1. Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models
- Author
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Esa Alhoniemi, Karl Ziegelbauer, Mari I. Suominen, Arne Scholz, Salla K. Laine, Robert L. Vessella, Eva Corey, Yvonne Konkol, Sanna-Maria Käkönen, Dominik Mumberg, Jukka P. Rissanen, Jussi M. Halleen, Jukka P. Morko, Z. Peng, and Katja M. Fagerlund
- Subjects
Male ,0301 basic medicine ,Radium-223 ,Cancer Research ,Pathology ,medicine.medical_specialty ,Osteoclasts ,Antineoplastic Agents ,Bone Neoplasms ,Bone and Bones ,Article ,Lesion ,Mice ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Cell Line, Tumor ,LNCaP ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Cell Proliferation ,Radioisotopes ,Bone growth ,Tumor microenvironment ,business.industry ,Cancer ,medicine.disease ,Disease Models, Animal ,Prostatic Neoplasms, Castration-Resistant ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,medicine.symptom ,business ,Radium ,medicine.drug - 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.
- Published
- 2017
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