口腔扁平上皮癌細胞に対するフッ化ピリミジン系経口抗癌剤TS-1と放射線との併用効果の解析

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Background: TS-1 is a new oral anti-neoplastic agent which can inhibit cell growth and induce apoptosis in certain types of cancer cells including gastric carcinomas, colorectal carcinomas, and oral squamous cell carcinomas. However, the combined effects of TS-1 and radiation on oral squamous cell carcinomas have not yet been clarified. Purpose: We evaluated anti-tumor effect of TS-1 in combination with radiation both in vitro and in vivo against a human oral squamous cell carcinoma cell line, and investigated the mechanism of apoptosis enhancing activity by the combination with TS-1 and radiation. Materials and Methods: A human oral squamous cell carcinoma cell line, B88, was used in vitro and in vivo xenografts of nude mice. In in vitro analysis, attached cells were treated with TS-1 (50μg/ml) for 1h and then irradiated (3, 6, 9, 12, 15 Gy), or they were treated with TS-1 for 1h after radiation. Cell survival was determined by MTT assay and clonogenic assay. In in vivo analysis, TS-1 (10mg/kg) was administered orally 1h before radiation (1.5 Gy), or 1h after radiation for five consecutive days. Apoptotic cells were detected by TdT-mediated dUTP-biotin nick end labeling method. Phosphorylated-Akt/protein kinase B (PKB) was examined by Western blotting. Expressions of Rad50, Ku70, Ku80 and catalytic subunit of DNA-dependent protein kinase in xenograft tumors were investigated by immunohistochemistry. Results: TS-1 in combination with radiation has a remarkable effect on decreasing in vitro cell growth. In vitro clonogenic survival experiments demonstrated the dose enhancement ratio of 1.22 (radiation+TS-1), or 1.45 (TS-1+radiation) in B88 cells. In addition, the combined treatment of TS-1 and radiation resulted in an increased DNA fragmentation by detecting Hoechst 33258 staining, and suppressing the activation of Akt/PKB. Moreover, apoptosis of the cells by combined treatment of TS-1 and radiation was associated with generation of reactive oxygen/nitrogen species and the activation of caspase-8, caspase-9 and caspase-3. The combination of TS-1 and radiation was more effective than either agent alone in in vivo nude mouse model. Moreover, TS-1 administration before radiation was more effective than TS-1 administration after radiation. Futhermore, the combination of TS-1 and radiation could induce apoptosis significantly than either agent alone. Conclusions: These data demonstrate that the combination of TS-1 and fractionated radiotherapy is more effective against a human oral squamous cell carcinoma cell than either agent alone, and that TS-1 administration before radiation is more effective than after radiation, suggesting a potential clinical applicability of combination treatment of TS-1 and radiation in oral squamous cell carcinoma therapies.
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