Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts
Positron Emission Tomography (PET) Imaging with [11C]-Labeled Erlotinib: A Micro-PET Study on Mice with Lung Tumor Xenografts
复制标题
DOI：
10.1158/0008-5472.can-08-3118
复制
发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Nexo, Ebba
中科院分区：
文献类型：
--
作者：
Memon, Ashfaque A.;Jakobsen, Steen;Nexo, Ebba
厄洛替尼（Tarceva）靶向表皮生长因子受体（EGFR），EGFR通常在人类癌症（包括肺癌）中过表达。我们表明，厄洛替尼可以标记与[C-11]-甲基碘反应的去甲甲基前体与[C-11]。通过使用3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑鎓增殖测定，显示两种肺癌细胞系（A549和NCI 358）与肺癌细胞系HCC 827相比对厄洛替尼不太敏感。这与HCC 827细胞中EGFR的表达和活性高于敏感性较低的细胞系相关。在携带A549、NCI 358和HCC 827细胞异种移植物的裸鼠中使用[C-11]-厄洛替尼进行了厄洛替尼的微正电子发射断层扫描（PET）和生物分布。动态micro-PET显示，HCC 827肿瘤具有最高的[C-11]-厄洛替尼摄取，并且与A549和NC 1358肿瘤相比，保留活性的时间显著更长。[C-11]-厄洛替尼在肺癌异种移植模型中的生物分布显示在肝脏中的蓄积最高。在携带敏感癌细胞的小鼠中，[C-11]-厄洛替尼在肿瘤中的积累高于其他器官。相比之下，药物在敏感性较低的癌细胞和其他器官的肿瘤中积累的程度相当。在A549、NCI 358和HCC 827细胞中，[C-11]-厄洛替尼在肿瘤中的摄取分别为1.6%、0.7%和3.7%（注射剂量百分比/g）。我们首次证明[C-11]-厄洛替尼可识别厄洛替尼敏感性肿瘤。这些结果为研究[C-11]-厄洛替尼PET在肺肿瘤或其他EGFR过表达肿瘤患者中的获益铺平了道路。[Cancer Res 2009;69（3）：873-8]
Erlotinib (Tarceva) targets the epidermal growth factor receptor (EGFR), which is commonly overexpressed in human cancers, including lung cancer. We show that erlotinib can be labeled with [C-11] by reacting the normethyl precursor with [C-11]-methyl iodide. By using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide proliferation assay, two lung cancer cell lines (A549 and NCI358) were shown to be less sensitive to erlotinib compared with the lung cancer cell line HCC827. This correlated with higher expression and activity of the EGFR in HCC827 cells as compared with the less sensitive cell lines. Micro-positron emission tomography (PET) and biodistribution of erlotinib was performed with [C-11]-erlotinib in nude mice bearing xenografts of A549, NCI358, and HCC827 cells. Dynamic micro-PET showed that HCC827 tumors had the highest [C-11]-erlotinib uptake and retained the activity significantly longer as compared with A549 and NC1358 tumors. Biodistribution of [C-11]-erlotinib in the xenograft models of lung cancer showed the highest accumulation in the liver. In mice carrying the sensitive cancer cells, the accumulation of [C-11]-erlotinib was higher in tumors than in the other organs. In contrast, the drug accumulated to a comparable extent in tumors from the less sensitive cancer cells and the other organs. Uptake of [C-11]-erlotinib in the tumors was 1.6%, 0.7%, and 3.7% (percentage of injected dose/g), in A549, NCI358, and HCC827 cells, respectively. We show for the first time that [C-11]-erlotinib identifies erlotinib-sensitive tumors. These results pave the road for studies examining the benefit of [C-11]-erlotinib PET in patients with lung tumors or other tumors overexpressing EGFR. [Cancer Res 2009;69(3):873-8]