The Royal Marsden National Health Service Foundation Trust-Institute of Cancer Research, Sutton, United Kingdom.
King's College, London, United Kingdom.
JAMA Oncol. 2018 Dec 1;4(12):1765-1772. doi: 10.1001/jamaoncol.2018.4044.
Targeted alpha therapy attempts to deliver systemic radiation selectively to cancer cells while minimizing systemic toxic effects and may lead to additional treatment options for many cancer types.
Theoretically, the high-energy emission of short-range alpha particles causes complex double-stranded DNA breaks, eliciting cell death. No known resistance mechanism to alpha particles has been reported or scientifically established. The short-range emission of alpha particle radiation confines its cytotoxic effect to cancerous lesions and the surrounding tumor microenvironment while limiting toxic effects to noncancerous tissues. The high level of radiobiological effectiveness of alpha particles, in comparison with beta emissions, requires fewer particle tracks to induce cell death. Clinically effective alpha particle-emitting isotopes for cancer therapy should have a short half-life, which will limit long-term radiation exposure and allow for the production, preparation, and administration of these isotopes for clinical use and application. Radium 223 dichloride is the first-in-class, commercially available targeted alpha therapy approved for the treatment of patients with metastatic castration-resistant prostate cancer with bone metastases. Given the established overall survival benefit conferred by radium 223 for patients with metastatic castration-resistant prostate cancer, several other targeted alpha therapies are being investigated in clinical trials across many tumor types.
Targeted alpha therapy represents an emerging treatment approach and provides for the possibility to bypass mechanisms of acquired resistance in selected tumors. In addition, developing novel radionuclide conjugation strategies may overcome targeting limitations. So far, the clinical success of radium 223 has demonstrated the proof of concept for targeted alpha therapy, and future studies may lead to additional treatment options for many cancer types.
靶向 alpha 疗法试图将全身辐射选择性地递送到癌细胞，同时将全身毒性作用降至最低，并可能为许多癌症类型提供额外的治疗选择。
从理论上讲，短程 alpha 粒子的高能发射会导致复杂的双链 DNA 断裂，引发细胞死亡。尚未报道或科学确立针对 alpha 粒子的已知耐药机制。alpha 粒子辐射的短程发射将其细胞毒性作用限制在癌变病变及其周围肿瘤微环境中，同时将毒性作用限制在非癌组织中。与 beta 发射相比，alpha 粒子的放射生物学效应水平较高，需要较少的粒子轨迹来诱导细胞死亡。用于癌症治疗的临床有效的 alpha 粒子发射同位素应具有短半衰期，这将限制长期辐射暴露，并允许生产、准备和管理这些同位素用于临床应用。镭 223 二氯化物是首个获批用于治疗转移性去势抵抗性前列腺癌伴骨转移患者的临床应用的靶向 alpha 疗法。鉴于镭 223 为转移性去势抵抗性前列腺癌患者带来的已确立的总生存获益，许多其他靶向 alpha 疗法正在多种肿瘤类型的临床试验中进行研究。
靶向 alpha 疗法代表了一种新兴的治疗方法，并为在选定的肿瘤中绕过获得性耐药机制提供了可能性。此外，开发新的放射性核素缀合策略可能会克服靶向限制。到目前为止，镭 223 的临床成功已经证明了靶向 alpha 疗法的概念验证，未来的研究可能会为许多癌症类型提供额外的治疗选择。
