18F-FAZA PET Imaging Response Tracks the Reoxygenation of Tumors in Mice upon Treatment with the Mitochondrial Complex I Inhibitor BAY 87-2243
18F-FAZA PET Imaging Response Tracks the Reoxygenation of Tumors in Mice upon Treatment with the Mitochondrial Complex I Inhibitor BAY 87-2243
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DOI：
10.1158/1078-0432.ccr-14-0217
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发表时间：
2015-01-15
影响因子：
11.5
通讯作者：
Gambhir, Sanjiv S.
中科院分区：
文献类型：
--
作者：
Chang, Edwin;Liu, Hongguang;Gambhir, Sanjiv S.
目的：我们描述了一种无创 PET 成像方法，用于监测 BAY 87-2243 的早期治疗效果，BAY 87-2243 是一种新型线粒体复合物 I 小分子抑制剂，作为缺氧诱导因子 1α (HIF1α) 活性的函数。实验设计：评估四种 PET 示踪剂 [18F-FDG、18F-Fpp(RGD)2、18F-FLT 和 18F-FAZA] 的吸收情况药物反应性（H460、PC3）或耐药性（786-0）癌细胞的肿瘤异种移植物。用 BAY 87-2243 或媒介物治疗小鼠。在每个点，分离来自经处理的H460肿瘤异种移植物和载体H460肿瘤异种移植物（每个n=3）的RNA并分析靶基因。结果：BAY 87-2243处理时18F-FAZA、18F-FLT和18F-Fpp(RGD)2的摄取发生显着变化（P<0.01），其中18F-FAZA最为突出。 18F-FDG摄取是不受影响。给药后 1 至 3 天，H460 (P< 0.001) 和 PC3 (P< 0.05) 异种移植物中 18F-FAZA 肿瘤摄取下降 55% 至 70%（1.21% ± 0.10%ID/g 至 0.35 ± 0.1%ID/g；n= 6，媒介物与治疗）。 18F-FAZA 786-0 异种移植物中的摄取不受影响。下降发生在肿瘤体积显着差异之前，因此表明 18 F-FAZA 下降反映了肿瘤代谢的早期变化。 BAY 87-2243使缺氧调节基因CA IX、ANGPTL4和EGLN-3的表达分别降低99%、93%和83%（全部P＜0.001），这与药物治疗后减少的 18 F-FAZA摄取相对应。观察到与葡萄糖代谢、血管密度和增殖相关的基因的异质表达。 结论：我们的研究表明 18 F-FAZA-PET 适合作为早期药效学监测器，用于监测靶向线粒体复合物 I 和肿瘤内氧水平的抗癌药物（例如 BAY 87-2243）的功效。 21(2)； 335–46。 ©2014 AACR。
Purpose:We describe a noninvasive PET imaging method that monitors early therapeutic efficacy of BAY 87-2243, a novel small-molecule inhibitor of mitochondrial complex I as a function of hypoxia-inducible factor-1α (HIF1α) activity.Experimental Design:Four PET tracers [18F-FDG,18F-Fpp(RGD)2,18F-FLT, and18F-FAZA] were assessed for uptake into tumor xenografts of drug-responsive (H460, PC3) or drug-resistant (786-0) carcinoma cells. Mice were treated with BAY 87-2243 or vehicle. At each point, RNA from treated and vehicle H460 tumor xenografts (n= 3 each) was isolated and analyzed for target genes.Results:Significant changes in uptake of18F-FAZA,18F-FLT, and18F-Fpp(RGD)2(P< 0.01) occurred with BAY 87-2243 treatment with18F-FAZA being the most prominent.18F-FDG uptake was unaffected.18F-FAZA tumor uptake declined by 55% to 70% (1.21% ± 0.10%ID/g to 0.35 ± 0.1%ID/g;n= 6, vehicle vs. treatment) in both H460 (P< 0.001) and PC3 (P< 0.05) xenografts 1 to 3 days after drug administration.18F-FAZA uptake in 786-0 xenografts was unaffected. Decline occurred before significant differences in tumor volume, thus suggesting18F-FAZA decrease reflected early changes in tumor metabolism. BAY 87-2243 reduced expression of hypoxia-regulated genesCA IX,ANGPTL4, andEGLN-3by 99%, 93%, and 83%, respectively (P< 0.001 for all), which corresponds with reduced18F-FAZA uptake upon drug treatment. Heterogeneous expression of genes associated with glucose metabolism, vessel density, and proliferation was observed.Conclusions:Our studies suggest suitability of18F-FAZA-PET as an early pharmacodynamic monitor on the efficacy of anticancer agents that target the mitochondrial complex I and intratumor oxygen levels (e.g., BAY 87-2243).Clin Cancer Res; 21(2); 335–46. ©2014 AACR.