We have already demonstrated that human head and neck cancer cells have significantly enhanced levels of transcription factor nuclear factor (NF)-κB activity compared to their normal counterparts, suggesting that NF-κB plays an important role in the development of head and neck cancer. However, it has been reported that chemotherapeutic agents and radiation activate NF-κB activity in cancer cells, thus making the cells radioresistant and chemoresistant. In addition, we have shown that the suppression of NF-κB activity enhanced apoptosis in oral squamous cell carcinoma cells. In this study, we examined whether cepharanthin-induced inhibition of NF-κB activity enhances radiosensitivity in human oral carcinoma cells. Cepharanthin is a biscoclaurine alkaloid extracted from the roots of Stephania cepharantha hayata, and is widely used in Japan for the treatment of patients with leucopenia, nasal allergy, and venomous snakebites. γirradiation (IR) induces NF-κB activity in oral carcinoma cells through the activation of upstream molecules, including Akt and IκB kinase. However, a luciferase assay revealed that cepharanthin suppresses IR-induced NF-κB activity in oral squamous cell carcinoma cells, thereby enhancing the radio-sensitivity. Western blot analysis showed an enhanced cleavage of poly-(ADP-ribose) polymerase protein in carcinoma cells by both cepharanthin treatment and IR exposure compared to IR or cepharanthin alone. In an in vivo study, B88 cells were s.c. inoculated into the backs of nude mice. Tumor-bearing nude mice received either cepharanthin, IR alone, or a combination of cepharanthin and IR. The combined treatment suppressed tumor growth significantly more than either cepharanthin or IR alone. Cepharanthin inhibited the production of IR-induced IL-6 and IL-8, which are downstream targets of NF-κB. In quantitative real-time RT-PCR, IR also induced the expression of anti-apoptotic proteins [cellular inhibitor of apoptosis protein (cIAP)-1 and-2] in carcinoma cells. Treatment of cancer cells with cepharanthin combined with exposure to IR decreased cIAP-1 and-2 mRNA expression. These findings suggested that the combination of radiotherapy and cepharanthin could enhance radiosensitivity in the treatment of human oral cancer.

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Abstract. The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), or orotate phosphoribosyltransferase (OPRT) genes for response to S-1. Twenty-five patients with oral squamous cell carcinoma (OSCC) received S-1 80 mg/m 2 /day. Pretreatment tumor biopsies were analyzed for TS, DPD, TP or OPRT mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. Twenty-five patients were evaluable for response and gene expression. Six of the 25 (24%) achieved complete remission and 4 of the 25 (16%) had a partial response. Median TS/ß-actin was 2.51 (range 0.98-7.07). Median TS/ß-actin was 1.26 in responding patients and 3.43 in non-responders (P=0.0001). Ten of 11 patients with TS/ß-actin <1.80 and 0 of 15 with higher values responded (P<0.0001). Overall survival was 29.7 months in patients with TS/ß-actin <1.80 and 41.7 months in patients with higher values (P=0.0013). No correlations were seen between expression of DPD, TP or OPRT mRNA and response or survival. Weak TS staining was seen in 6 of 25 tumors evaluable for immunohistochemistry, including 5 responders. All 4 of the patients with both weak staining and TS/ß-actin <1.80 responded. High TS mRNA expression predicts non-response to S-1. On the other hand, high levels of DPD or TP mRNA and low levels of OPRT mRNA are not associated with S-1 resistance. TS mRNA expression is considered to be a useful prognostic factor in OSCC patients with S-1 single-agent therapy.

Type 2 diabetes is a typical lifestyle disease. We aimed to identify the factors affecting glycemic control in 64 outpatients with type 2 diabetes over a 2-year period. We defined poor glycemic control using a change in glycosylated hemoglobin (ΔHbA1c) of ≥ 0.5% over 2 years and/or HbA1c ≥ 7.5% at the end of the study period. We used a questionnaire to collect information on oral health behavior and lifestyle, including eating and smoking habits, and analyzed the relationships between indices of diabetes control and responses to the questionnaire. The mean (SD) HbA1c of the participants was 6.87% (0.77%) at a baseline, and 6.93% (0.69%) after 2 years. Twenty-three participants (36.0%) had poor glycemic control. ΔHbA1c and the change in body mass index (ΔBMI) correlated (Spearman's rank correlation, r = 0.350, p < 0.01). The HbA1c at baseline was associated with eating slowly / chewing well, and ΔBMI was associated with perceived oral symptoms. Binominal logistic regression analysis revealed that poor glycemic control was associated with ΔBMI and a smoking habit (odds ratio : 1.62, 95% confidence interval : 1.08-2.42 ; and 4.01, 1.12-14.36, respectively). These findings imply that weight gain and a smoking habit are associated with poor glycemic control in patients with type 2 diabetes.