Monitoring Mitochondrial Complex-I Activity Using Novel PET Probe 18F-BCPP-EF Allows Early Detection of Radiotherapy Effect in Murine Squamous Cell Carcinoma.
Monitoring Mitochondrial Complex-I Activity Using Novel PET Probe 18F-BCPP-EF Allows Early Detection of Radiotherapy Effect in Murine Squamous Cell Carcinoma.
复制标题
使用新型PET探针18F-BCPP-EF监测线粒体复合物I活性，可以尽早检测到鼠鳞状细胞癌中放射疗法的效应。
DOI：
10.1371/journal.pone.0170911
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Tsukada H
中科院分区：
文献类型：
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作者：
Murayama C;Kawaguchi AT;Kamijo A;Naito K;Kanazawa M;Tsukada H
有氧糖酵解是肿瘤能量产生的主要途径(Warburg效应)，通过使用18F-氟-2-脱氧-D-葡萄糖(18F-FDG)的正电子发射断层扫描(PET)可以检测到肿瘤。由于电离辐射(IR)被报道可将有氧糖酵解转换为线粒体氧化磷酸化，使用新的正电子发射计算机断层扫描探针18F-BCPP-EF，18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy]-吡啶-3-甲氧基-2H-哒嗪-3-酮，通过18F-脱氧葡萄糖摄取和细胞凋亡指数来监测放射治疗的疗效。采用0、6、15、30GyX射线单次照射，观察接种小鼠鳞状细胞癌SCCVII的C3H/HEN小鼠肿瘤对18F-BCPP-EF或18F-FDG的摄取。采用原位末端标记法检测切除肿瘤组织中的细胞凋亡率。肿瘤生长抑制呈剂量依赖性，治疗后第14天，肿瘤体积分别增加10倍(0Gy0)、5倍(6Gy3)、2倍(15Gy)，体积缩小一半(30Gy2)。18F-BCPP-EF对18F-BCPP-EF的摄取在15Gy3d和30Gy3d时显著增加，此时肿瘤大小和细胞凋亡指数在不同照射剂量之间无明显差异。相反，18F-FDG摄取率最初呈剂量依赖性增加，持续到7天，最后在30Gy10天和15Gy14天后下降，此时肿瘤大小已经缩小。细胞凋亡指数在照射后有所增加，但与肿瘤反应无关。肿瘤对18F-BCPP-EF的摄取在有效剂量IR后早期呈剂量依赖性增加，而18F-FDG摄取和细胞凋亡率不能作为肿瘤反应的指标。结果表明，18F-BCPP-EF是一种有希望的“阳性”的MC-I成像PET探针，可用于肿瘤放疗疗效的早期检测。
Aerobic glycolysis, the main pathway of energy production in tumors (Warburg effect) allows detection of tumors by positron emission tomography (PET) using 18F-fluoro-2-deoxy-D-glucose (18F-FDG). Since ionizing radiation (IR) is reported to switch aerobic glycolysis to mitochondrial oxidative phosphorylation, radiotherapeutic efficacy was monitored by the activity of mitochondrial complex I (MC-I), using a new PET probe 18F-BCPP-EF, 18F-2-tert-butyl-4-chloro-5-{6-[2-(2-fluoro-ethoxy)-ethoxy] -pyridine-3-ylmethoxy}-2H-pyridazin-3-one, compared with 18F-FDG uptake and the apoptosis index. Tumor uptake of 18F-BCPP-EF or 18F-FDG was examined in C3H/HeN mice inoculated with murine squamous cell carcinoma SCCVII at various time points after a single dose of x-ray irradiation at 0, 6, 15, or 30 Gy. Apoptosis incidence was determined by TUNEL staining in excised tumor tissue. Tumor growth suppression was dose-dependent; tumor grew 10-fold (0 Gy), 5-fold (6 Gy), 2-fold (15 Gy), and reduced to half in its volume (30 Gy) 14 days after treatment. 18F-BCPP-EF uptake was significantly increased as early as 3 days after 15 Gy or 30 Gy, when tumor size and apoptosis index showed no difference among radiation doses. In contrast, 18F-FDG uptake was initially increased dose-dependently, remained elevated up to 7 days, and eventually decreased 10 days after 30 Gy and also 14 days after 15 Gy when tumor size was already reduced. Apoptosis index was increased after irradiation but failed to correlate with tumor response. Tumor uptake of 18F-BCPP-EF was increased dose-dependently early after effective doses of IR when 18F-FDG uptake as well as apoptosis incidence were not indicative of tumor response. The results suggest that 18F-BCPP-EF is a promising “positive” MC-I imaging PET probe for early detection of efficacy of tumor radiotherapy.