Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity
Radioimmunotherapy of solid tumors targeting a cell-surface protein, FZD10: therapeutic efficacy largely depends on radiosensitivity
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DOI：
10.1007/s12149-009-0265-1
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发表时间：
2009-07-01
影响因子：
2.6
通讯作者：
Endo, Keigo
中科院分区：
文献类型：
--
作者：
Hanaoka, Hirofumi;Katagiri, Toyomasa;Endo, Keigo
卷曲同源物10 （FZD10）在几乎所有滑膜肉瘤组织的细胞表面高水平表达，但在大多数正常器官中不存在。在先前的一项研究中，钇-90 （Y-90）标记的抗fzd10抗体（MAb 92-13）在滑膜肉瘤细胞携带小鼠中显示出相当大的治疗效果。本研究的目的是阐明与Y-90-MAb 92-13治疗效果相关的因素。通过细胞结合法检测SYO-1（过表达FZD10的滑膜肉瘤细胞系）和ddd -1/FZD10（转染FZD10的ddd -1细胞）的FZD10表达水平，并通过Y-90-MAb 92-13体外培养评估其放射敏感性。研究铟-111 (in -111)-MAb 92-13在SYO-1和DLD-1/FZD10荷瘤小鼠体内的生物分布。在治疗性研究中，用Y-90-MAb 92-13（100、150和200 μ Ci）治疗SYO-1和DLD-1/FZD10荷瘤小鼠，之后测量肿瘤体积的变化。对切除肿瘤进行免疫组化染色。FZD10在DLD-1/FZD10上的表达量远大于SYO-1。在DLD-1/FZD10荷瘤小鼠中，in -111- mab 92-13的积累量远高于SYO-1荷瘤小鼠（给药后48 h，分别为49.0 +/- A 4.2和22.0 +/- A 4.5% ID/g）。在SYO-1肿瘤中，Y-90-MAb 92-13治疗后，所有小鼠的肿瘤体积均明显减小（治疗后11天肿瘤体积减小至小于0.1 cm(3)），大多数小鼠未观察到肿瘤再生。相比之下，在DLD-1/FZD10肿瘤中只观察到缓慢的进展。与Y-90-MAb 92-13孵育时，需要高放射性才能破坏DLD-1/FZD10。免疫组化显示SYO-1肿瘤细胞凋亡。RIT的治疗效果似乎在很大程度上取决于肿瘤的放射敏感性。
Frizzled homolog 10 (FZD10) is expressed at high levels on the cell surface of almost all synovial sarcoma tissues, but is absent in most normal organs. In a previous study, yttrium-90 (Y-90)-labeled anti-FZD10 antibody (MAb 92-13) showed considerable therapeutic efficacy in synovial sarcoma cell-bearing mice. The purpose of the present study was to elucidate the factors associated with this therapeutic efficacy of Y-90-MAb 92-13.FZD10 expression levels of SYO-1 (FZD10-overexpressing synovial sarcoma cell line) and DLD-1/FZD10 (FZD10-transfected DLD-1 cell) were determined by the cell binding assay, and their radiosensitivity was evaluated by incubation with Y-90-MAb 92-13 in vitro. Biodistribution study of indium-111 (In-111)-MAb 92-13 was performed in SYO-1 and DLD-1/FZD10 tumor-bearing mice. For therapeutic studies, SYO-1 and DLD-1/FZD10 tumor-bearing mice were treated with Y-90-MAb 92-13 (100, 150, and 200 mu Ci), after which the change in tumor volume was measured. Immunohistochemical staining was performed on the excised tumor.Expression level of FZD10 on DLD-1/FZD10 was much greater than that on SYO-1. The accumulation of In-111-MAb 92-13 was much higher in DLD-1/FZD10 tumor-bearing mice than in SYO-1 tumor-bearing mice (49.0 +/- A 4.2 and 22.0 +/- A 4.5% ID/g, respectively, at 48 h after administration). In SYO-1 tumor, substantial tumor size reduction was observed in all mice treated with Y-90-MAb 92-13 (tumor volume decreased to less than 0.1 cm(3) at 11 days after treatment) and tumor regrowth was not observed in most of them. In contrast, only slow progression was observed in DLD-1/FZD10 tumor. When incubated with Y-90-MAb 92-13, high radioactivity was needed to damage DLD-1/FZD10. Immunohistochemical study indicated apoptosis of SYO-1 tumor.The therapeutic efficacy of RIT seems to largely depend on the tumor radiosensitivity.