Abstract
223Ra is a bone-seeking, a-particle–emitting radionuclide approved for the treatment of patients with metastatic prostate cancer and is currently being tested in a variety of clinical trials for primary and metastatic cancers to bone. Clinical evaluation of 223Ra hematologic safety showed a significantly increased rate of neutropenia and thrombocytopenia in patients, hinting at myelosuppression as a side effect. Methods: In this study, we investigated the consequences of 223Ra treatment on bone marrow biology by combining flow cytometry, single-cell RNA sequencing, three-dimensional multiphoton microscopy and bone marrow transplantation analyses. Results: 223Ra accumulated in bones and induced zonal radiation damage confined to the bone interface, followed by replacement of the impaired areas with adipocyte infiltration, as monitored by 3-dimensional multiphoton microscopy ex vivo. Flow cytometry and single-cell transcriptomic analyses on bone marrow hematopoietic populations revealed transient, nonspecific 223Ra-mediated cytotoxicity on resident populations, including stem, progenitor, and mature leukocytes. This toxicity was paralleled by a significant decrease in white blood cells and platelets in peripheral blood—an effect that was overcome within 40 d after treatment. 223Ra exposure did not impair full hematopoietic reconstitution, suggesting that bone marrow function is not permanently hampered. Conclusion: Our results provide a comprehensive explanation of 223Ra reversible effects on bone marrow cells and exclude long-term myelotoxicity, supporting safety for patients.
Original language | English (US) |
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Pages (from-to) | 1544-1550 |
Number of pages | 7 |
Journal | Journal of Nuclear Medicine |
Volume | 63 |
Issue number | 10 |
DOIs | |
State | Published - 2022 |
Keywords
- 223Ra
- bone marrow
- myelotoxicity
ASJC Scopus subject areas
- General Medicine
MD Anderson CCSG core facilities
- Advanced Technology Genomics Core
- Research Animal Support Facility
- Tissue Biospecimen and Pathology Resource
- Flow Cytometry and Cellular Imaging Facility