Choline transporter as a novel target for molecular imaging of cancer
Choline transporter as a novel target for molecular imaging of cancer
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DOI：
10.2310/7290.2006.00032
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发表时间：
2006-10-01
影响因子：
2.8
通讯作者：
DeGrado, Timothy R.
中科院分区：
文献类型：
--
作者：
Hara, Toshihiko;Bansal, Aditya;DeGrado, Timothy R.
胆碱在癌细胞中的加工的抑制已经被用作正电子发射断层扫描和磁共振波谱成像的癌症的基础。在这项研究中，胆碱的运输机制进行了研究，在培养的PC-3前列腺癌细胞。此外，氚标记的半胆碱3（HC-3），一个众所周知的胆碱转运抑制剂，作为一个原型的分子成像探针在PC-3细胞和9 L胶质瘤荷瘤大鼠进行了研究。[H-3]发现PC-3细胞摄取胆碱具有促进和非促进成分。促进转运的特征在于部分钠依赖性和中等亲和力（Km = 9.7 +/- 0.8 ILIVI）。HC-3抑制胆碱的K-I为10.5 +/- 2.2 μ M。哇巴因（1 mM）引起胆碱摄取减少94%。在生理胆碱浓度，磷酸胆碱是快速和主要的代谢命运。[H-3]HC-3与PC-3细胞的结合是快速和特异性的（与未标记的HC-3竞争性阻断）。[3] HIHC-3在荷9 L胶质瘤大鼠体内的生物分布显示摄取顺序为肾>肺>肿瘤>肝>骨骼肌血>脑。与[C-14]胆碱相比，[H-3]HC-3显示出高两倍以上的肿瘤吸收以及肿瘤与血液、肿瘤与肌肉、肿瘤与肺和肿瘤与肝脏的有利吸收比。这些数据表明，在PC-3癌细胞中，中等亲和力，部分钠依赖性胆碱转运系统对胆碱加工的定量重要性。[H-3]HC-3在荷瘤大鼠中的生物分布特性促进了基于胆碱转运蛋白结合配体的分子成像探针的开发。
Abnormalities of choline processing in cancer cells have been used as a basis for imaging of cancer with positron emission tomography and magnetic resonance spectroscopy. In this study, the transport mechanism for choline was investigated in cultured PC-3 prostate cancer cells. Furthermore, tritiated hemicholinium 3 (HC-3), a well-known inhibitor of choline transport, was studied as a prototypic molecular imaging probe in PC-3 cells and 9L glioma-bearing rats. [H-3]Choline uptake by PC-3 cells was found to have both facilitative and nonfacilitative components. Facilitative transport was characterized by partial sodium dependence and intermediate affinity (K-m = 9.7 +/- 0.8 ILIVI). HC-3 inhibited choline with a K-I of 10.5 +/- 2.2 mu M. Ouabain (1 mM) caused a 94% reduction in choline uptake. At physiologic choline concentration, phosphocholine was the rapid and predominant metabolic fate. The binding of [H-3]HC-3 to PC-3 cells was rapid and specific (competitively blocked with unlabeled HC-3). Biodistribution of [3 HIHC-3 in 9L glioma-bearing rats showed the ranking of uptake to be kidney > lung > tumor > liver > skeletal muscle blood > brain. In comparison with [C-14]choline, [H-3]HC-3 showed over twofold higher tumor uptake and favorable uptake ratios of tumor to blood, tumor to muscle, tumor to lung, and tumor to liver. The data demonstrate the quantitative importance of an intermediate-affinity, partially sodium-dependent choline transport system on choline processing in PC-3 cancer cells. The biodistribution properties of [H-3]HC-3 in tumor-bearing rats encourage the development of molecular imaging probes based on choline transporter binding ligands.