From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
Circ Cardiovasc Imaging. 2015 Feb;8(2):e001952. doi: 10.1161/CIRCIMAGING.114.001952.
Anthracycline-induced cardiotoxicity and myocardial dysfunction may be associated with apoptosis. Caspase 3 catalyzes a terminal step in apoptosis, and its expression may serve as a marker of cardiomyocyte apoptosis. We synthesized 18F-CP18, a caspase-3 substrate and evaluated cardiac 18F-CP18 uptake in a mouse model of anthracycline cardiotoxicity.
For 12 weeks, mice were injected with doxorubicin, 3 mg/kg/week, or vehicle (control). Left ventricular fractional shortening was quantified by echocardiography. CP18 uptake after intravenous injection of 250 μCi of 18F-CP18, 24 hours post-doxorubicin treatment was quantified by microPET, autoradiography, and gamma counting. Apoptosis was assessed by enzymatic assay of myocardial caspase 3 and TUNEL staining of tissue sections. Compared with controls, at 6 and 12 weeks of doxorubicin treatment, fractional shortening was reduced (20.7%±2.5% versus 31%±3.5%, P=0.010; and 20.3%±3.1% versus 32.4%±2.1%, P=0.011). Doxorubicin treatment was associated with increased 18F-CP18 uptake in %ID/g by gamma counting from 0.36±0.01 (week 1) to 0.78±0.01 (week 12), P=0.003. A similar increase in 18F-CP18 uptake was observed by microPET (0.41±0.04 versus 0.73±0.1, P=0.014) and autoradiography (1.1±0.3 versus 2.8±0.2 P=0.001). Caspase 3 enzymatic activity and apoptosis by TUNEL staining were also increased after 12 weeks of doxorubicin compared with weeks 1 and 3. CP18 uptake in controls was relatively unchanged at weeks 1, 3, and 12.
In a mouse model of cardiotoxicity, doxorubicin treatment is associated with increased myocardial caspase 3 expression and an increase in CP18 uptake. 18F-CP18 may be useful for detection of anthracycline-induced myocardial apoptosis.
蒽环类药物诱导的心脏毒性和心肌功能障碍可能与细胞凋亡有关。半胱天冬酶 3 催化细胞凋亡的终末步骤，其表达可以作为心肌细胞凋亡的标志物。我们合成了 18F-CP18，一种半胱天冬酶 3 的底物，并在蒽环类药物心脏毒性的小鼠模型中评估了心脏 18F-CP18 的摄取。
12 周内，小鼠每周注射多柔比星 3mg/kg 或载体（对照）。通过超声心动图定量左心室缩短分数。在多柔比星治疗后 24 小时，通过 microPET、放射自显影和伽马计数定量静脉注射 250μCi 18F-CP18 后的 CP18 摄取。通过心肌半胱天冬酶 3 的酶促测定和组织切片的 TUNEL 染色评估细胞凋亡。与对照组相比，在多柔比星治疗 6 周和 12 周时，缩短分数降低（20.7%±2.5%对 31%±3.5%，P=0.010；20.3%±3.1%对 32.4%±2.1%，P=0.011）。多柔比星治疗与 γ 计数的 18F-CP18 摄取增加有关，从 0.36±0.01（第 1 周）增加到 0.78±0.01（第 12 周），P=0.003。microPET（0.41±0.04 对 0.73±0.1，P=0.014）和放射自显影（1.1±0.3 对 2.8±0.2，P=0.001）也观察到 18F-CP18 摄取的类似增加。与第 1 周和第 3 周相比，多柔比星治疗 12 周后，半胱天冬酶 3 的酶活性和 TUNEL 染色的细胞凋亡也增加。对照组在第 1 周、第 3 周和第 12 周时 CP18 的摄取没有明显变化。
在心脏毒性的小鼠模型中，多柔比星治疗与心肌半胱天冬酶 3 表达增加和 CP18 摄取增加有关。18F-CP18 可能对检测蒽环类药物诱导的心肌细胞凋亡有用。
