FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo.
FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo.
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DOI：
10.1038/sj.bjc.6605076
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发表时间：
2009-06-02
影响因子：
8.8
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中科院分区：
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本研究旨在测试通过正电子发射断层扫描（PET）测量的肿瘤[18 F]氟-D-葡萄糖（FDG）摄取是否可用作替代标记物，以定义体内mTOR抑制剂的最佳生物剂量（OBD）。将依维莫司以0.05、0.5、5和15 mg kg-1/天的剂量给予携带胃癌异种移植物的小鼠，持续23天，并使用PET从第1天至第8天测量肿瘤的FDG摄取。为了提供FDG摄取的标准比较物，评价了肿瘤体积、S6蛋白磷酸化、Ki-67染色和依维莫司血液水平。依维莫司血药浓度以剂量依赖性方式增加，但依维莫司的抗肿瘤活性在剂量≤ 5 mg kg−1/天时达到平台期（治疗组与对照组（T/C）的肿瘤体积：5 mg kg−1/天为51%，15 mg kg−1/天为57%）。相应地，每天约5 mg kg-1的剂量导致肿瘤的FDG摄取显著减少。剂量增加至5 mg kg−1/天以上，FDG摄取量不再进一步降低（FDG摄取T/C：5 mg kg−1/天为49%，15 mg kg−1/天为52%）。S6蛋白磷酸化和Ki-67指数的差异反映了肿瘤体积和FDG摄取的变化，但没有达到统计学意义。总之，FDG摄取可作为（预）临床试验中mTOR抑制剂剂量探索研究的替代标志物。
This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.