18F-FLT and 125I-IdUrd uptake increase in human tumour cell lines induced by the thymidylate synthase inhibitor FdUrd.

Abstract

AIM:

5-fluoro-2'-deoxyuridine (FdUrd) depletes the endogenous 5'-deoxythymidine triphosphate (dTTP) pool. We hypothesized whether uptake of exogenous dThd analogues could be favoured through a feedback enhanced salvage pathway and studied the FdUrd effect on cellular uptake of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) and 5-125I-iodo-2'-deoxyuridine (125I-IdUrd) in different cancer cell lines in parallel.

METHODS:

Cell uptake of 18F-FLT and 125I-IdUrd was studied in 2 human breast, 2 colon cancer and 2 glioblastoma lines. Cells were incubated with/without 1 µmol/l FdUrd for 1 h and, after washing, with 1.2 MBq 18F-FLT or 125I-IdUrd for 0.3 to 2 h. Cell bound 18F-FLT and 125I-IdUrd was counted and expressed in % incubated activity (%IA). Kinetics of 18F-FLT cell uptake and release were studied with/without FdUrd modulation. 2'-3H-methyl-fluorothymidine (2'-3H-FLT) uptake with/without FdUrd pretreatment was tested on U87 spheroids and monolayer cells.

RESULTS:

Basal uptake at 2 h of 18F-FLT and 125I-IdUrd was in the range of 0.8-1.0 and 0.4-0.6 Bq/cell, respectively. FdUrd pretreatment enhanced 18F-FLT and 125I-IdUrd uptake 1.2-2.1 and 1.7-4.4 fold, respectively, while co-incubation with excess thymidine abrogated all 18F-FLT uptake. FdUrd enhanced 18F-FLT cellular inflow in 2 breast cancer lines by factors of 1.8 and 1.6, respectively, while outflow persisted at a slightly lower rate. 2'-3H-FLT basal uptake was very low while uptake increase after FdUrd was similar in U87 monolayer cells and spheroids.

CONCLUSIONS:

Basal uptake of 18F-FLT was frequently higher than that of 125I-IdUrd but FdUrd induced uptake enhancement was stronger for 125I-IdUrd in five of six cell lines. 18F-FLT outflow from cells might be an explanation for the observed difference with 125I-IdUrd.

• Authors: D Viertl, F Perillo-Adamer, P-A André, S M Ametamey, T L Ross, M Kosinski, Y M Dupertuis, A Bischof Delaloye, F Buchegger
• Journal: Nuklearmedizin. Nuclear medicine (Nuklearmedizin) Vol. 51 Issue 5 Pg. 163-9 ( 2012) ISSN: 2567-6407 [Electronic] Germany
• PMID: 22576273 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dideoxynucleosides
• Radiopharmaceuticals
• Floxuridine
• Nucleoside-Phosphate Kinase
• dTMP kinase
• Idoxuridine
• alovudine

Topics

• Cell Line, Tumor (diagnostic imaging, metabolism)
• Dideoxynucleosides (pharmacokinetics)
• Floxuridine (administration & dosage)
• Humans
• Idoxuridine (pharmacokinetics)
• Metabolic Clearance Rate (drug effects)
• Nucleoside-Phosphate Kinase (antagonists & inhibitors)
• Radionuclide Imaging
• Radiopharmaceuticals (pharmacokinetics)