Additive effect of radiosensitization by 2-deoxy-D-glucose delays DNA repair kinetics and suppresses cell proliferation in oral squamous cell carcinoma.

BACKGROUND: It has well known that, compared to normal cells, tumor cells have a different manner of energy metabolism, which influences the sensitivity of radiotherapy. However, whether inhibition of glycolysis enhances the efficacy of radiotherapy is a matter of debate in oral squamous cell carcinoma (OSCC). The aim of this study was to characterize whether the combination of radiotherapy with the glucose inhibitor 2-deoxy-D-glucose (2-DG) affected DNA repair kinetics. METHODS: To compare the synergistic effect of 2-DG, we examined the cell survival after treatment with radiation, 2-DG, and a combination of the two in five OSCC cell lines and one lip fibroblast cell line, determined using clonogenic survival assay. Changes in the protein levels of DNA repair kinetics such as PARP, Rad51, and Ku-70 were analyzed by Western blotting. Then, using one of the five OSCC cell lines, we assessed the inhibition of xenograft tumor growth in vivo. RESULTS: We found that 2-DG with radiation induced significant inhibition of cell proliferation in cell line SAS (P<.01, one-way ANOVA). Radiation treatment was associated with decreased expression of the DNA repair markers. In additional, combinational treatment with 2-DG and radiation significantly inhibited the xenograft tumor growth compared to the control (P<.05), and treatment with 2-DG or radiation alone. CONCLUSIONS: Our study suggests that 2-DG has synergistic cytotoxic effects when combined with radiotherapy, which might lead to the design of an effective metabolic target therapy in vitro and in vivo.

Silencing of GLUT-1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia.

BACKGROUND: During tumor development, cells are exposed to a hypoxic microenvironment. Tumor hypoxia also has a profound influence on the sensitivity of cancer chemotherapy. The objective of this study was to investigate the mechanism of cisplatin (CDDP) resistance of oral squamous cell carcinoma (OSCC) cells under hypoxia by analyzing gene expression profiles to identify key genes and factors involved. METHODS: Cell viability was measured following culture of the cells in the presence or absence of CDDP, under normoxic or hypoxic conditions, using a CCK-8 assay. Analysis of the expression of HIF target genes in hypoxia-treated cells was performed using an HIF-regulated cDNA plate array. Changes in the mRNA expression of selected HIF target genes were analyzed using RT-PCR, and changes in the protein levels of these genes were analyzed by Western blotting. Tumor cell apoptosis was assessed by flow cytometry. RESULTS: The OSCC cell lines responded differently to CDDP under normoxic and hypoxic conditions. The expression of glucose transporter protein-1 (GLUT-1) was up-regulated in human squamous cell carcinoma of mouth (HSC-2) cells under hypoxia. Furthermore, there was little correlation between the cisplatin sensitivity of human squamous cell carcinoma of tongue (SAS) in normoxia and hypoxia. After GLUT-1 knockdown, CDDP treatment resulted in increased rates of apoptosis under hypoxia as compared with normoxia in cell lines HSC-2, Ca9-22, and SAS (P = 0.025). CONCLUSION: The results of this study suggest that knockdown of GLUT-1 inhibits sensitization of oral squamous cells to CDDP during hypoxia in HSC-2, Ca9-22, and SAS cells.

[Clinical investigation of bisphosphonate-related osteonecrosis of the jaws].

We examined the clinical features of bisphosphonate(BP)-related osteonecrosis of the jaws(BRONJ), a serious complication resulting from intravenous BP treatment for multiple myeloma and malignant tumors with bone metastasis. We retrospectively reviewed the medical records of 36 patients who received intravenous BP therapy for the above-mentioned conditions, at Sapporo Medical University Hospital between July 2006 and October 2008. BP therapy caused BRONJ in 7 of 24 patients, but did not affect the bones of the other 17 patients. The other 12 of the 36 patients involved in the study were prescribed BP only after they had undergone an oral examination and treatment for dental inflammation. Of these patients, 7 developed BRONJ with BP treatment, after tooth extraction or acute dental inflammation. Treating dental inflammation before prescribing BP prevented the development of BRONJ. BRONJ is highly intractable and does not resolve with the standard treatment for osteomyelitis. Therefore, preventive therapy, which can be achieved by cooperation between medical doctors and dentists, is currently the most effective strategy for BRONJ. Conservative treatment with antibiotics may also be useful for maintaining or improving the quality of life of BRONJ patients.

Clinical assessment of the relationship between the third molar and the inferior alveolar canal using panoramic images and computed tomography.

PURPOSE: To predict the relationship between lower third molars and the inferior alveolar canal (IAC) from panoramic radiographs, and to establish criteria for using computed tomography (CT). MATERIALS AND METHODS: A retrospective cohort study was performed involving 443 patients (695 teeth). Predictor variables were the distance between the third molar and the IAC, and findings according to the Rood's criteria. Outcome variables were the absence of cortication between the third molar and the IAC on the CT image, and injury of the inferior alveolar nerve (IAN). Statistical analysis was performed to assess the relationship between predictor and outcome variables. RESULTS: All patients had preoperative panoramic radiographs, and 71 patients (119 teeth) also had CT images. On CT examination, 48 teeth (40.3%) showed absence of cortication. Injury of the IAN was reported in 7 cases (1.0%), 5 of which exhibited absence of cortication; the remaining 2 did not have CT scans. Five of the 48 cases showing absence of cortication exhibited IAN injury, and none of the cases with cortication exhibited IAN injury. On the panoramic images, the following signs were strongly correlated with absence of cortication: a superimposed relationship between the third molar and the IAC; darkness of the root; and diversion and narrowing of the IAC. CONCLUSION: Presence of Rood's criteria was a predictor for a contact relationship between the third molar and the IAC, and an indication for CT examination. However, a superimposed relationship and the absence of Rood's criteria did not necessarily signify a separate relationship between third molar and the IAC.