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Research ArticleBasic Science Investigation

223Ra Induces Transient Functional Bone Marrow Toxicity

Maria Parlani, Francesco Boccalatte, Anna Yeaton, Feng Wang, Jianhua Zhang, Iannis Aifantis and Eleonora Dondossola
Journal of Nuclear Medicine October 2022, 63 (10) 1544-1550; DOI: https://doi.org/10.2967/jnumed.121.263310
Maria Parlani
1Genitourinary Medical Oncology Department and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas M.D. Anderson Cancer Center, Houston, Texas;
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Francesco Boccalatte
2Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York; and
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Anna Yeaton
2Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York; and
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Feng Wang
3Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Jianhua Zhang
3Department of Genomic Medicine, University of Texas M.D. Anderson Cancer Center, Houston, Texas
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Iannis Aifantis
2Department of Pathology and Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, New York, New York; and
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Eleonora Dondossola
1Genitourinary Medical Oncology Department and David H. Koch Center for Applied Research of Genitourinary Cancers, University of Texas M.D. Anderson Cancer Center, Houston, Texas;
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Abstract

223Ra is a bone-seeking, α-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.

  • 223Ra
  • myelotoxicity
  • bone marrow

Footnotes

  • Published online Feb. 17, 2022.

  • © 2022 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 63 (10)
Journal of Nuclear Medicine
Vol. 63, Issue 10
October 1, 2022
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223Ra Induces Transient Functional Bone Marrow Toxicity
Maria Parlani, Francesco Boccalatte, Anna Yeaton, Feng Wang, Jianhua Zhang, Iannis Aifantis, Eleonora Dondossola
Journal of Nuclear Medicine Oct 2022, 63 (10) 1544-1550; DOI: 10.2967/jnumed.121.263310

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223Ra Induces Transient Functional Bone Marrow Toxicity
Maria Parlani, Francesco Boccalatte, Anna Yeaton, Feng Wang, Jianhua Zhang, Iannis Aifantis, Eleonora Dondossola
Journal of Nuclear Medicine Oct 2022, 63 (10) 1544-1550; DOI: 10.2967/jnumed.121.263310
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Keywords

  • 223Ra
  • myelotoxicity
  • bone marrow
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