Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo
Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo
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DOI：
10.3892/or_00000987
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发表时间：
2010-11-01
期刊：
影响因子：
4.2
通讯作者：
Sakata, Yu
中科院分区：
文献类型：
--
作者：
Fukushima, Masakazu;Sakamoto, Kazuki;Sakata, Yu
放化疗是治疗局部晚期癌症的有效方法。特别地，5-氟尿嘧啶（5-FU）与X射线照射的组合对于治疗某些类型的胃肠道癌症是有效的。我们研究了X射线和S-1（一种独特的5-FU制剂）联合治疗对裸鼠人癌异种移植瘤的抗肿瘤作用，并将这种治疗的疗效与放疗联合顺铂的疗效进行了比较。UFT，另一种口服5-FU前药，和静脉注射5-FU。在第1天和第8天，用接近2或5戈伊X射线照射小鼠左后腿中植入的肿瘤，并给予S-1、UFT和5-FU 14天。8.3 mg/kg S-1联合2戈伊X射线照射治疗非小细胞肺癌（Lu-99和LC-11）的疗效显著高于单用S-1或单用2戈伊X射线照射，其抗肿瘤活性与单用5戈伊X射线照射相似。尽管8.3 mg/kg S-1和17.5 mg/kg UFT具有等效的抗肿瘤活性，但S-1和2戈伊X射线照射联合给药对LC-11肿瘤的抗肿瘤疗效显著高于UFT和2戈伊X射线照射联合给药。S-1和X射线照射联合治疗对胰腺肿瘤的疗效也优于5-FU和X射线照射联合治疗。为了阐明S-1和X射线照射联合治疗的抗肿瘤疗效增加的原因，检测了S-1组分之一吉美拉西与2戈伊X射线照射联合治疗的抗肿瘤作用。这些实验表明，吉美拉西以剂量依赖性方式增强X射线照射对肺癌以及头颈癌异种移植物的功效。此外，我们观察到，与仅用X射线照射治疗的肿瘤相比，用X射线照射和吉美拉西治疗的LC-11肿瘤中γ-H2 AX蛋白（DNA修复的标志物）的表达降低，这表明吉美拉西可能抑制肿瘤中X射线诱导的DNA损伤的快速修复。目前的研究表明，使用S-1的放化疗通过一种新的机制发挥作用，并可能被证明可用于治疗局部晚期癌症患者，这些患者的疾病进展难以单独使用化疗控制。
Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin. UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a close of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dose-dependent manner. Furthermore, we observed decreased expression of gamma-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.