Basak Preetam, Mittal B R, Shukla Jaya, Chadha Vijayta Dani
Centre for Nuclear Medicine (UIEAST), Panjab University, Chandigarh, India.
Department of Endocrinology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.
Eur J Nucl Med Mol Imaging. 2025 Apr 23. doi: 10.1007/s00259-025-07291-2.
The present study aimed to evaluate the systemic redox status in metastatic neuroendocrine tumor (NET) patients following Lu-DOTATATE therapy and to explore the role of exosomes in communicating the redox signals in-vitro.
Levels of reactive oxygen species (ROS), enzymes associated with oxidative stress and lipid peroxidation, gene expression of oxidative stress markers (COX2, iNOS, NF-κB and SOD) were determined in peripheral blood mononuclear cells (PBMCs) and serum isolated from a total of 30 NET subjects at three time points viz.: before, 4 weeks after first and fourth cycle of Lu-DOTATATE therapy. Serum cytokine levels (IL-2, IL-6, IFN-γ, TNF-α, IL-4, IL-10 and TGF-β) were measured by ELISA. DNA damage was assessed by checking the expression of γH2AX and DNA repair genes (ATM: Ataxia-Telangiectasia Mutated and ATR: Ataxia-Telangiectasia and Rad3-related). Plasma-derived exosomes were characterized, their uptake by PBMCs was visualized and consequent ROS generation was assessed in in-vitro co-culture.
The study exhibits a significant increase in ROS level and relatively higher expression of COX2 and iNOS in PBMCs of NET patients post therapy. Serum inflammatory cytokines including IL-2, IL-6 and TNF-α were found elevated. The study did not find any change in the expression of genes associated with DNA damage. In-vitro co-culture of PBMCs (isolated before therapy) with exosomes derived after therapy exhibited significant increase in ROS as compared to control cells.
The study concludes that Lu-DOTATATE therapy alters redox status, however it does not cause DNA damage, suggestive of its safety. Further, the study demonstrates the role of exosomes in spreading of oxidative stress systemically.
本研究旨在评估镥[¹⁷⁷Lu] DOTATATE治疗后转移性神经内分泌肿瘤（NET）患者的全身氧化还原状态，并在体外探索外泌体在传递氧化还原信号中的作用。
在三个时间点测定30例NET患者外周血单个核细胞（PBMC）和血清中的活性氧（ROS）水平、与氧化应激和脂质过氧化相关的酶以及氧化应激标志物（COX2、iNOS、NF-κB和SOD）的基因表达，这三个时间点分别为：镥[¹⁷⁷Lu] DOTATATE治疗前、第一个周期和第四个周期治疗后4周。通过酶联免疫吸附测定法（ELISA）检测血清细胞因子水平（IL-2、IL-6、IFN-γ、TNF-α、IL-4、IL-10和TGF-β）。通过检查γH2AX和DNA修复基因（ATM：共济失调毛细血管扩张突变基因和ATR：共济失调毛细血管扩张症和Rad3相关基因）的表达来评估DNA损伤。对血浆来源的外泌体进行表征，观察其被PBMC摄取的情况，并在体外共培养中评估随后产生的ROS。
研究显示治疗后NET患者PBMC中的ROS水平显著升高，COX2和iNOS的表达相对较高。发现包括IL-2、IL-6和TNF-α在内的血清炎性细胞因子升高。研究未发现与DNA损伤相关的基因表达有任何变化。与对照细胞相比，治疗前分离的PBMC与治疗后获得的外泌体进行体外共培养时，ROS显著增加。
该研究得出结论，镥[¹⁷⁷Lu] DOTATATE治疗会改变氧化还原状态，但不会导致DNA损伤，表明其安全性。此外，该研究证明了外泌体在全身传播氧化应激中的作用。
