期刊
NUCLEAR MEDICINE AND BIOLOGY
卷 31, 期 7, 页码 829-837出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.nucmedbio.2004.06.004
关键词
FLT; nucleoside metabolism; PET; fluorothymidine; DNA salvage pathway
资金
- NCI NIH HHS [CA34570, CA42045, P01 CA042045] Funding Source: Medline
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.
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