C-kit-targeted imaging of gastrointestinal stromal tumor using radiolabeled anti-c-kit monoclonal antibody in a mouse tumor model
C-kit-targeted imaging of gastrointestinal stromal tumor using radiolabeled anti-c-kit monoclonal antibody in a mouse tumor model
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DOI：
10.1016/j.nucmedbio.2009.10.008
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发表时间：
2010-02-01
影响因子：
3.1
通讯作者：
Saga, Tsuneo
中科院分区：
文献类型：
--
作者：
Sogawa, Chizuru;Tsuji, Atsushi B.;Saga, Tsuneo
胃肠道间质瘤（GIST）是最常见的发生于胃肠道的间质肿瘤，高表达突变的c-kit。本研究旨在建立一种特异、灵敏的放射标记抗c-kit单克隆抗体检测gist的方法。方法：将c-kit突变基因表达载体转染HEK293人胚胎肾细胞，建立表达突变c-kit的细胞克隆。将表达c-kit的细胞接种于裸鼠体内，形成肿瘤。I-125和in -111标记的抗c-kit抗体（12A8和41A11）在体外通过细胞结合、竞争抑制和细胞内化试验进行评估，在体内通过荷瘤小鼠的生物分布和成像研究进行评估。结果：I-125和in -111标记的抗体均与表达c-kit的细胞特异性结合，具有高亲和力（解离常数= 2.2-7.1 × 10(9) M-1）。内化实验表明，I-125标记的抗体被快速内化和脱卤，随着I-125从细胞中释放出来，导致细胞相关放射性随时间降低。相比之下，In-111标记的抗体被内化，但没有导致与肿瘤细胞相关的放射性降低。反映这一现象的是，i -125标记抗体的体内肿瘤摄取在第1天较低，随着滴度的增加而进一步降低，而in -111标记抗体的体内肿瘤摄取在第1天较高，随着时间的增加而进一步增加。注射in -111标记的抗体后，异种移植肿瘤的显像清晰可见。结论：金属放射性核素标记的抗c-kit单克隆抗体有望用于gist的c-kit靶向显像。(C) 2010爱思唯尔公司版权所有。
Introduction: Gastrointestinal stromal tumor (GIST) is the most common a mesenchymal tumor arising from the gastrointestinal tract and highly expresses mutated c-kit. We aimed to develop a specific and sensitive method for detecting GISTs using radiolabeled anti-c-kit monoclonal antibody.Methods: A mutated c-kit-expressing cell clone was established by transfecting an expressing vector of mutated c-kit gene into HEK293 human embryonic kidney cells. The tumors were developed by inoculating c-kit-expressing cells into nude mice. I-125- and In-111-labeled anti-c-kit antibodies (12A8 and 41A11) were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays, and in vivo by biodistribution and imaging studies in tumor-bearing mice.Results: Both I-125- and In-111-labeled antibodies showed specific binding with c-kit-expressing cells with high affinity (dissociation constants = 2.2-7.1 x 10(9) M-1). Internalization assay showed that I-125-labeled antibodies were rapidly internalized and dehalogenated, with the release of I-125 from the cells, resulting in reduction of cell-associated radioactivity with time. In contrast, In-111-labeled antibody was internalized but did not result in the reduced radioactivity associated with tumor cells. Reflecting this phenomenon, the in vivo tumor uptake of I-125-labeled antibody was low on Day 1, further decreasing with titre, while tumor uptake of In-111-labeled antibody was high on Day 1, further increasing with time. The xenografted tumor was clearly visualized by scintigraphy after injection of In-111-labeled antibody.Conclusion: The anti-c-kit monoclonal antibody labeled with a metal radionuclide would be promising for c-kit-targeted imaging of GISTs. (C) 2010 Elsevier Inc. All rights reserved.