macroscopically localized type without preoperative treatment (PT), 20 macroscopically infiltrative type without PT and 5 macroscopically infiltrative type with PT] were stained for MT by immunohistochemistry and were analyzed. MT expression level of macroscopically localized type of esophageal carcinoma was significantly higher than that of infiltrative type without PT (P=0.026) and was significantly higher than that of infiltrative type with PT (P=0.024). No significant difference was found between MT expression levels in infiltrative type of esophageal carcinoma without PT and that with PT. The results of this study suggest that there is less possibility that clinical radioresistance of the tumor is due to MT expression in esophageal carcinoma and also suggest that there is less possibility that MT synthesis is induced by fractionated irradiation of a moderate dose or by an anti-cancer agent during a course of treatment.