Nakata Eiko, Fukushima Masakazu, Takai Yoshihiro, Nemoto Kenji, Ogawa Yoshihiro, Nomiya Takuma, Nakamura Yasuhiro, Milas Luka, Yamada Shogo
Tohoku University Biomedical Engineering Research Organaization, Miyagi 980-8575, Japan.
Oncol Rep. 2006 Sep;16(3):465-71.
S-1, a novel oral fluoropyrimidine, is increasingly used for the treatment of human cancer including gastrointestinal carcinomas. Using the 5-FU resistant DLD-1/FU human colon cancer cell xenografts, the present study investigated whether S-1 enhances the therapeutic efficacy of radiation and if so what are the underlying mechanisms. Nude mice bearing tumor xenografts were treated with radiation, S-1, or both. Tumor growth delay was the treatments' endpoint. To determine whether S-1 enhances intrinsic cell radiosensitivity, we performed clonogenic cell survival assay. Also we assessed the expression of thymidylate synthase (TS) using immunohistochemistry assay. While S-1 or 5 Gy were only slightly effective as single agents in delaying tumor growth, the combined treatment was highly effective. Clonogenic cell survival showed that S-1 strongly enhanced cell radiosensitivity. Immunohistochemistry showed that the expression of TS was down-regulated in tumors treated by S-1 plus radiation. Combined S-1 plus radiation treatment resulted in a synergistic effect in the therapy of 5-FU resistant human colon carcinoma xenografts (EF = 2.06). The effect could be attributed to the ability of S-1 to increase cell radiosensitivity (EF = 1.9) and to the down-regulation of TS involved in cellular processes leading to radio- and (or) chemo-resistance.
新型口服氟嘧啶S-1越来越多地用于治疗包括胃肠道癌在内的人类癌症。本研究利用对5-氟尿嘧啶（5-FU）耐药的DLD-1/FU人结肠癌细胞异种移植模型，研究S-1是否能增强放疗的疗效，若能增强，其潜在机制是什么。将荷瘤异种移植裸鼠分别用放疗、S-1或两者联合进行治疗。以肿瘤生长延迟作为治疗终点。为确定S-1是否增强细胞内在放射敏感性，我们进行了克隆形成细胞存活试验。我们还使用免疫组织化学分析法评估胸苷酸合成酶（TS）的表达。虽然S-1或5 Gy作为单一药物在延迟肿瘤生长方面效果甚微，但联合治疗却非常有效。克隆形成细胞存活试验表明，S-1能显著增强细胞放射敏感性。免疫组织化学显示，在接受S-1加放疗的肿瘤中，TS的表达下调。S-1加放疗联合治疗对5-FU耐药的人结肠癌异种移植瘤具有协同治疗作用（增效系数=2.06）。这种作用可归因于S-1增加细胞放射敏感性的能力（增效系数=1.9）以及参与导致放射和（或）化学耐药的细胞过程的TS表达下调。
