基本原因：目前尚未为基于Lutetium-177的放射性核素疗法，例如177Lu-DOTATATE和177Lu-PSMA建立有效的吸收剂量反应关系。神经内分泌和前列腺癌本身的生物学异质性可能使得建立基于队列的剂量-反应关系的前景困难。相反，监测每个肿瘤的剂量-反应，采取个体化方法可能为监测治疗疗效提供必要的度量标准。 方法：我们开发了一种双同位素SPECT影像策略，来监测在携带大鼠胰腺癌异种移植小鼠中，177Lu-DOTATATE和111In-anti-γH2AX-TAT之间的关系随时间的变化，后者是一种改良的放射性标记抗体，可用于成像DNA双链断裂。在体内和外体的肿瘤切片中，进一步研究了暴露于177Lu-DOTATATE后的γH2AX斑点、凋亡和细胞衰老的动态变化。 结果：111In-anti-γH2AX-TAT到177Lu信号在第5天和第7天之间斜率的变化预测生存的准确性极高（r = 0.955，P <0.0001）。这个关键的时间窗口在体外进一步研究：在第6天，成簇生存与γH2AX 斑点的数目相关(r = -0.995, P < 0.0005)。虽然存在持续低水平的凋亡证据，但在体内延迟诱导的细胞衰老似乎更好地解释了177Lu对γH2AX的反应。外体分析进一步研究了细胞衰老的诱导，并与肿瘤区域内177Lu的持续滞留相对应。 结论：双同位素SPECT影像可以提供个性化的肿瘤剂量-反应，可用于预测Lutetium-177的治疗效果。这种生物剂量计度量标准似乎依赖于细胞衰老的程度，暗示着细胞衰老在Lutetium-177的治疗效果中起着重要的作用。©作者。

Rationale: An effective absorbed dose response relationship is yet to be established for Lutetium-177 based radionuclide therapies such as 177Lu-DOTATATE and 177Lu-PSMA. The inherent biological heterogeneity of neuroendocrine and prostate cancers may make the prospect of establishing cohort-based dose-response relationships unobtainable. Instead, an individual-based approach, monitoring the dose-response within each tumor could provide the necessary metric to monitor treatment efficacy. Methods: We developed a dual isotope SPECT imaging strategy to monitor the change over time in the relationship between 177Lu-DOTATATE and 111In-anti-γH2AX-TAT, a modified radiolabelled antibody that allows imaging of DNA double strand breaks, in mice bearing rat pancreatic cancer xenografts. The dynamics of γH2AX foci, apoptosis and senescence following exposure to 177Lu-DOTATATE was further investigated in vitro and in ex vivo tumor sections. Results: The change in slope of the 111In-anti-γH2AX-TAT to 177Lu signal between days 5 and 7 was found to be highly predictive of survival (r = 0.955, P < 0.0001). This pivotal timeframe was investigated further in vitro: clonogenic survival correlated with the number of γH2AX foci at day 6 (r = -0.995, P < 0.0005). While there was evidence of continuously low levels of apoptosis, delayed induction of senescence in vitro appeared to better account for the γH2AX response to 177Lu. The induction of senescence was further investigated by ex vivo analysis and corresponded with sustained retention of 177Lu within tumor regions. Conclusions: Dual isotope SPECT imaging can provide individualized tumor dose-responses that can be used to predict lutetium-177 treatment efficacy. This bio-dosimeter metric appears to be dependent upon the extent of senescence induction and suggests an integral role that senescence plays in lutetium-177 treatment efficacy.© The author(s).