Modeling bystander effects that cause growth delay of breast cancer xenografts in bone marrow of mice treated with radium-223

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.

Keywords:

• Bystander effect
• breast cancer; RBE
• Monte Carlo
• alpha particle
• Radium-223

Acknowledgements

We thank Patricia Buckendahl and the Rutgers Molecular Imaging Center for the µCT imaging.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This study was supported in part by grant [1R01CA198073] from the NIH, and New Jersey Commission on Cancer Research Pre-doctoral Fellowship Grants #[DFHS15PPC009] (CNL) and #[DFHS17PPC029] (BSC).

Notes on contributors

Didier A. Rajon

Didier A. Rajon is an Associate Scientist at the Department of Neurosurgery, University of Florida, Gainesville, Florida, USA

Brian S. Canter

Brian S. Canter completed a PhD in the Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New-Jersey, USA

Calvin N. Leung

Calvin N. Leung is a Doctoral Student at the Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New-Jersey, USA

Tom A. Bäck

Tom A. Bäck is a Researcher at the Department of Radiation Physics, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

J. Christopher Fritton

J. Christopher Fritton is an Associate Professor in the Departments of Mechanical and Biomedical Engineering, The City College of New York, New York, USA

Edouard I. Azzam

Edouard I. Azzam is Professor Emeritus of Radiology, New Jersey Medical School, Rutgers University, Newark, New-Jersey, USA; currently, Radiobiology Scientific Lead, Radiobiology and Health Branch, Canadian Nuclear Laboratories, Chalk River, Ontario, Canada

Roger W. Howell

Roger W. Howell is a Distinguished Professor at the Department of Radiology, New Jersey Medical School, Rutgers University, Newark, New-Jersey, USA