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Metformin as an Alternative Radiosensitizing Agent to 5FU During Neoadjuvant Treatment for Rectal Cancer.

二甲双胍作为直肠癌新辅助治疗期间 5FU 的替代放射增敏剂。

  • 影响因子:2.60
  • DOI:10.1097/DCR.0000000000001626
  • 作者列表:"Fernandes JM","Jandrey EHF","Koyama FC","Leite KRM","Camargo AA","Costa ÉT","Perez RO","Asprino PF
  • 发表时间:2020-03-30
Abstract

BACKGROUND:Neoadjuvant chemoradiation for locally advanced rectal cancer combining 5FU to radiation increases tumor regression compared to radiation alone. However, it occurs at the cost of significant treatment-related toxicity. Patients with rectal cancer using metformin have been associated with improved response to radiotherapy. OBJECTIVE:To evaluate the radiosensitizing effects of metformin in vitro and in vivo and compare it to standard combination of radiation/5FU. DESIGN:Colorectal cancer cell lines SW480, HT29, and HCT116 were used as models. Cell viability was compared under treatments with radiation, radiation/5FU, metformin, radiation/metformin, and radiation/5FU/metformin. Nude mice were injected subcutaneously with SW480 cells and treated for one week with radiation/5FU, metformin, radiation/metformin or radiation/5FU/metformin. Tumor volume was evaluated for 4 weeks after treatment completion. The phosphorylation status of key proteins of the PI3K/Akt/mTOR pathway was determined by immunoblots. SETTINGS:Experimental study in vitro and in vivo. PATIENTS:Animal model/cell lines. MAIN OUTCOME MEASURES:The end point was to investigate how metformin compares to 5FU as a radiosensitizer. RESULTS:All cell lines significantly decreased cell viability after treatment with radiation/metformin when compared to radiation alone. Radiation/metformin was superior to radiation/5FU in SW480 (37% vs 74%; p<0.001). In HT29 and in HCT116 radiation/metformin was inferior to radiation/5FU (40%vs13.8%, p<0.001 and 40%vs7%, p<0.001; respectively), mainly due to increased 5FU toxicity (≤20% of cell viability). In vivo assays indicated that radiation/metformin treatment was comparable to radiation/5FU (557vs398mm, p>0.05), and that the addition of metformin to the standard radiation/5FU did not improve tumor response (349mm, p>0.05). Metformin exerted strong PI3K/Akt/mTOR pathway inactivation effects after 24-hour exposure (increasing pAMPK p<0.01, decreasing pAkt, p<0.01; and pS6, p<0.05). LIMITATIONS:In vitro and in vivo CRT regimens cannot be directly translated to human delivery methods. CONCLUSIONS:Metformin enhances tumor response to radiation in vitro and in vivo. Metformin is an attractive alternative radiosensitizing agent to be considered in future studies/trials. See Video Abstract at http://links.lww.com/DCR/B219.

摘要

背景: 与单纯放疗相比,局部晚期直肠癌新辅助放化疗联合 5FU 放疗可增加肿瘤消退。然而,它的发生是以显著的治疗相关毒性为代价的。直肠癌患者使用二甲双胍与放疗反应改善相关。 目的: 评价二甲双胍的体内外放射增敏作用,并与放射/5FU 标准组合进行比较。 设计: 以结直肠癌细胞系 SW480 、 HT29 和 HCT116 为模型。比较放射、放射/5FU 、二甲双胍、放射/二甲双胍和放射/5FU/二甲双胍处理下的细胞活力。裸鼠皮下注射 SW480 细胞,用放射/5FU 、二甲双胍、放射/二甲双胍或放射/5FU/二甲双胍治疗一周。治疗完成后评估肿瘤体积 4 周。通过免疫印迹确定 PI3K/Akt/mTOR 通路关键蛋白的磷酸化状态。 设置: 体外和体内实验研究。 患者: 动物模型/细胞系。 主要观察指标: 终点是研究二甲双胍与 5FU 作为放射增敏剂的比较。 结果: 与单纯放疗相比,放疗/二甲双胍处理后,所有细胞系均显著降低细胞存活率。SW480 中放疗/二甲双胍优于放疗/5FU (37% vs 74%; p<0.001)。在 HT29 和 HCT116 辐射/二甲双胍低于辐射/5FU (分别为 40% vs13.8 %,p<0.001 和 40% vs7 %,p<0.001),主要是由于增加了 5FU 毒性 (≤ 20% 的细胞活力)。体内试验表明,辐射/二甲双胍治疗与辐射/5FU 相当 (557vs398mm,p>0.05),在标准放疗/5FU 基础上加用二甲双胍未改善肿瘤反应 (349毫米,p>0.05)。二甲双胍在暴露 24 小时后发挥了强烈的 PI3K/Akt/mTOR 通路失活作用 (增加 pAMPK p<0.01,降低 pAkt,p<0.01; 和 pS6,p<0.05)。 局限性: 体外和体内 CRT 方案不能直接转化为人类给药方法。 结论: 二甲双胍在体外和体内增强肿瘤对辐射的反应。二甲双胍是未来研究/试验中考虑的有吸引力的替代放射增敏剂。请参阅视频摘要 http://links.lww.com/DCR/B219 。

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DOI:10.1080/09553002.2020.1721609
作者列表:["Anuja K","Kar M","Chowdhury AR","Shankar G","Padhi S","Roy S","Akhter Y","Rath AK","Banerjee B"]

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影响因子:2.69
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DOI:10.1016/j.bbrc.2020.01.048
作者列表:["Li Y","Wang Z","Jin J","Zhu SX","He GQ","Li SH","Wang J","Cai Y"]

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影响因子:2.46
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DOI:10.1097/COC.0000000000000609
作者列表:["Appelt AL","Andersen RF","Lindebjerg J","Jakobsen A"]

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