Purpose

Apoptosis, in the context of cancer, is a form of programmed cell death induced by chemotherapy, radiotherapy, and immunotherapy. As this is a central pathway in treatment response, considerable effort has been expended on the development of molecular imaging agents to non-invasively measure tumor apoptosis prior to quantitative changes in tumor dimensions. Despite these efforts, clinical trials directed at imaging apoptosis by PET, SPECT, and MRI have failed to robustly predict response to treatment with high sensitivity and specificity. Although these shortcomings may be linked to probe design, we propose that the combination of variability in the timing of maximal in vivo tumor apoptosis and sub-optimal sampling times fundamentally limits the predictive power of PET/SPECT apoptosis imaging.

Procedures

Herein, we surveyed the literature describing the time course of therapy-induced tumor apoptosis in vivo and used these data to construct a mathematical model describing the onset, duration, amplitude, and variability of the apoptotic response. Uncertainty in the underlying time of initiation of tumor apoptosis was simulated by Gaussian, uniform, and Landau distributions centered at the median time-to-maximum apoptotic rate derived from the literature. We then computationally sampled these models for various durations to simulate PET/SPECT imaging agents with variable effective half-lives.

Results

Models with a narrow Gaussian distribution of initiation times for tumor apoptosis predicted high contrast ratios and strong predictive values for all effective tracer half-lives. However, when uncertainty in apoptosis initiation times were simulated with uniform and Landau distributions, high contrast ratios and predictive values were only obtained with extremely long imaging windows (days). The imaging contrast ratios predicted in these models were consistent with those seen in pre-clinical apoptosis PET/SPECT imaging studies and suggest that uncertainty in the timing of tumor cell death plays a significant role in the maximal contrast obtainable. Moreover, when uncertainty in both apoptosis initiation and imaging start times were simulated, the predicted contrast ratios were dramatically reduced for all tracer half-lives.

Conclusions

These studies illustrate the effect of uncertainty of apoptosis initiation on the predictive power of PET/SPECT apoptosis imaging agents and suggest that long integration times are required to surmount uncertainty in the time domain of this biological process.

中文翻译：

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错误时机死亡：模拟肿瘤细胞凋亡的时域变异性和对细胞死亡分子成像的影响。

目的

在癌症的背景下，细胞凋亡是一种由化学疗法、放射疗法和免疫疗法诱导的程序性细胞死亡形式。由于这是治疗反应的核心途径，因此在开发分子成像剂以在肿瘤尺寸发生定量变化之前非侵入性地测量肿瘤细胞凋亡方面付出了相当大的努力。尽管做出了这些努力，针对 PET、SPECT 和 MRI 成像细胞凋亡的临床试验未能以高灵敏度和特异性可靠地预测对治疗的反应。尽管这些缺点可能与探针设计有关，但我们认为最大体内肿瘤细胞凋亡时间的可变性和次优采样时间的组合从根本上限制了 PET/SPECT 细胞凋亡成像的预测能力。

程序

在此，我们调查了描述体内治疗诱导的肿瘤细胞凋亡的时间过程的文献，并使用这些数据构建了描述细胞凋亡反应的发生、持续时间、幅度和可变性的数学模型。肿瘤细胞凋亡起始时间的不确定性通过高斯分布、均匀分布和朗道分布来模拟，这些分布以文献中获得的最大凋亡率的中值时间为中心。然后，我们对这些模型进行了不同持续时间的计算采样，以模拟具有可变有效半衰期的 PET/SPECT 成像剂。

结果

肿瘤细胞凋亡起始时间的窄高斯分布模型预测了所有有效示踪剂半衰期的高对比度和强预测值。然而，当用均匀分布和朗道分布模拟细胞凋亡起始时间的不确定性时，只有在极长的成像窗口（天）下才能获得高对比度和预测值。在这些模型中预测的成像对比度与在临床前细胞凋亡 PET/SPECT 成像研究中看到的一致，并表明肿瘤细胞死亡时间的不确定性在可获得的最大对比度中起着重要作用。此外，当模拟细胞凋亡开始和成像开始时间的不确定性时，所有示踪剂半衰期的预测对比度都显着降低。

结论

这些研究说明了细胞凋亡起始的不确定性对 PET/SPECT 细胞凋亡成像剂的预测能力的影响，并表明需要较长的积分时间来克服该生物过程时域中的不确定性。