Molecular Imaging Center Antwerp (MICA), University of Antwerp, Wilrijk, Belgium.
Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium; and.
J Nucl Med. 2019 Jan;60(1):34-40. doi: 10.2967/jnumed.118.212225. Epub 2018 Jul 6.
Metformin may improve tumor oxygenation and thus radiotherapy response, but imaging biomarkers for selection of suitable patients are still under investigation. First, we assessed the effect of acute metformin administration on non-small cell lung cancer xenograft tumor hypoxia using PET imaging with the hypoxia tracer F-flortanidazole. Second, we verified the effect of a single dose of metformin before radiotherapy on long-term treatment outcome. Third, we examined the potential of baseline F-flortanidazole as a prognostic or predictive biomarker for treatment response. A549 tumor-bearing mice underwent a F-flortanidazole PET/CT scan to determine baseline tumor hypoxia. The next day, mice received a 100 mg/kg intravenous injection of metformin. F-flortanidazole was administered intravenously 30 min later, and a second PET/CT scan was performed to assess changes in tumor hypoxia. Two days later, the mice were divided into 3 therapy groups: controls (group 1), radiotherapy (group 2), and metformin + radiotherapy (group 3). Animals received saline (groups 1-2) or metformin (100 mg/kg; group 3) intravenously, followed by a single radiotherapy dose of 10 Gy (groups 2-3) or sham irradiation (group 1) 30 min later. Tumor growth was monitored triweekly by caliper measurement, and tumor volume relative to baseline was calculated. The tumor doubling time (TDT), that is, the time to reach twice the preirradiation tumor volume, was defined as the endpoint. Thirty minutes after metformin treatment, F-flortanidazole demonstrated a significant change in tumor hypoxia, with a mean intratumoral reduction in F-flortanidazole tumor-to-background ratio (TBR) from 3.21 ± 0.13 to 2.87 ± 0.13 ( = 0.0001). Overall, relative tumor volume over time differed across treatment groups ( < 0.0001). Similarly, the median TDT was 19, 34, and 52 d in controls, the radiotherapy group, and the metformin + radiotherapy group, respectively (log-rank < 0.0001). Both baseline F-flortanidazole TBR (hazard ratio, 2.0; = 0.0004) and change from baseline TBR (hazard ratio, 0.39; = 0.04) were prognostic biomarkers for TDT irrespective of treatment, and baseline TBR predicted metformin-specific treatment effects that were dependent on baseline tumor hypoxia. Using F-flortanidazole PET imaging in a non-small cell lung cancer xenograft model, we showed that metformin may act as a radiosensitizer by increasing tumor oxygenation and that baseline F-flortanidazole shows promise as an imaging biomarker.
二甲双胍可能通过改善肿瘤氧合作用从而提高放疗的效果，但用于选择合适患者的影像学生物标志物仍在研究中。首先，我们使用缺氧示踪剂 F-氟替唑胺通过 PET 成像评估了急性二甲双胍给药对非小细胞肺癌异种移植肿瘤缺氧的影响。其次，我们验证了放疗前单次给予二甲双胍对长期治疗结果的影响。第三，我们研究了基线 F-氟替唑胺作为治疗反应的预后或预测生物标志物的潜力。A549 荷瘤小鼠进行 F-氟替唑胺 PET/CT 扫描以确定基线肿瘤缺氧。次日，小鼠接受 100 mg/kg 的静脉注射二甲双胍。30 分钟后静脉给予 F-氟替唑胺，进行第二次 PET/CT 扫描以评估肿瘤缺氧的变化。两天后，将小鼠分为 3 个治疗组：对照组（第 1 组）、放疗组（第 2 组）和二甲双胍+放疗组（第 3 组）。动物接受生理盐水（第 1-2 组）或二甲双胍（100 mg/kg；第 3 组）静脉注射，30 分钟后接受单次 10 Gy 的放疗（第 2-3 组）或假照射（第 1 组）。每周通过卡尺测量监测肿瘤生长，并计算肿瘤体积相对于基线的变化。肿瘤倍增时间（TDT），即达到放疗前肿瘤体积两倍所需的时间，定义为终点。 二甲双胍治疗 30 分钟后，F-氟替唑胺显示肿瘤缺氧发生显著变化，肿瘤内 F-氟替唑胺肿瘤与背景的比值（TBR）平均从 3.21 ± 0.13 降至 2.87 ± 0.13（ = 0.0001）。总体而言，随时间推移，各组间的相对肿瘤体积存在差异（ < 0.0001）。同样，对照组、放疗组和二甲双胍+放疗组的中位 TDT 分别为 19、34 和 52 d（对数秩检验 < 0.0001）。基线 F-氟替唑胺 TBR（风险比，2.0； = 0.0004）和基线 TBR 变化（风险比，0.39； = 0.04）均为 TDT 的预后生物标志物，与治疗无关，并且基线 TBR 预测了依赖于基线肿瘤缺氧的二甲双胍特异性治疗效果。 在非小细胞肺癌异种移植模型中使用 F-氟替唑胺 PET 成像，我们表明二甲双胍可能通过增加肿瘤氧合作用而发挥放射增敏作用，并且基线 F-氟替唑胺显示出作为成像生物标志物的潜力。
