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Radium-223 mechanism of action: implications for use in treatment combinations.
Nature Reviews Urology ( IF 12.1 ) Pub Date : 2019-11-11 , DOI: 10.1038/s41585-019-0251-x Michael J Morris 1 , Eva Corey 2 , Theresa A Guise 3 , James L Gulley 4 , William Kevin Kelly 5 , David I Quinn 6, 7 , Arne Scholz 8 , George Sgouros 9
Nature Reviews Urology ( IF 12.1 ) Pub Date : 2019-11-11 , DOI: 10.1038/s41585-019-0251-x Michael J Morris 1 , Eva Corey 2 , Theresa A Guise 3 , James L Gulley 4 , William Kevin Kelly 5 , David I Quinn 6, 7 , Arne Scholz 8 , George Sgouros 9
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The targeted alpha therapy radium-223 (223Ra) can prolong survival in men with castration-resistant prostate cancer (CRPC) who have symptomatic bone metastases and no known visceral metastases. Preclinical studies demonstrate that 223Ra preferentially incorporates into newly formed bone matrix within osteoblastic metastatic lesions. The emitted high-energy alpha particles induce DNA double-strand breaks that might be irreparable and lead to cell death in nearby exposed tumour cells, osteoblasts and osteoclasts. Consequently, tumour growth and abnormal bone formation are inhibited by these direct effects and by the disruption of positive-feedback loops between tumour cells and the bone microenvironment. 223Ra might also modulate immune responses within the bone. The clinical utility of 223Ra has encouraged the development of other anticancer targeted alpha therapies. A thorough understanding of the mechanism of action could inform the design of new combinatorial treatment strategies that might be more efficacious than monotherapy. On the basis of the current mechanistic knowledge and potential clinical benefits, combination therapies of 223Ra with microtubule-stabilizing cytotoxic drugs and agents targeting the androgen receptor axis, immune checkpoint receptors or DNA damage response proteins are being explored in patients with CRPC and metastatic bone disease.
中文翻译：
Radium-223 作用机制：对治疗组合使用的影响。
靶向 α 疗法镭 223 (223Ra) 可以延长患有去势抵抗性前列腺癌 (CRPC) 且有症状骨转移且无已知内脏转移的男性患者的生存期。临床前研究表明，223Ra 优先融入成骨细胞转移病灶内新形成的骨基质中。发射的高能α粒子会引起DNA双链断裂，这种断裂可能是不可修复的，并导致附近暴露的肿瘤细胞、成骨细胞和破骨细胞死亡。因此，肿瘤生长和异常骨形成受到这些直接作用以及肿瘤细胞和骨微环境之间正反馈环的破坏的抑制。223Ra 还可能调节骨骼内的免疫反应。223Ra 的临床应用鼓励了其他抗癌靶向 α 疗法的开发。对作用机制的透彻理解可以为新的组合治疗策略的设计提供信息，这些策略可能比单一疗法更有效。基于目前的机制知识和潜在的临床益处，正在探索 223Ra 与微管稳定细胞毒性药物和靶向雄激素受体轴、免疫检查点受体或 DNA 损伤反应蛋白的药物联合治疗 CRPC 和转移性骨病患者。
更新日期：2019-11-11
中文翻译：
Radium-223 作用机制：对治疗组合使用的影响。
靶向 α 疗法镭 223 (223Ra) 可以延长患有去势抵抗性前列腺癌 (CRPC) 且有症状骨转移且无已知内脏转移的男性患者的生存期。临床前研究表明，223Ra 优先融入成骨细胞转移病灶内新形成的骨基质中。发射的高能α粒子会引起DNA双链断裂，这种断裂可能是不可修复的，并导致附近暴露的肿瘤细胞、成骨细胞和破骨细胞死亡。因此，肿瘤生长和异常骨形成受到这些直接作用以及肿瘤细胞和骨微环境之间正反馈环的破坏的抑制。223Ra 还可能调节骨骼内的免疫反应。223Ra 的临床应用鼓励了其他抗癌靶向 α 疗法的开发。对作用机制的透彻理解可以为新的组合治疗策略的设计提供信息，这些策略可能比单一疗法更有效。基于目前的机制知识和潜在的临床益处，正在探索 223Ra 与微管稳定细胞毒性药物和靶向雄激素受体轴、免疫检查点受体或 DNA 损伤反应蛋白的药物联合治疗 CRPC 和转移性骨病患者。
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