Qin Chunxia, Liu Hongguang, Chen Kai, Hu Xiang, Ma Xiaowei, Lan Xiaoli, Zhang Yongxue, Cheng Zhen
Molecular Imaging Program at Stanford (MIPS), Canary Center at Stanford for Cancer Early Detection, Department of Radiology and Bio-X Program, Stanford University, Stanford, California; and.
J Nucl Med. 2014 May;55(5):812-7. doi: 10.2967/jnumed.113.133850. Epub 2014 Mar 13.
Human copper transporter 1 (CTR1) is overexpressed in a variety of cancers. This study aimed to evaluate the use of (64)CuCl2 as a theranostic agent for PET and radionuclide therapy of malignant melanoma.
CTR1 expression levels were detected by Western blot analysis of a group of tumor cell lines. Two melanoma cell lines (B16F10 and A375M) that highly expressed CTR1 were then selected to study the uptake and efflux of (64)CuCl2. Mice bearing B16F10 or A375M tumors (n = 4 for each group) were subjected to 5 min of static whole-body PET scans at different time points after intravenous injection of (64)CuCl2. Dynamic scans were also obtained for B16F10 tumor-bearing mice. All mice were sacrificed at 72 h after injection of (64)CuCl2, and biodistribution studies were performed. Mice bearing B16F10 or A375M tumors were further subjected to (64)CuCl2 radionuclide therapy. Specifically, when the tumor size reached 0.5-0.8 cm in diameter, tumor-bearing mice were systemically administered (64)CuCl2 (74 MBq) or phosphate-buffered saline, and tumor sizes were monitored over the treatment period.
CTR1 was found to be overexpressed in the cancer cell lines tested at different levels, and high expression levels in melanoma cells and tissues were observed (melanotic B16F10 and amelanotic A375M). (64)CuCl2 displayed high and specific uptake in B16F10 and A375M cells. In vivo (64)CuCl2 PET imaging demonstrated that both B16F10 and A375M tumors were clearly visualized. Radionuclide treatment studies showed that the tumor growth in both the B16F10 and the A375M models under (64)CuCl2 treatment were much slower than that of the control group.
Both melanotic and amelanotic melanomas (B16F10 and A375M) tested were found to overexpress CTR1. The tumors can be successfully visualized by (64)CuCl2 PET and further treated by (64)CuCl2, highlighting the high potential of using (64)CuCl2 as a theranostic agent for the management of melanoma.
人铜转运蛋白1（CTR1）在多种癌症中过表达。本研究旨在评估（64）CuCl2作为恶性黑色素瘤正电子发射断层显像（PET）和放射性核素治疗的诊疗剂的应用。
通过对一组肿瘤细胞系进行蛋白质免疫印迹分析来检测CTR1表达水平。然后选择两个高表达CTR1的黑色素瘤细胞系（B16F10和A375M）来研究（64）CuCl2的摄取和流出。给荷B16F10或A375M肿瘤的小鼠（每组n = 4）静脉注射（64）CuCl2后，在不同时间点进行5分钟的静态全身PET扫描。对荷B16F10肿瘤的小鼠也进行了动态扫描。在注射（64）CuCl2后72小时处死所有小鼠，并进行生物分布研究。对荷B16F10或A375M肿瘤的小鼠进一步进行（64）CuCl2放射性核素治疗。具体而言，当肿瘤直径达到0.5 - 0.8厘米时，给荷瘤小鼠全身注射（64）CuCl2（74 MBq）或磷酸盐缓冲盐水，并在治疗期间监测肿瘤大小。
发现CTR1在测试的癌细胞系中不同程度地过表达，并且在黑色素瘤细胞和组织中观察到高表达水平（黑色素性的B16F10和无黑色素的A375M）。（64）CuCl2在B16F10和A375M细胞中表现出高特异性摄取。体内（64）CuCl2 PET显像表明B16F10和A375M肿瘤均能清晰显影。放射性核素治疗研究表明，在（64）CuCl2治疗下，B16F10和A375M模型中的肿瘤生长均比对照组慢得多。
所测试的黑色素性和无黑色素性黑色素瘤（B16F10和A375M）均被发现过表达CTR1。肿瘤可以通过（64）CuCl2 PET成功显影，并进一步用（64）CuCl2治疗，突出了使用（64）CuCl2作为黑色素瘤治疗诊断剂的巨大潜力。
