Cheng Jordan, Zink Joke, O'Neill Edward, Cornelissen Bart, Nonnekens Julie, Livieratos Lefteris, Terry Samantha Y A
Department of Imaging Chemistry and Biology, School of Biomedical Engineering and Imaging Sciences, King's College London, London, SE1 7EH, UK.
Department of Molecular Genetics, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands.
EJNMMI Res. 2024 Aug 13;14(1):73. doi: 10.1186/s13550-024-01135-0.
Peptide receptor radionuclide therapy (PRRT) uses [Lu]Lu-[DOTA-Tyr]octreotate ([Lu]Lu-DOTA-TATE) to treat patients with neuroendocrine tumours (NETs) overexpressing the somatostatin receptor 2A (SSTR2A). It has shown significant short-term improvements in survival and symptom alleviation, but there remains room for improvement. Here, we investigated whether combining [Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [Lu]Lu-DOTA-TATE.
Transfected human osteosarcoma (U2OS + SSTR2A, high SSTR2A expression) and pancreatic NET (BON1 + STTR2A, medium SSTR2A expression) cells were subjected to hydroxyurea, gemcitabine or triapine for 24 h at 37C and 5% CO. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7-1.03 MBq [Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [Lu]Lu-DOTA-TATE from 0.2 ± 0.1 in untreated cells to 0.4 ± 0.1, 1.1 ± 0.2, and 0.9 ± 0.2 Bq/cell in U2OS + SSTR2A cells, respectively. Cell viability post treatment with [Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [Lu]Lu-DOTA-TATE decreased from 59.5 ± 22.3% to 18.8 ± 5.2% when pre-treated with hydroxyurea. Control conditions showed no reduced metabolic viability. Cells were also harvested to assess cell cycle progression, SSTR2A expression, and cell size by flow cytometry. Chemotherapeutics increased SSTR2A expression and cell size in U2OS + SSTR2A and BON1 + STTR2A cells. The S-phase sub-population of asynchronous U2OS + SSTR2A cell cultures was increased from 45.5 ± 3.3% to 84.8 ± 2.5%, 85.9 ± 1.9%, and 86.6 ± 2.2% when treated with hydroxyurea, gemcitabine, and triapine, respectively.
Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [Lu]Lu-DOTA-TATE.
肽受体放射性核素治疗（PRRT）使用[镥]镥 - [DOTA - 酪氨酸]奥曲肽（[镥]镥 - DOTA - TATE）治疗过表达生长抑素受体2A（SSTR2A）的神经内分泌肿瘤（NETs）患者。它已显示出在生存和症状缓解方面有显著的短期改善，但仍有改进空间。在此，我们研究了将[镥]镥 - DOTA - TATE与化疗药物联合使用是否能增强[镥]镥 - DOTA - TATE的体外治疗效果。
将转染的人骨肉瘤细胞（U2OS + SSTR2A，高SSTR2A表达）和胰腺NET细胞（BON1 + STTR2A，中等SSTR2A表达）在37℃和5%二氧化碳条件下用羟基脲、吉西他滨或曲磷胺处理24小时。然后细胞恢复4小时，接着与0.7 - 1.03 MBq [镥]镥 - DOTA - TATE（25 nM）孵育24小时，用于摄取和代谢活力研究。用羟基脲、吉西他滨和曲磷胺处理U2OS + SSTR2A细胞后，[镥]镥 - DOTA - TATE的摄取量分别从未处理细胞的0.2±0.1增加到U2OS + SSTR2A细胞中的0.4±0.1、1.1±0.2和0.9±0.2 Bq/细胞。与[镥]镥 - DOTA - TATE单药治疗相比，用化疗药物预处理的细胞在用[镥]镥 - DOTA - TATE处理后的细胞活力降低。例如，用羟基脲预处理后，与[镥]镥 - DOTA - TATE孵育的U2OS + SSTR2A细胞活力从59.5±22.3%降至18.8±5.2%。对照条件下未显示代谢活力降低。还通过流式细胞术收获细胞以评估细胞周期进程、SSTR2A表达和细胞大小。化疗药物增加了U2OS + SSTR2A和BON1 + STTR2A细胞中的SSTR2A表达和细胞大小。异步U2OS + SSTR2A细胞培养物的S期亚群在用羟基脲、吉西他滨和曲磷胺处理后分别从45.5±3.3%增加到84.8±2.5%、85.9±1.9%和86.6±2.2%。
与[镥]镥 - DOTA - TATE单药治疗相比，羟基脲、吉西他滨和曲磷胺均增加了U2OS + SSTR2A细胞的细胞大小、SSTR2A表达和[镥]镥 - DOTA - TATE摄取，同时降低了细胞代谢活力。进一步的研究可能会改变患者护理，并积极改善接受[镥]镥 - DOTA - TATE治疗的患者的预后。
