Abstract

Rationale

The role of radiation-induced bystander effects in cancer therapy with alpha-particle emitting radiopharmaceuticals remains unclear. With renewed interest in using alpha-particle emitters to sterilize disseminated tumor cells, micrometastases, and tumors, a better understanding of the direct effects of alpha particles and the contribution of the bystander responses they induce is needed to refine dosimetric models that help predict clinical benefit. Accordingly, this work models and quantifies the relative importance of direct effects (DE) and bystander effects (BE) in the growth delay of human breast cancer xenografts observed previously in the tibiae of mice treated with ²²³RaCl₂.

Methods

A computational model of MDA-MB-231 and MCF-7 human breast cancer xenografts in the tibial bone marrow of mice administered ²²³RaCl₂ was created. A Monte Carlo radiation transport simulation was performed to assess individual cell absorbed doses. The responses of the breast cancer cells to direct alpha particle irradiation and gamma irradiation were needed as input data for the model and were determined experimentally using a colony-forming assay and compared to the responses of preosteoblast MC3T3-E1 and osteocyte-like MLO-Y4 bone cells. Using these data, a scheme was devised to simulate the dynamic proliferation of the tumors in vivo, including DE and BE propagated from the irradiated cells. The parameters of the scheme were estimated semi-empirically to fit experimental tumor growth.

Results

A robust BE component, in addition to a much smaller DE component, was required to simulate the in vivo tumor proliferation. We also found that the relative biological effectiveness (RBE) for cell killing by alpha particle radiation was greater for the bone cells than the tumor cells.

Conclusion

This modeling study demonstrates that DE of radiation alone cannot explain experimental observations of ²²³RaCl₂-induced growth delay of human breast cancer xenografts. Furthermore, while the mechanisms underlying BE remain unclear, the addition of a BE component to the model is necessary to provide an accurate prediction of the growth delay. More complex models are needed to further comprehend the extent and complexity of ²²³RaCl₂-induced BE.

中文翻译：

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模拟导致镭223治疗小鼠骨髓中乳腺癌异种移植物生长延迟的旁观者效应

摘要

基本原理

辐射诱导的旁观者效应在使用 α 粒子发射放射性药物治疗癌症中的作用仍不清楚。随着人们对使用 α 粒子发射器对播散性肿瘤细胞、微转移灶和肿瘤进行消毒的兴趣重新燃起，需要更好地了解 α 粒子的直接影响以及它们诱导的旁观者反应的贡献，以改进有助于预测临床益处的剂量学模型. ^{因此，这项工作对先前在用223} RaCl ₂治疗的小鼠胫骨中观察到的人乳腺癌异种移植物的生长延迟中的直接效应 (DE) 和旁观者效应 (BE) 的相对重要性进行建模和量化。

方法

创建了 MDA-MB-231 和 MCF-7 人乳腺癌异种移植物在施用²²³ RaCl ₂的小鼠胫骨骨髓中的计算模型。进行蒙特卡罗辐射传输模拟以评估单个细胞的吸收剂量。乳腺癌细胞对直接 α 粒子照射和 γ 照射的反应需要作为模型的输入数据，并使用集落形成试验进行实验确定，并与前成骨细胞 MC3T3-E1 和骨细胞样 MLO-Y4 的反应进行比较骨细胞。使用这些数据，设计了一种方案来模拟体内肿瘤的动态增殖，包括从辐照细胞中传播的 DE 和 BE。该方案的参数是半经验估计的，以适应实验性肿瘤生长。

结果

除了更小的 DE 组件外，还需要一个强大的 BE 组件来模拟体内肿瘤增殖。我们还发现，α 粒子辐射对细胞杀伤的相对生物有效性 (RBE) 对骨细胞的影响大于对肿瘤细胞的影响。

结论

该模型研究表明，仅辐射的 DE 无法解释²²³ RaCl ₂诱导的人类乳腺癌异种移植物生长延迟的实验观察结果。此外，虽然 BE 的潜在机制仍不清楚，但在模型中添加 BE 组件对于准确预测生长延迟是必要的。需要更复杂的模型来进一步理解²²³ RaCl ₂诱导的 BE 的范围和复杂性。