Romiani A, Simonsson K, Pettersson D, Al-Awar A, Rassol N, Bakr H, Lind D E, Umapathy G, Spetz J, Palmer R H, Hallberg B, Helou K, Forssell-Aronsson E
Department of Medical Radiation Sciences, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Sahlgrenska Center for Cancer Research, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Heliyon. 2024 May 18;10(10):e31409. doi: 10.1016/j.heliyon.2024.e31409. eCollection 2024 May 30.
Patients with high-risk neuroblastoma (NB) have a 5-year event-free survival of less than 50 %, and novel and improved treatment options are needed. Radiolabeled somatostatin analogs (SSTAs) could be a treatment option. The aims of this work were to compare the biodistribution and the therapeutic effects of Lu-octreotate and Lu-octreotide in mice bearing the human CLB-BAR NB cell line, and to evaluate their regulatory effects on apoptosis-related genes.
The biodistribution of Lu-octreotide in mice bearing CLB-BAR tumors was studied at 1, 24, and 168 h after administration, and the absorbed dose was estimated to tumor and normal tissues. Further, animals were administered different amounts of Lu-octreotate or Lu-octreotide. Tumor volume was measured over time and compared to a control group given saline. RNA was extracted from tumors, and the expression of 84 selected genes involved in apoptosis was quantified with qPCR.
The activity concentration was generally lower in most tissues for Lu-octreotide compared to Lu-octreotate. Mean absorbed dose per administered activity to tumor after injection of 1.5 MBq and 15 MBq was 0.74 and 0.03 Gy/MBq for Lu-octreotide and 2.9 and 0.45 Gy/MBq for Lu-octreotate, respectively. Lu-octreotide treatment resulted in statistically significant differences compared to controls. Fractionated administration led to a higher survival fraction than after a single administration. The pro-apoptotic genes , , and were regulated after administration with Lu-octreotate. Treatment with Lu-octreotide yielded regulation of the pro-apoptotic genes and , and of the anti-apoptotic gene as well as the apoptosis-related gene .
Lu-octreotide gave somewhat better anti-tumor effects than Lu-octreotate. The similar effect observed in the treated groups with Lu-octreotate suggests saturation of the somatostatin receptors. Pronounced anti-tumor effects following fractionated administration merited receptor saturation as an explanation. The gene expression analyses suggest apoptosis activation through the extrinsic pathway for both radiopharmaceuticals.
高危神经母细胞瘤（NB）患者的5年无事件生存率低于50%，因此需要新的和改进的治疗方案。放射性标记的生长抑素类似物（SSTAs）可能是一种治疗选择。本研究的目的是比较177Lu-奥曲肽和177Lu-奥曲核苷酸在携带人CLB-BAR NB细胞系的小鼠体内的生物分布和治疗效果，并评估它们对凋亡相关基因的调控作用。
在给药后1、24和168小时研究177Lu-奥曲核苷酸在携带CLB-BAR肿瘤的小鼠体内的生物分布，并估计肿瘤和正常组织的吸收剂量。此外，给动物施用不同剂量的177Lu-奥曲肽或177Lu-奥曲核苷酸。随时间测量肿瘤体积，并与给予生理盐水的对照组进行比较。从肿瘤中提取RNA，并用qPCR定量84个与凋亡相关的选定基因的表达。
与177Lu-奥曲肽相比，177Lu-奥曲核苷酸在大多数组织中的活性浓度通常较低。注射1.5MBq和15MBq后，177Lu-奥曲核苷酸和177Lu-奥曲肽对肿瘤的每给药活度平均吸收剂量分别为0.74和0.03Gy/MBq以及2.9和0.45Gy/MBq。与对照组相比，177Lu-奥曲核苷酸治疗导致统计学上的显著差异。分次给药导致的存活分数高于单次给药后。177Lu-奥曲肽给药后，促凋亡基因、和受到调控。177Lu-奥曲核苷酸治疗使促凋亡基因和以及抗凋亡基因和凋亡相关基因受到调控。
177Lu-奥曲核苷酸的抗肿瘤效果略优于177Lu-奥曲肽。在177Lu-奥曲肽治疗组中观察到的类似效果表明生长抑素受体饱和。分次给药后明显的抗肿瘤效果值得将受体饱和作为一种解释。基因表达分析表明，两种放射性药物均通过外源性途径激活凋亡。
