The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization
The combination of hyperthermia or chemotherapy with gimeracil for effective radiosensitization
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DOI：
10.1007/s00066-011-0043-6
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发表时间：
2012-03-01
影响因子：
3.1
通讯作者：
Fukushima, M.
中科院分区：
文献类型：
--
作者：
Takagi, M.;Sakata, K.;Fukushima, M.
目的. 5-氯-2，4-二羟基吡啶（吉美嘧啶）是口服氟嘧啶衍生物S-1的组分。吉美拉西最初加入S-1中，通过抑制降解5-FU的二氢嘧啶脱氢酶，延长血清和肿瘤组织中5-FU的浓度。我们先前证明吉美拉西通过抑制DNA双链修复中的同源重组（HR）来增强放射治疗的疗效。本文的目的是研究吉美拉西对抗癌药物和热疗敏感性的影响，以获得有效的放射增敏。在克隆形成测定中使用各种细胞系，包括DLD 1（人结肠癌细胞）和HR或非同源末端连接（NHEJ）缺陷的细胞。这些细胞在各种处理（例如，药物处理、热处理和辐射）基于它们的集落形成能力来确定。吉美嘧啶增强喜树碱（CPT）、5-FU和羟基脲的细胞杀伤作用。CPT或5-FU对HR或NHEJ缺陷细胞的致敏作用与其他细胞（DLD 1和亲本细胞）相似，表明其致敏机制可能不同于HR或NHEJ抑制。吉美拉西联合CPT或5-FU敏化放射比单独使用每种方式更有效。吉美拉西还增强了在42摄氏度或更高温度下的热敏性。随着温度的升高，吉美拉西的热致敏程度增加，吉美拉西与热致敏辐射联合应用比单独应用更有效。吉美嘧啶增强CPT、5-FU和热疗的敏感性。这些方式的组合比单独使用每种方式更有效地敏化辐射。
Purpose. 5-chloro-2,4-dihydroxypyridine (gimeracil) is a component of the oral fluoropyrimidine derivative S-1. Gimeracil was originally added to S-1 to yield prolonged 5-fluorouracil (5-FU) concentrations in serum and tumor tissues by inhibiting dihydropyrimidine dehydrogenase, which degrades 5-FU. We previously demonstrated that gimeracil enhances the efficacy of radiotherapy through the suppression of homologous recombination (HR) in DNA double strand repair. The goal of this paper was to examine the effects of gimeracil on the sensitivity of anticancer drugs and hyperthermia in order to obtain effective radiosensitization.Materials and methods. Various cell lines, including DLD 1 (human colon carcinoma cells) and cells deficient in HR or nonhomologous end-joining (NHEJ), were used in clonogenic assays. The survival of these cells after various treatments (e.g., drug treatment, heat treatment, and radiation) was determined based on their colony-forming ability.Results. Gimeracil enhanced cell-killing effects of camptothecin (CPT), 5-FU, and hydroxyurea. Gimeracil sensitized effects of CPT or 5-FU to cells deficient in HR or NHEJ to a similar extent as in other cells (DLD1 and a parent cell), indicating that its sensitizing mechanisms may be different from inhibition of HR or NHEJ. Combination of gimeracil and CPT or 5-FU sensitized radiation more effectively than each modality alone. Gimeracil also enhanced heat sensitivity at 42 degrees C or more. The degree of heat sensitization with gimeracil increased as the temperature increased, and the combination of gimeracil and heat-sensitized radiation was more effective than each modality alone.Conclusion. Gimeracil enhanced sensitivity of CPT, 5-FU, and hyperthermia. Combination of these modalities sensitized radiation more efficiently than each modality alone.