223Ra Induces Transient Functional Bone Marrow Toxicity

Maria Parlani, Francesco Boccalatte, Anna Yeaton, Feng Wang, Jianhua Zhang, Iannis Aifantis, Eleonora Dondossola

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)1544-1550
Number of pages7
JournalJournal of Nuclear Medicine
Volume63
Issue number10
DOIs
StatePublished - 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

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