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Clin Cancer Res. 2017 Aug 1;23(15):4335-4346. doi: 10.1158/1078-0432.CCR-16-2955. Epub 2017 Mar 31.

Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models.

Author information

1
Pharmatest Services Ltd., Turku, Finland.
2
Avoltus Oy, Turku, Finland.
3
Aurexel Life Sciences Ltd., Askainen, Finland.
4
Department of Urology, University of Washington, Seattle, Washington.
5
Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany.
6
Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.
7
Bayer AG, Pharmaceuticals Division, Drug Discovery, Therapeutic Research Groups Oncology, Berlin, Germany. arne.scholz@bayer.com.

Abstract

Purpose: Radium-223 dichloride (radium-223, Xofigo), a targeted alpha therapy, is currently used for the treatment of patients with castration-resistant prostate cancer (CRPC) with bone metastases. This study examines the mode-of-action and antitumor efficacy of radium-223 in two prostate cancer xenograft models.Experimental Design: Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups (n = 12-17) based on lesion grade and/or serum PSA level and administered radium-223 (300 kBq/kg) or vehicle, twice at 4-week intervals. X-rays and serum samples were obtained biweekly. Soft tissue tumors were observed macroscopically at sacrifice. Tibiae were analyzed by gamma counter, micro-CT, autoradiography and histology.Results: Radium-223 inhibited tumor-induced osteoblastic bone growth and protected normal bone architecture, leading to reduced bone volume in LNCaP and abiraterone-resistant LuCaP 58 models. Furthermore, radium-223 resulted in lower PSA values and reduced total tissue and tumor areas, indicating that treatment constrains prostate cancer growth in bone. In addition, radium-223 suppressed abnormal bone metabolic activity as evidenced by decreased number of osteoblasts and osteoclasts and reduced level of the bone formation marker PINP. Mode-of-action studies revealed that radium-223 was deposited in the intratumoral bone matrix. DNA double-strand breaks were induced in cancer cells within 24 hours after radium-223 treatment, and PSA levels were significantly lower 72 hours after treatment, providing further evidence of the antitumor effects.Conclusions: Taken together, radium-223 therapy exhibits a dual targeting mode-of-action that induces tumor cell death and suppresses tumor-induced pathologic bone formation in tumor microenvironment of osseous CRPC growth in mice. Clin Cancer Res; 23(15); 4335-46. ©2017 AACR.

PMID:
28364014
PMCID:
PMC5540794
DOI:
10.1158/1078-0432.CCR-16-2955
[Indexed for MEDLINE]
Free PMC Article

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