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Background: Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence combined treatment of cancer cells with cepharanthine and S-1 might exert dramatic antitumor effects on OSCC cells., Materials and Methods: In this study, the response of human OSCC cells to cepharanthine alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and cepharanthine (20 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA., Results: Combined therapy of cepharanthine and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with cepharanthine plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with cepharanthine plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy., Conclusion: These findings demonstrate that the combination of cepharanthine and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

Background: Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor ligand family that selectively induces apoptosis of cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with TRAIL and S-1 might exert dramatic antitumor effects on OSCC cells., Materials and Methods: In this study, the response of human OSCC cells to TRAIL alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and TRAIL (1 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA., Results: Combined therapy of TRAIL and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with TRAIL plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with TRAIL plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy., Conclusion: These findings demonstrate that the combination of TRAIL and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

Low expression of p27(Kip1) is associated with disease progression and an unfavorable outcome in several malignancies including oral squamous cell carcinoma (SCC). In addition, p27(Kip1) protein is thought to be degraded by Skp2 (S-phase kinase-associated protein 2). The purpose of this study was to examine whether Skp2 expression can be a useful prognostic factor in oral SCC patients treated by UFT in combination with radiation. The Skp2 expression was investigated by immunohistochemistry in biopsy samples from 102 oral SCC patients, who were treated by UFT in combination with radiation. Associations of each expression with the clinicopathological characteristics and patient survival were also analyzed. A significant association was found between Skp2 expression and tumor size (p = 0.0462), cervical lymph node metastasis (p = 0.0209), therapeutic effect (p = 0.0490) and patient outcome (p = 0.0002). The 5-year survival rates of Skp2 high and low expression tumors were 40.5% and 78.5%, respectively, and this difference was significant (p = 0.0001) by log-rank test. Multivariate analysis revealed that reduced term of survival was related to high levels of Skp2 expression (p = 0.0001). These results suggest that Skp2 may be a useful prognostic factor in oral SCC patients treated by UFT in combination with radiation.