De Bruycker Sven, Vangestel Christel, Staelens Steven, Wyffels Leonie, Detrez Jan, Verschuuren Marlies, De Vos Winnok H, Pauwels Patrick, Van den Wyngaert Tim, Stroobants Sigrid
Molecular Imaging Center Antwerp (MICA), University of Antwerp, Universiteitsplein 1, Antwerp, 2610, Belgium.
Department of Nuclear Medicine, Antwerp University Hospital (UZA), Wilrijkstraat 10, Edegem, 2650, Belgium.
EJNMMI Res. 2019 Aug 2;9(1):74. doi: 10.1186/s13550-019-0543-4.
In a colorectal cancer xenograft model, we investigated the therapeutic effect of metformin on tumor hypoxia with [F]flortanidazole ([F]HX4) small-animal positron emission tomography (μPET). We also assessed the additive effect of metformin on long-term radiotherapy outcome and we studied the potential of [F]HX4 as a predictive and/or prognostic biomarker within this setup.
Colo205-bearing mice (n = 40) underwent a baseline [F]HX4 hypoxia μPET/computed tomography (CT) scan. The next day, mice received 100 mg/kg metformin or saline intravenously (n = 20/group) and [F]HX4 was administered intravenously 30 min later, whereupon a second μPET/CT scan was performed to assess changes in tumor hypoxia. Two days later, mice were further divided into four therapy groups (n = 10/group): control (1), metformin (2), radiotherapy (3), and metformin + radiotherapy, i.e., combination (4). Then, they received a second dose of metformin (groups 2 and 4) or saline (groups 1 and 3), followed by a single radiotherapy dose of 15 Gy (groups 3 and 4) or sham irradiation (groups 1 and 2) 30 min later. Tumor growth was followed three times a week by caliper measurements to assess the therapeutic outcome.
[F]HX4 uptake decreased in metformin-treated tumors with a mean intratumoral reduction in [F]HX4 tumor-to-background ratio (TBR) from 2.53 ± 0.30 to 2.28 ± 0.26 (p = 0.04), as opposed to saline treatment (2.56 ± 0.39 to 3.08 ± 0.39; p = 0.2). The median tumor doubling time (TDT) was 6, 8, 41, and 43 days in the control, metformin, radiotherapy and combination group, respectively (log-rank p < 0.0001), but no metformin-specific therapy effects could be detected. Baseline [F]HX4 TBR was a negative prognostic biomarker for TDT (hazard ratio, 2.39; p = 0.02).
Metformin decreased [F]HX4 uptake of Colo205-tumors, but had no additive effect on radiotherapy efficacy. Nevertheless, [F]HX4 holds promise as a prognostic imaging biomarker.
在结直肠癌异种移植模型中，我们使用[F]氟替硝唑（[F]HX4）小动物正电子发射断层扫描（μPET）研究了二甲双胍对肿瘤缺氧的治疗效果。我们还评估了二甲双胍对长期放疗结果的附加作用，并在此设置下研究了[F]HX4作为预测和/或预后生物标志物的潜力。
携带Colo205的小鼠（n = 40）接受基线[F]HX4缺氧μPET/计算机断层扫描（CT）扫描。第二天，小鼠静脉注射100 mg/kg二甲双胍或生理盐水（n = 20/组），30分钟后静脉注射[F]HX4，随后进行第二次μPET/CT扫描以评估肿瘤缺氧的变化。两天后，小鼠进一步分为四个治疗组（n = 10/组）：对照组（1）、二甲双胍组（2）、放疗组（3）和二甲双胍+放疗组，即联合组（4）。然后，它们接受第二剂二甲双胍（第2组和第4组）或生理盐水（第1组和第3组），30分钟后接受单次15 Gy的放疗剂量（第3组和第4组）或假照射（第1组和第2组）。每周用卡尺测量三次肿瘤生长情况以评估治疗效果。
二甲双胍治疗的肿瘤中[F]HX4摄取减少，[F]HX4肿瘤与背景比值（TBR）的平均瘤内降低从2.53±0.30降至2.28±0.26（p = 0.04），而生理盐水治疗则为（2.56±0.39至3.08±0.39；p = 0.2）。对照组、二甲双胍组、放疗组和联合组的肿瘤中位倍增时间（TDT）分别为6、8、41和43天（对数秩检验p < 0.0001），但未检测到二甲双胍特异性的治疗效果。基线[F]HX4 TBR是TDT的负性预后生物标志物（风险比，2.39；p = 0.02）。
二甲双胍降低了Colo205肿瘤的[F]HX4摄取，但对放疗疗效没有附加作用。尽管如此，[F]HX4有望成为一种预后成像生物标志物。
