Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.
Consuming a Ketogenic Diet while Receiving Radiation and Chemotherapy for Locally Advanced Lung Cancer and Pancreatic Cancer: The University of Iowa Experience of Two Phase 1 Clinical Trials.
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DOI：
10.1667/rr14668.1
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发表时间：
2017-06
影响因子：
3.4
通讯作者：
Allen BG
中科院分区：
文献类型：
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作者：
Zahra A;Fath MA;Opat E;Mapuskar KA;Bhatia SK;Ma DC;Rodman SN III;Snyders TP;Chenard CA;Eichenberger-Gilmore JM;Bodeker KL;Ahmann L;Smith BJ;Vollstedt SA;Brown HA;Hejleh TA;Clamon GH;Berg DJ;Szweda LI;Spitz DR;Buatti JM;Allen BG
生酮饮食（KD）是低碳水化合物和高脂肪的饮食，其迫使细胞更严重地依赖于脂肪酸的线粒体氧化来获得能量。相对于正常细胞，认为癌细胞存在于慢性线粒体氧化应激的条件下，其通过葡萄糖代谢的增加来补偿以产生还原当量。目前的研究测试了这样一种假设，即在接受同步放疗和化疗的同时服用KD在局部晚期非小细胞肺癌（NSCLC）和胰腺癌中具有临床耐受性，并且可能利用癌细胞氧化代谢来改善治疗结果。给携带MIA PaCa-2胰腺癌异种移植物的小鼠喂食KD或标准啮齿动物食物，用常规分次辐射（2戈伊/ fx）处理，并且每天评估肿瘤生长速率。评估肿瘤的免疫反应性4-羟基-2-壬烯醛-（4 HNE）修饰蛋白作为氧化应激的标志物。基于该研究和另一项先前发表的临床前研究，启动了局部晚期NSCLC和胰腺癌的I期临床试验，将标准放疗和化疗与KD（肺部6周持续时间;胰腺5周持续时间）相结合。异种移植实验表明，与单独的辐射相比，在消耗KD与辐射组合的动物中，存活期延长，4 HNE修饰的蛋白质增加。在I期临床试验中，在三年的时间内，七名NSCLC受试者入组研究。其中，4例患者无法遵守饮食并退出，2例完成研究，1例因剂量限制性毒性而退出。在同一时期，两名胰腺癌患者参加了试验。其中，1例完成了研究，另1例因剂量限制性毒性而退出研究。临床前实验证明KD增加胰腺癌异种移植模型中的辐射敏感性。然而，接受同步放疗和化疗的局部晚期NSCLC和胰腺癌受试者的口服KD依从性欠佳，因此耐受性较差。
Ketogenic diets (KD) are low in carbohydrates and high in fat which force cells to rely more heavily upon mitochondrial oxidation of fatty acids for energy. Cancer cells, relative to normal cells, are believed to exist under a condition of chronic mitochondrial oxidative stress that is compensated for by increases in glucose metabolism to generate reducing equivalents. The current study tests the hypothesis that consuming a KD while receiving concurrent radiation and chemotherapy would be clinically tolerable in locally advanced non-small cell lung (NSCLC) and pancreatic cancer and could potentially exploit cancer cell oxidative metabolism to improve therapeutic outcomes. Mice bearing MIA PaCa-2 pancreatic cancer xenografts were fed either a KD or standard rodent chow, treated with conventionally fractionated radiation (2 Gy / fx), and tumor growth rates were assessed daily. Tumors were assessed for immuno-reactive 4-hydroxy-2-nonenal-(4HNE) modified proteins as a marker of oxidative stress. Based on this and another previously published pre-clinical study, phase I clinical trials in locally advanced NSCLC and pancreatic cancer were initiated combining standard radiation and chemotherapy with a KD (lung 6 weeks duration; pancreas 5 weeks duration). Xenograft experiments demonstrated prolonged survival and increased 4HNE modified proteins in animals consuming a KD combined with radiation compared to radiation alone. In the phase I clinical trial, over a period of three years, seven NSCLC subjects enrolled in the study. Of these, four were unable to comply with the diet and withdrew, two completed the study, and one was withdrawn due to a dose limiting toxicity. Over the same time period, two pancreatic cancer patients enrolled in the trial. Of these, one completed the study and the other was withdrawn due to a dose limiting toxicity. The pre-clinical experiments demonstrate that a KD increases radiation sensitivity in a pancreatic cancer xenograft model. However, subjects with locally advanced NSCLC and pancreatic cancer receiving concurrent radiation and chemotherapy had suboptimal oral KD compliance and hence poor tolerance.