Alpha-particle emitting atomic generator (actinium-225)-labeled trastuzumab (herceptin) targeting of breast cancer spheroids:: Efficacy versus HER2/neu expression
Alpha-particle emitting atomic generator (actinium-225)-labeled trastuzumab (herceptin) targeting of breast cancer spheroids:: Efficacy versus HER2/neu expression
复制标题
DOI：
10.1158/1078-0432.ccr-03-0800
复制
发表时间：
2004-07-01
影响因子：
11.5
通讯作者：
Sgouros, G
中科院分区：
文献类型：
--
作者：
Ballangrud, ÅM;Yang, WH;Sgouros, G
目的：针对HER2/neu的人源化单克隆抗体曲妥珠单抗（赫赛汀）在乳腺癌恶性肿瘤的治疗中具有良好的疗效。然而，临床活性依赖于HER2/neu的表达。放射标记曲妥珠单抗以前被认为是放射免疫治疗的潜在药物。本研究的目的是研究用a粒子发射原子发生器锕-225 （Ac-225）标记的曲妥珠单抗对不同HER2/neu表达水平的乳腺癌球体的疗效。Ac-225的半衰期为10天，衰变方案产生4个α粒子。实验设计：选用HER2/neu相对表达量（流式细胞术）为1:4:18的乳腺癌细胞系MCF7、MDA- mb -361 （MDA）、BT-474 （BT）。将这些细胞系的球体与不同浓度的ac -225-曲妥珠单抗一起培养，在50天的时间内通过光学显微镜测量球体的生长情况。结果：在第35天，MCF7、MDA和BT球体产生50%球体体积减少所需的活性浓度分别为18.1、1.9和0.6 kBq/ml（490、52、14 nCi/ml）。MCF7球体继续生长，但生长延迟20-30天，速度为18.5 kBq/ml。3.7 kBq/ml时MDA球状体生长延迟30-40天；在18.5 kBq/ml的浓度下，12个球体中有12个在70天后分解，每个球体中剩余的细胞在2周内转移到贴壁皿中未能形成菌落。在1.85 kBq/ml浓度下，10个BT球体中有8个无法再生。活性浓度为3.7 kBq/ml时，所有BT球体均不能再生和形成菌落。这三条线作为球体的放射敏感性被评估为将处理后的球体体积比降低到0.37所需的活性浓度，表示DVR37。发现所有三种细胞系的球状体的外束辐射敏感性为2gy。α粒子辐照后，测定MCF7、MDA和BT的DVR37分别为1.5、3.0和2.0 kBq/ml。结论：这些研究表明，ac -225标记的曲妥珠单抗可能是一种有效的治疗药物，用于治疗HER2/neu中高表达的转移性乳腺癌细胞。
Purpose: The humanized monoclonal antibody, trastuzumab (Herceptin), directed against HER2/neu, has been effective in the treatment of breast cancer malignancies. However, clinical activity has depended on HER2/neu expression. Radiolabeled trastuzumab has been considered previously as a potential agent for radioimmunotherapy. The objective of this study was to investigate the efficacy of trastuzumab labeled with the a-particle emitting atomic generator, actinium-225 (Ac-225), against breast cancer spheroids with different HER2/neu expression levels. Ac-225 has a 10-day half-life and a decay scheme yielding four alpha-particles.Experimental Design: The breast carcinoma cell lines MCF7, MDA-MB-361 (MDA), and BT-474 (BT) with relative HER2/neu expression (by flow cytometry) of 1:4:18 were used. Spheroids of these cell lines were incubated with different concentrations of Ac-225-trastuzumab, and spheroid growth was measured by light microscopy over a 50-day period.Results: The activity concentration required to yield a 50% reduction in spheroid volume at day 35 was 18.1, 1.9, and 0.6 kBq/ml (490, 52, 14 nCi/ml) for MCF7, MDA, and BT spheroids, respectively. MCF7 spheroids continued growing but with a 20-30 day growth delay at 18.5 kBq/ml. MDA spheroid growth was delayed by 30-40 days at 3.7 kBq/ml; at 18.5 kBq/ml, 12 of 12 spheroids disaggregated after 70, days and cells remaining from each spheroid failed to form colonies within 2 weeks of being transferred to adherent dishes. Eight of 10 BT spheroids failed to regrow at 1.85 kBq/ml. All of the BT spheroids at activity concentrations 3.7 kBq/ml failed to regrow and to form colonies. The radiosensitivity of these three lines as spheroids was evaluated as the activity concentration required to reduce the treated to untreated spheroid volume ratio to 0.37, denoted DVR37. An external beam radiosensitivity of 2 Gy was found for spheroids of all three of the cell lines. After alpha-particle irradiation a DVR37 of 1.5, 3.0, and 2.0 kBq/ml was determined for MCF7, MDA, and BT, respectively.Conclusion: These studies suggest that Ac-225-labeled trastuzumab may be a potent therapeutic agent against metastatic breast cancer cells exhibiting intermediate to high HER2/neu expression.