用[Lu]Lu-DOTATATE 研究肽受体放射性核素治疗中内在放射敏感性生物标志物在一系列癌细胞系中的应用。
Investigating intrinsic radiosensitivity biomarkers to peptide receptor radionuclide therapy with [Lu]Lu-DOTATATE in a panel of cancer cell lines.
机构信息
Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium; Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
Nuclear Medicine Department, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium.
出版信息
Nucl Med Biol. 2021 May-Jun;96-97:68-79. doi: 10.1016/j.nucmedbio.2021.03.006. Epub 2021 Mar 27.
INTRODUCTION
[Lu]Lu-DOTATATE is an effective systemic targeted radionuclide therapy for somatostatin receptor (SSTR) positive metastatic or inoperable neuroendocrine tumours (NET). However, for a given injected activity, tumour responses are variable. Our aim was to investigate whether SSTR expression/functionality and known characteristics of intrinsic radiosensitivity, namely proliferation rate, glucose metabolism, cell cycle phase, DNA repair and antioxidant defences were predictors of sensitivity to [Lu]Lu-DOTATATE in SSTR expressing human cancer cell lines.
METHODS
In six human cancer cell lines and under basal condition, SSTR expression was assessed by qRT-PCR and immunocytochemistry. Its functionality was evaluated by binding/uptake assays with [Ga]Ga- and [Lu]Lu-DOTATATE. The radiosensitivity parameters were evaluated as follows: proliferation rate (cell counting), glucose metabolism ([F]FDG uptake), antioxidant defences (qRT-PCR, colorimetric assay, flow cytometry), DNA repair (qRT-PCR) and cell cycle (flow cytometry). Effect of [Lu]Lu-DOTATATE on cell viability was assessed 3, 7 and 10 days after 4 h incubation with [Lu]Lu-DOTATATE using crystal violet.
RESULTS
Based on cell survival at day 10, cell lines were classified into two groups of sensitivity to [Lu]Lu-DOTATATE. One group with <20% of survival decrease (-14 to -1%) and one group with >20% of survival decrease (-22 to -33%) compared to the untreated control cell lines. The latter had significantly lower total antioxidant capacity, glutathione (GSH) levels and glucose metabolism (p < 0.05) compared to the first group. SSTR (p = 0.64), proliferation rate (p = 0.74), cell cycle phase (p = 0.55), DNA repair (p > 0.22), combined catalase and GSH peroxidase expression (p = 0.42) and superoxide dismutase (SOD) activity (p = 0.41) were not significantly different between the two groups.
CONCLUSION
Antioxidant defences may be major determinants in [Lu]Lu-DOTATATE radiosensitivity.
简介
[Lu]Lu-DOTATATE 是一种有效的全身靶向放射性核素疗法，可用于治疗生长抑素受体（SSTR）阳性的转移性或不可手术的神经内分泌肿瘤（NET）。然而，对于给定的注入活动，肿瘤反应是可变的。我们的目的是研究 SSTR 表达/功能以及内在放射敏感性的已知特征（即增殖率、葡萄糖代谢、细胞周期阶段、DNA 修复和抗氧化防御）是否可预测 SSTR 表达的人类癌细胞系对[Lu]Lu-DOTATATE 的敏感性。
方法
在六种人类癌细胞系中，并在基础条件下，通过 qRT-PCR 和免疫细胞化学评估 SSTR 表达。通过结合/摄取实验用[Ga]Ga-和[Lu]Lu-DOTATATE 评估其功能。通过以下方法评估放射敏感性参数：增殖率（细胞计数）、葡萄糖代谢（[F]FDG 摄取）、抗氧化防御（qRT-PCR、比色法、流式细胞术）、DNA 修复（qRT-PCR）和细胞周期（流式细胞术）。用结晶紫评估[Lu]Lu-DOTATATE 在 4 小时孵育后 3、7 和 10 天对细胞活力的影响。
结果
根据第 10 天的细胞存活率，将细胞系分为两组对[Lu]Lu-DOTATATE 的敏感性。一组存活率降低<20%（-14%至-1%），一组存活率降低>20%（-22%至-33%）与未处理的对照细胞系相比。后者的总抗氧化能力、谷胱甘肽（GSH）水平和葡萄糖代谢明显低于第一组（p < 0.05）。SSTR（p = 0.64）、增殖率（p = 0.74）、细胞周期阶段（p = 0.55）、DNA 修复（p > 0.22）、过氧化氢酶和谷胱甘肽过氧化物酶表达的组合（p = 0.42）和超氧化物歧化酶（SOD）活性（p = 0.41）在两组之间无显著差异。
结论
抗氧化防御可能是[Lu]Lu-DOTATATE 放射敏感性的主要决定因素。
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