Pharmatest Services Ltd., Turku, Finland.
Avoltus Oy, Turku, Finland.
Clin Cancer Res. 2017 Aug 1;23(15):4335-4346. doi: 10.1158/1078-0432.CCR-16-2955. Epub 2017 Mar 31.
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. Mice bearing intratibial LNCaP or LuCaP 58 tumors were randomized into groups ( = 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. 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. 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. .
镭-223 二氯化物（镭-223，Xofigo），一种靶向α疗法，目前用于治疗有骨转移的去势抵抗性前列腺癌（CRPC）患者。本研究在两种前列腺癌异种移植模型中检查镭-223 的作用模式和抗肿瘤功效。携带胫骨内 LNCaP 或 LuCaP 58 肿瘤的小鼠根据病变分级和/或血清 PSA 水平随机分为组（n=12-17），并接受镭-223（300 kBq/kg）或载体，每 4 周两次。每两周获取 X 射线和血清样本。处死时观察软组织肿瘤的大体情况。通过伽马计数器、微 CT、放射自显影和组织学分析胫骨。镭-223 抑制肿瘤诱导的成骨细胞骨生长并保护正常骨结构，导致 LNCaP 和阿比特龙耐药 LuCaP 58 模型中的骨体积减少。此外，镭-223 导致 PSA 值降低和总组织和肿瘤面积减少，表明治疗可限制前列腺癌在骨中的生长。此外，镭-223 抑制异常骨代谢活性，表现为成骨细胞和破骨细胞数量减少以及骨形成标志物 PINP 水平降低。作用模式研究表明，镭-223 沉积在肿瘤内骨基质中。镭-223 治疗后 24 小时内，癌细胞中诱导 DNA 双链断裂，治疗后 72 小时 PSA 水平显著降低，进一步证明了抗肿瘤作用。总之，镭-223 治疗表现出双重靶向作用模式，可诱导肿瘤细胞死亡并抑制肿瘤微环境中肿瘤诱导的病理性骨形成，从而抑制小鼠骨内 CRPC 生长。
