背景:肽受体放射性核素治疗(PRRT)使用[177Lu]Lu-[DOTA0-Tyr3]奥曲酯([177Lu]Lu-DOTA-TATE)治疗过度表达生长抑素受体2A(SSTR2A)的神经内分泌肿瘤(NETs)患者。它在生存和症状缓解方面显示出显着的短期改善,但仍有改进的余地。这里,我们研究了[177Lu]Lu-DOTA-TATE与化疗药联合使用是否能增强[177Lu]Lu-DOTA-TATE的体外疗效。
结果:转染的人骨肉瘤(U2OS+SSTR2A,高SSTR2A表达)和胰腺网络(BON1+STTR2A,培养基SSTR2A表达)细胞接受羟基脲,吉西他滨或triapine在37℃和5%CO2下24小时。然后将细胞回收4小时,然后与0.7-1.03MBq[177Lu]Lu-DOTA-TATE(25nM)孵育24小时,用于摄取和代谢活力研究。U2OS+SSTR2A细胞与羟基脲的孵育,吉西他滨,和triapine增强[177Lu]Lu-DOTA-TATE的摄取从未处理细胞中的0.2±0.1增加到U2OSSSTR2A细胞中的0.4±0.1、1.1±0.2和0.9±0.2Bq/细胞,分别。与用[177Lu]Lu-DOTA-TATE单一疗法处理的细胞相比,用[177Lu]Lu-DOTA-TATE处理后的细胞活力降低。例如,用羟基脲预处理后,用[177Lu]Lu-DOTA-TATE孵育的U2OSSSTR2A细胞的活力从59.5±22.3%降低到18.8±5.2%。对照条件显示没有降低的代谢活力。还收获细胞以评估细胞周期进展。SSTR2A表达式,和细胞大小通过流式细胞术。化疗增加了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期亚群从45.5±3.3%增加到84.8±2.5%,85.9±1.9%,用羟基脲处理时,86.6±2.2%,吉西他滨,和triapine,分别。
结论:羟基脲,吉西他滨和曲平都增加了细胞大小,SSTR2A表达式,和[177Lu]Lu-DOTA-TATE摄取,与[177Lu]Lu-DOTA-TATE单一疗法相比,同时降低了U2OS+SSTR2A细胞中的细胞代谢活力。进一步的调查可以改变患者的护理,并积极增加接受[177Lu]Lu-DOTA-TATE治疗的患者的预后。
BACKGROUND: Peptide receptor radionuclide therapy (PRRT) uses [177Lu]Lu-[DOTA0-Tyr3]octreotate ([177Lu]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 [177Lu]Lu-DOTA-TATE with chemotherapeutics enhanced the in vitro therapeutic efficacy of [177Lu]Lu-DOTA-TATE.
RESULTS: 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 37oC and 5% CO2. Cells were then recovered for 4 h prior to a 24-hour incubation with 0.7-1.03 MBq [177Lu]Lu-DOTA-TATE (25 nM) for uptake and metabolic viability studies. Incubation of U2OS + SSTR2A cells with hydroxyurea, gemcitabine, and triapine enhanced uptake of [177Lu]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 [177Lu]Lu-DOTA-TATE in cells pre-treated with chemotherapeutics was decreased compared to cells treated with [177Lu]Lu-DOTA-TATE monotherapy. For example, the viability of U2OS + SSTR2A cells incubated with [177Lu]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.
CONCLUSIONS: Hydroxyurea, gemcitabine and triapine all increased cell size, SSTR2A expression, and [177Lu]Lu-DOTA-TATE uptake, whilst reducing cell metabolic viability in U2OS + SSTR2A cells when compared to [177Lu]Lu-DOTA-TATE monotherapy. Further investigations could transform patient care and positively increase outcomes for patients treated with [177Lu]Lu-DOTA-TATE.