Nuclear Medicine, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Nuclear Medicine, Department of Health Sciences (DISSAL), University of Genoa, Largo R. Benzi 10, 16132, Genoa, Italy.
J Nucl Cardiol. 2020 Dec;27(6):2183-2194. doi: 10.1007/s12350-019-01618-x. Epub 2019 Feb 8.
Oxidative stress and its interference on myocardial metabolism play a major role in Doxorubicin (DXR) cardiotoxic cascade.
Mice models of neuroblastoma (NB) were treated with 5 mg DXR/kg, either free (Free-DXR) or encapsulated in untargeted (SL[DXR]) or in NB-targeting Stealth Liposomes (pep-SL[DXR] and TP-pep-SL[DXR]). Control mice received saline. FDG-PET was performed at baseline (PET1) and 7 days after therapy (PET2). At PET2 Troponin-I and NT-proBNP were assessed. Explanted hearts underwent biochemical, histological, and immunohistochemical analyses. Finally, FDG uptake and glucose consumption were simultaneously measured in cultured H9c2 in the presence/absence of Free-DXR (1 μM).
Free-DXR significantly enhanced the myocardial oxidative stress. Myocardial-SUV remained relatively stable in controls and mice treated with liposomal formulations, while it significantly increased at PET2 with respect to baseline in Free-DXR. At this timepoint, myocardial-SUV was directly correlated with both myocardial redox stress and hexose-6-phosphate-dehydrogenase (H6PD) enzymatic activity, which selectively sustain cellular anti-oxidant mechanisms. Intriguingly, in vitro, Free-DXR selectively increased FDG extraction fraction without altering the corresponding value for glucose.
The direct correlation between cardiac FDG uptake and oxidative stress indexes supports the potential role of FDG-PET as an early biomarker of DXR oxidative damage.
氧化应激及其对心肌代谢的干扰在多柔比星（DXR）心脏毒性级联反应中起着重要作用。
用 5mg DXR/kg 对神经母细胞瘤（NB）小鼠模型进行处理，处理方式为游离（Free-DXR）或包封于未靶向（SL[DXR]）或 NB 靶向隐形脂质体（pep-SL[DXR]和 TP-pep-SL[DXR]）中。对照组小鼠接受生理盐水。在基线（PET1）和治疗后 7 天（PET2）进行 FDG-PET。在 PET2 时评估肌钙蛋白 I 和 NT-proBNP。取出的心脏进行生化、组织学和免疫组织化学分析。最后，在存在/不存在游离 DXR（1μM）的情况下，同时测量培养的 H9c2 中的 FDG 摄取和葡萄糖消耗。
游离 DXR 显著增强了心肌的氧化应激。在对照组和脂质体制剂治疗的小鼠中，心肌-SUV 保持相对稳定，而在游离 DXR 治疗后，与基线相比，心肌-SUV 在 PET2 时显著增加。在此时点，心肌-SUV 与心肌氧化还原应激和己糖-6-磷酸脱氢酶（H6PD）酶活性直接相关，后者选择性维持细胞抗氧化机制。有趣的是，在体外，游离 DXR 选择性增加 FDG 提取分数，而不改变相应的葡萄糖值。
心脏 FDG 摄取与氧化应激指标之间的直接相关性支持 FDG-PET 作为 DXR 氧化损伤早期生物标志物的潜在作用。
