Radioimmunotherapy of Breast Cancer Metastases with α-Particle Emitter 225Ac: Comparing Efficacy with 213Bi and 90Y
Radioimmunotherapy of Breast Cancer Metastases with α-Particle Emitter 225Ac: Comparing Efficacy with 213Bi and 90Y
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DOI：
10.1158/0008-5472.can-09-1828
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发表时间：
2009-12-01
期刊：
影响因子：
11.2
通讯作者：
Sgouros, George
中科院分区：
文献类型：
--
作者：
Song, Hong;Hobbs, Robert F.;Sgouros, George
α -粒子具有射程短、线性能量转移高的特点，适用于肿瘤微转移的治疗。基于α粒子发射器bi -213的放射免疫疗法在多种转移性动物癌症模型中显示出疗效，如乳腺癌、卵巢癌和前列腺癌。然而，由于Ac-225的供应有限，现场制备半衰期极短（T-1/2 = 45.6分钟）的放射免疫偶联物的技术要求高，以及高昂的成本，其临床实施具有挑战性。在这项研究中，我们研究了α粒子发射器Ac-225 （Bi-213的母体）在乳腺癌转移小鼠模型中的作用。单次给药Ac-225 （400 nCi）标记的抗大鼠HER-2/neu单克隆抗体（7.16.4）完全根除了67%的HER-2/neu转基因小鼠的乳腺癌肺微转移，并使这些小鼠的长期生存期长达1年。Ac-225-7.16.4治疗显著优于Bi-213-7.16.4（120亩Ci，中位生存期61天，P = 0.001）和Y-90-7.16.4（120亩Ci，中位生存期50天，P < 0.001）以及未经治疗的对照组（中位生存期41天，P < 0.0001）。剂量学分析显示，ac -225治疗的转移瘤总剂量为9.6 Gy，显著高于Bi-213治疗的2.0 Gy和Y-90治疗的2.4 Gy。生物分布研究表明，Ac-225子代Fr-221和Bi-213在肾脏中积累，并可能导致存活小鼠的长期肾毒性。这些数据表明ac -225标记的抗HER-2/neu单克隆抗体可以显著延长HER-2/neu阳性转移性乳腺癌患者的生存期。[癌症研究2009；69 (23): 8941 - 8]
alpha-Particles are suitable to treat cancer micrometastases because of their short range and very high linear energy transfer. alpha-Particle emitter Bi-213-based radioimmunotherapy has shown efficacy in a variety of metastatic animal cancer models, such as breast, ovarian, and prostate cancers. Its clinical implementation, however, is challenging due to the limited supply of Ac-225, high technical requirement to prepare radioimmunoconjugate with very short half-life (T-1/2 = 45.6 min) on site, and prohibitive cost. In this study, we investigated the efficacy of the alpha-particle emitter Ac-225, parent of Bi-213, in a mouse model of breast cancer metastases. A single administration of Ac-225 (400 nCi)-labeled anti-rat HER-2/neu monoclonal antibody (7.16.4) completely eradicated breast cancer lung micrometastases in similar to 67% of HER-2/neu transgenic mice and led to long-term survival of these mice for up to I year. Treatment with Ac-225-7.16.4 is significantly more effective than Bi-213-7.16.4 (120 mu Ci; median survival, 61 days; P = 0.001) and Y-90-7.16.4 (120 mu Ci; median survival, 50 days; P < 0.001) as well as untreated control (median survival, 41 days; P < 0.0001). Dosimetric analysis showed that Ac-225-treated metastases received a total dose of 9.6 Gy, significantly higher than 2.0 Gy from Bi-213 and 2.4 Gy from Y-90. Biodistribution studies revealed that Ac-225 daughters, Fr-221 and Bi-213, accumulated in kidneys and probably contributed to the long-term renal toxicity observed in surviving mice. These data Suggest Ac-225-labeled anti-HER-2/neu monoclonal antibody could significantly prolong survival in HER-2/neu-positive metastatic breast cancer patients. [Cancer Res 2009;69(23):8941-8]