Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells:: validations for positron emission tomography
Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells:: validations for positron emission tomography
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DOI：
10.1016/j.nucmedbio.2004.06.004
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发表时间：
2004-10-01
影响因子：
3.1
通讯作者：
Krohn, KA
中科院分区：
文献类型：
--
作者：
Grierson, JR;Schwartz, JL;Krohn, KA
3 '-脱氧-3'-[F-18]氟胸苷（FLT）作为一种代谢探针正在接受临床评价，用于使用正电子发射断层扫描（PET）对体内细胞增殖进行成像。作为验证工作的一部分，我们跟踪了FLT在指数生长肿瘤细胞中的短期代谢，以证明DNA补救途径中影响放射性保留的酶活性。在A549细胞中，胸苷激酶-1（TK 1）的活性产生FLTMP，其在标记的核苷酸池中占主导地位。随后由胸苷酸激酶（TMPK）和核苷酸二磷酸激酶（NDPK）进行的核苷酸磷酸化导致FLTTP。1h后，细胞代谢池中含有约30%的FLTTP。一种推定的脱氧核苷酸酶（dNT），可将FLTMP降解为FLT，为示踪剂从细胞中流出提供了主要机制。相反，FLTTP耐降解且保留率高。还比较了FLT与胸苷、FMAU（2 '-阿拉伯氟-TdR）和FIAU（2'-阿拉伯氟-5-碘-2 '-脱氧尿苷）的摄取和保留特征。尽管FLT缺乏其掺入DNA所必需的3 '-羟基，但它在摄取和保留方面表现出FMAU和FIAU。(C)2004年爱思唯尔公司All rights reserved.
3'-Deoxy-3'-[F-18]fluorothymidine (FLT) is under clinical evaluation as a metabolic probe for imaging cell proliferation in vivo using positron emission tomography (PET). As part of our validation effort, we followed the short-term metabolism of FLT in exponentially growing tumor cells to demonstrate the enzyme activities within the DNA salvage pathway that influence retention of radioactivity. In A549 cells, thymidine kinase-1 (TK1) activity produced FLTMP, which dominated the labeled nucleotide pool. Subsequent nucleotide phosphorylations by thymidylate kinase (TMPK) and nucleotide diphosphate kinase (NDPK) led to FLTTP. After 1h, the cellular metabolic pool contained similar to30% FLTTP. A putative deoxynucleotidase (dNT), which degrades FLTMP to FLT, provided the primary mechanism for tracer efflux from cells. In contrast, FLTTP was resistant to degradation and highly retained. The uptake and retention characteristics of FLT were also compared to those of thymidine, FMAU (2'-arabino-fluoro-TdR) and FIAU (2'-arabino-fluoro-5-iodo-2'-dexoyuridine). Despite the fact that FLT lacks the 3'-hydroxy necessary for its incorporation into DNA it out performed both FMAU and FIAU in terms of uptake and retention. (C) 2004 Elsevier Inc. All rights reserved.