A1 Refereed original research article in a scientific journal
Survival Benefit With Radium-223 Dichloride in a Mouse Model of Breast Cancer Bone Metastasis
Authors: Suominen MI, Rissanen JP, Kakonen R, Fagerlund KM, Alhoniemi E, Mumberg D, Ziegelbauer K, Halleen JM, Kakonen S, Scholz A
Publisher: OXFORD UNIV PRESS INC
Publishing place: CARY; JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA
Publication year: 2013
Journal: JNCI: Journal of the National Cancer Institute
Journal name in source: Jnci-Journal of the National Cancer Institute
Journal acronym: JNCI-.Natl.Cancer Inst.
Number in series: 12
Volume: 105
Issue: 12
First page : 908
Last page: 916
Number of pages: 9
ISSN: 0027-8874
DOI: https://doi.org/10.1093/jnci/djt116
Abstract
Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] 26.6 to 31.8 days, P .039) and in combination with zoledronic acid (31.4 days, 95% CI 28.8 to 34.0 days, P .004) or doxorubicin (31.5 days, 95% CI 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.
Bone metastases are associated with increased morbidity and poor prognosis in breast cancer patients. Radium-223 dichloride is a calcium mimetic that localizes to bone, providing targeted therapy for skeletal metastasis. We investigated the mode of action of radium-223 dichloride using breast cancer cell, osteoclast, and osteoblast cultures as well as a mouse model of breast cancer bone metastasis. A single dose of radium-223 dichloride was used in three different settings mimicking the prevention or treatment of bone metastasis. Disease progression was monitored using fluorescence and radiographic imaging and histological analyses. The effect of radium-223 dichloride alone and in combination with doxorubicin or zoledronic acid on survival of mice was analyzed by Kaplan-Meier methods. All statistical tests used were two-sided. Radium-223 dichloride incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. In an established bone metastasis setting, radium-223 dichloride prevented tumor-induced cachexia (0/14 vs 7/14 control mice) and decreased osteolysis by 56% and tumor growth by 43% (all P values < .05). Radium-223 dichloride induced double-strand DNA breaks in cancer cells in vivo. Finally, radium-223 dichloride extended survival as a monotherapy (29.2 days, 95% confidence interval [CI] 26.6 to 31.8 days, P .039) and in combination with zoledronic acid (31.4 days, 95% CI 28.8 to 34.0 days, P .004) or doxorubicin (31.5 days, 95% CI 29.5 to 33.5 days, P < .001) compared to the vehicle group (24.9 days, 95% CI 23.4 to 26.4 days). Similar but even more pronounced effects were observed when radium-223 dichloride was administered in a preventive or micrometastatic setting. Our findings strongly support the development of radium-223 dichloride for the treatment of breast cancer patients with or at high risk of developing bone metastases.
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