Radioimmune & Inorganic Chemistry Section, ROB, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
Clin Cancer Res. 2013 Feb 1;19(3):530-7. doi: 10.1158/1078-0432.CCR-12-0298. Epub 2012 Dec 10.
An α-particle, a (4)He nucleus, is exquisitely cytotoxic and indifferent to many limitations associated with conventional chemo- and radiotherapy. The exquisite cytotoxicity of α-radiation, the result of its high mean energy deposition [high linear energy transfer (LET)] and limited range in tissue, provides for a highly controlled therapeutic modality that can be targeted to selected malignant cells [targeted α-therapy (TAT)] with minimal normal tissue effects. A burgeoning interest in the development of TAT is buoyed by the increasing number of ongoing clinical trials worldwide. The short path length renders α-emitters suitable for treatment and management of minimal disease such as micrometastases or residual tumor after surgical debulking, hematologic cancers, infections, and compartmental cancers such as ovarian cancer or neoplastic meningitis. Yet, despite decades of study of high LET radiation, the mechanistic pathways of the effects of this modality remain not well defined. The modality is effectively presumed to follow a simple therapeutic mechanism centered on catastrophic double-strand DNA breaks without full examination of the actual molecular pathways and targets that are activated that directly affect cell survival or death. This Molecular Pathways article provides an overview of the mechanisms and pathways that are involved in the response to and repair of TAT-induced DNA damage as currently understood. Finally, this article highlights the current state of clinical translation of TAT as well as other high-LET radionuclide radiation therapy using α-emitters such as (225)Ac, (211)At, (213)Bi, (212)Pb, and (223)Ra.
α 粒子，即氦核，具有极高的细胞毒性，且不受许多与传统化疗和放疗相关的限制。α 射线的细胞毒性非常高，这是由于其具有高平均能量沉积（高线性能量转移（LET））和在组织中有限的射程，为一种高度可控的治疗方式提供了基础，这种治疗方式可以靶向选择的恶性细胞（靶向 α 治疗（TAT）），而对正常组织的影响最小。由于全球范围内越来越多的临床试验正在进行，对 TAT 开发的兴趣日益浓厚，这为 TAT 的发展提供了动力。由于 α 发射体的路径较短，因此非常适合治疗和管理微小疾病，例如手术切除后的微小转移或残留肿瘤、血液癌症、感染以及卵巢癌或肿瘤性脑膜炎等局限性癌症。然而，尽管对高 LET 辐射进行了数十年的研究，但这种治疗方式的作用机制途径仍未得到很好的定义。这种治疗方式被认为是基于灾难性的双链 DNA 断裂的简单治疗机制，而没有充分检查实际激活的直接影响细胞存活或死亡的分子途径和靶点。这篇分子途径文章概述了目前已知的 TAT 诱导的 DNA 损伤的反应和修复所涉及的机制和途径。最后，本文还重点介绍了 TAT 以及其他使用α发射体（如 225Ac、211At、213Bi、212Pb 和 223Ra）的高 LET 放射性核素放射疗法的临床转化现状。
