Department of Preclinical Imaging and Radiopharmacy, Laboratory for Preclinical Imaging and Imaging Technology of the Werner Siemens-Foundation, Eberhard Karls University Tübingen, Tübingen, Germany.
Mol Imaging Biol. 2013 Apr;15(2):203-11. doi: 10.1007/s11307-012-0580-0.
Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) versus 3'-deoxy-3'-18F-fluorothymidine ([(18)F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET.
The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96 h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels.
BAY 853474 significantly reduces tumor growth. [(18)F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [(18)F]FLT uptake in the tumor tissue was completely absent 96 h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals.
These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.
本研究描述了新型小分子 c-Met 抑制剂 BAY 853474 抑制 Hs746T 胃癌异种移植模型肿瘤生长的疗效，并通过小动物 PET 检测 2-脱氧-2-[(18)F]氟-D-葡萄糖 ([(18)F]FDG)与 3'-脱氧-3'-18F-氟胸苷 ([(18)F]FLT)在胃癌异种移植小鼠模型中用于反应监测的适用性。
在荷瘤小鼠中以不同剂量口服给予 c-Met 抑制剂或载体对照。在首次治疗后 48 和 96 小时，使用 PET 测量葡萄糖摄取和增殖。将 PET 数据与肿瘤生长曲线、放射性自显影、肿瘤切片 Glut-1 和 Ki-67 染色以及组织探针（即 c-Met 和 ERK 磷酸化以及细胞周期蛋白 D1 水平）的生化分析数据进行比较。
BAY 853474 显著抑制肿瘤生长。与对照组相比，接受药物治疗的 Hs746T 肿瘤的 [(18)F]FDG 摄取显著降低。治疗后 96 小时，肿瘤组织中的 [(18)F]FLT 摄取完全消失。放射性自显影、免疫组织化学和生化分析证实了 PET 发现。c-Met 抑制剂治疗未影响体重或血糖水平，且动物未观察到不良反应。
这些临床前研究结果表明，临床 PET 成像可作为临床研究中早期反应监测的有用工具。
