Modeling Bystander Effects That Cause Growth Delay of Breast Cancer Xenografts in Bone Marrow of Mice Treated with Radium-223

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 (RaCl2)-Ra-223. Methods A computational model of MDA-MB-231 and MCF-7 human breast cancer xenografts in the tibial bone marrow of mice administered (RaCl2)-Ra-223 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 (RaCl2)-Ra-223-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 (RaCl2)-Ra-223-induced BE.