TY - JOUR
T1 - Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells
T2 - Validations for positron emission tomography
AU - Grierson, John R.
AU - Schwartz, Jeffery L.
AU - Muzi, Mark
AU - Jordan, Robert
AU - Krohn, Kenneth A.
PY - 2004/10
Y1 - 2004/10
N2 - 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 ∼30% 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.
AB - 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 ∼30% 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.
KW - DNA salvage pathway
KW - FLT
KW - Fluorothymidine
KW - Nucleoside metabolism
KW - PET
UR - http://www.scopus.com/inward/record.url?scp=4644361597&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=4644361597&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2004.06.004
DO - 10.1016/j.nucmedbio.2004.06.004
M3 - Article
C2 - 15464384
AN - SCOPUS:4644361597
VL - 31
SP - 829
EP - 837
JO - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
JF - International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology
SN - 0969-8051
IS - 7
ER -