CEA-DSV-I2BM-SHFJ, Orsay, France.
J Nucl Med. 2013 Dec;54(12):2125-31. doi: 10.2967/jnumed.112.118794. Epub 2013 Nov 8.
On the one hand, the translocator protein (TSPO) radioligand N,N-diethyl-2-(2-(4-(2-(18)F-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ((18)F-DPA-714) has been suggested to serve as an alternative radiotracer to image human glioma, and on the other hand the alkylphosphocholine erufosine (ErPC3) has been reported to induce apoptosis in otherwise highly apoptosis-resistant glioma cell lines. The induction of apoptosis by ErPC3 requires TSPO, a mitochondrial membrane protein highly expressed in malignant gliomas. In this preclinical study, we monitored the effect of ErPC3 treatment in vivo using (18)F-DPA-714 PET.
In vitro studies investigated the antitumor effect of ErPC3 in 9L rat gliosarcoma cells. In vivo, glioma-bearing rats were imaged with (18)F-DPA-714 for the time of treatment.
A significant decrease in 9L cell proliferation and viability and a significant increase in apoptosis and caspase-3 activation were demonstrated on ErPC3 treatment in cell culture. In the rat model, ErPC3 administration resulted in significant changes in (18)F-DPA-714 tumor uptake over the course of the treatment. Immunohistochemistry revealed reduced tumor volume and increased cell death in ErPC3-treated animals accompanied by infiltration of the tumor core by CD11b-positive microglia/macrophages and glial fibrillary acidic protein-positive astrocytes.
Our findings demonstrate a potent antitumor effect of ErPC3 in vitro, in vivo, and ex vivo. PET imaging of TSPO expression using (18)F-DPA-714 allows effective monitoring and quantification of disease progression and response to ErPC3 therapy in intracranial 9L gliomas.
一方面，转位蛋白（TSPO）放射性配体 N，N-二乙基-2-（2-（4-（2-（18）F-氟乙氧基）苯基）-5，7-二甲基吡唑并[1，5-a]嘧啶-3-基）乙酰胺（（18）F-DPA-714）被建议作为一种替代放射性示踪剂来成像人类脑胶质瘤，另一方面，烷基膦胆碱 erufosine（ErPC3）已被报道在其他高度抗凋亡的神经胶质瘤细胞系中诱导细胞凋亡。ErPC3 诱导细胞凋亡需要 TSPO，一种在恶性神经胶质瘤中高度表达的线粒体膜蛋白。在这项临床前研究中，我们使用（18）F-DPA-714 PET 监测 ErPC3 治疗的体内效果。
体外研究探讨了 ErPC3 在 9L 大鼠神经胶质瘤肉瘤细胞中的抗肿瘤作用。在体内，荷瘤大鼠在治疗期间进行（18）F-DPA-714 成像。
在细胞培养中，ErPC3 处理显示 9L 细胞增殖和活力显著下降，凋亡和 caspase-3 激活显著增加。在大鼠模型中，ErPC3 给药导致（18）F-DPA-714 肿瘤摄取在治疗过程中发生显著变化。免疫组织化学显示，ErPC3 治疗动物的肿瘤体积减小，细胞死亡增加，肿瘤核心浸润 CD11b 阳性小胶质细胞/巨噬细胞和胶质纤维酸性蛋白阳性星形细胞。
我们的研究结果表明 ErPC3 在体外、体内和离体具有强大的抗肿瘤作用。使用（18）F-DPA-714 对 TSPO 表达进行 PET 成像可有效监测和量化颅内 9L 神经胶质瘤的疾病进展和对 ErPC3 治疗的反应。
