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Background: Antitumor effects of chemotherapeutic agents are commonly associated with the induction of apoptosis. Bax belongs to the Bcl-2 family and induces apoptosis. The present study was conducted to investigate the relationship between enhanced Bax expression in oral squamous cell carcinoma (SCC; cell lines and clinical cases) and the antitumor effects of chemotherapy. Methods: In three oral SCC cell lines, Bax expression before and after treatment with chemotherapeutic agents [docetaxel (TXT), cisplatin and 5-fluorouracil] was examined by reverse transcriptase-polymerase chain reaction and immunoblotting. The effects of treatment were assessed by counting the number of viable cells and determining sub-G1 cells. Tissue samples (both biopsy specimens before chemotherapy and surgically excised specimens after chemotherapy) from nine patients with oral SCC who underwent neoadjuvant chemotherapy were immunostained for Bax. The relationship between enhancement of Bax expression and chemotherapeutic effects was established. Results: Two of three cell lines did not express Bax mRNA or protein before treatment. After treatment, Bax expression was enhanced only by TXT in one cell line, but by all chemotherapeutic agents in the other two cell lines. In three of nine patients, Bax expression was not found before chemotherapy. Two of these three patients showed enhanced Bax expression after chemotherapy including TXT, but one still failed to express Bax. Both in cell lines and clinical cases, enhancement of Bax after chemotherapy was associated with antitumor effects. Conclusion: Certain chemotherapeutic agents enhance Bax expression in oral SCC, and it is suggested that this contributes to the antitumor effects of chemotherapy.

In this retrospective study, the relations between changes in cell proliferation kinetics and induced apoptosis in oral squamous cell carcinoma were examined before and after preoperative chemotherapy to clarify significance of such changes. In an additional study, multivariate analysis was performed to attempt to predict changes in cell proliferation kinetics.Apoptotic index (AI) increased in all cases, although there were some differences in degree. With respect to the change in cell proliferation kinetics, left-shift-type and right-shift-type AI was clearly high before chemotherapy and increased significantly after chemotherapy as compared with the non-effective type of AI.The 5-year cumulative survival rate was 91% in patients with less than 10% of the exceeding 4 c rate of nuclear DNA content (4 cER) and 62% in patients with 10% or higher 4 cER. In patients with low 4 cER, survival rates were excellent regardless the change in cell proliferation. On the other hand, survival rate was significantly worse in the non-effective type, while survival rates were relatively good in the leftshif t type and the right-shift type: 76% for the left-shift type, 74% for the right-shift type, and 35% for the non-effective type. Thus, we attempted to predict the non-effective type. Clinical stage (UICC), Gcategory (UICC), mitotic index, 4 cER, and AI were entered into logistic regression analysis as covariates. AI and 4 cER were selected as independent variables for the prediction of non-effective type.In conclusion, left-shift-type and the right-shift-type changes in cell proliferation kinetics seemed to be favorable in terms of induced apoptosis, and had excellent survival rates. AI and 4 cER were the most powerful predictors of the change in cell proliferation kinetics.

We examined occlusal status in 18 patients with mandibular prognathism (mandibular prognathism group) as compared with that of 14 adults with normal occlusion (control group). We also studied changes in occlusal status after orthognathic surgery (1, 3, 6, and 12 months) in the patients with mandibular prognathism. The occlusal contact area, maximum voluntary isometric bite force, and occlusal pressure were recorded using a pressure-sensitive sheet (Dental Prescale ® 30HW type, Fuji Photo Film Co.) and the data were analyzed with an analysis system (FPD-703, Fuji Photo Film Co.).The results were as follows:1) Preoperatively, the mandibular prognathism group had a significantly smaller occlusal contact area and a lower bite force than the control group, but had a higher occlusal pressure.2) Changes in occlusal contact area and bite force were evaluated in the patients with mandibular prognathism from before operation to 12 months after operation. Occlusal contact area and bite force decreased significantly 1 month after operation, increased significantly to preoperative levels 6 months after operation, and were about 40% of preoperative levels 12 months after operation. However, 12 months after operation occlusal contact area was smaller and bite force was lower than those in the control group.3) Occlusal pressure was evaluated in the patients with mandibular prognathism from before operation to 12 months after operation. The value increased significantly 1 month after operation, but decreased subsequently. Twelve months after operation, occlusal pressure in the prognathism group was similar to that in the control group.4) Few studies have used pressure-sensitive sheets. This method permits assessment of occlusal status of all teeth easily and promptly. Pressure-sensitive sheets are useful for understanding occlusal status clinically.

Summary The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m 2 ) combined with a fixed dose of docetaxel (60 mg/m 2 ) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m 2 ) was determined to be 90 mg/m 2 . Docetaxel 60 mg/m 2 plus nedaplatin 90 mg/m 2 induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.

Neoadjuvant chemotherapy (NAC) for oral squamous cell carcinoma has a positive impact on organ preservation and/or survival only in patients who achieve an excellent anti-tumour effect with this therapy. Predictive assay for NAC can play an important role in establishing tailor-made treatments for oral squamous cell carcinoma. In this retrospective study, the anti-tumour effects of cisplatin-based NAC in 70 patients with oral squamous cell carcinoma were reviewed in relation to biological markers of tumour cell proliferation activity: tumour grade, cellular DNA content, mitotic index, apoptotic index, ki-67 positive rate, and p53 and Bax expression. Tumour grade, Bax expression, apoptotic index and cellular DNA content were significantly correlated with the anti-tumour effects of NAC in univariate analysis. Tumour grade, Bax expression and apoptotic index were selected as independent predictive factors by means of multiple logistic analysis. Using the regression equation from these results, the prediction rate for anti-tumour effects was 70%. For patients in whom NAC is predicted to be ineffective, it may be necessary to choose another treatment option in order to improve their survival and quality of life.