Journal
BIOCHEMICAL PHARMACOLOGY
Volume 80, Issue 10, Pages 1528-1536Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2010.08.004
Keywords
5-Fluorouracil; Thymidine kinase 1; Thymidylate synthase; Positron emission tomography; [F-18]fluorothymidine
Categories
Funding
- Korea Healthcare Technology
- Ministry for Health, Welfare & Family Affairs, Republic of Korea [A062254]
- Real Time Molecular Imaging Research Program [2010-002040]
- Ministry of Education, Science and Technology, Republic of Korea
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Imaging the pharmacodynamics of anti-cancer drugs may allow early assessment of anti-cancer effects. Increases in 3'-deoxy-3'-[F-18]fluorothymidine ([F-18]FLT) uptake early after thymidylate synthase inhibition (TS) inhibition, the so-called flare response, is considered to be largely due to an increase in binding sites for type-1 equilibrative nucleoside transporter. We investigated the induction of thymidine kinase 1 (TK1) after 5-fluorouracil (5-FU) treatment as one of mechanisms for [F-18]FLT flare. Exposure of nine cancer cell lines to 5-FU for 24 h induced a 2.5- to 3.5-fold increase in [F-18]FLT uptake, significantly higher than the 1.5-fold increase observed 2 h after treatment. The increase of [F-18]FLT uptake 24 h after 5-FU exposure accompanied TK1 induction in most cell lines. In representative cell lines (A431 and HT29), 5-FU time-dependently increased [F-18]FLT uptake, kinase activity and the levels of protein and mRNA for TK1, sequential cyclin E and A induction, and G1-S phase transition. Cycloheximide treatment and knockdown of TK1 completely inhibited 5-FU-induced [F-18]FLT flare. On the other hand. HCT8 cells showed a biphasic [F-18]FLT flare with lacked TK1 induction in response to the dosage of 5-FU. Cycloheximide did not inhibit 5-FU-induced [F-18]FLT flare in this cells. In vivo dynamic [F-18]FLT-PET and ex vivo analysis in HT29 tumor-bearing mice showed significantly increased [F-18]FLT flux and TK1 activity of tumor tissue 24 h after 5-FU administration (P < 0.05). Conclusively, 5-FU induced TK1 and TK1-mediated high [F-18]FLT flare in most of cell lines. [F-18]FLT-PET may be used to assess pharmacodynamics of TS inhibitor by a mechanism involving TK1 induction. (c) 2010 Elsevier Inc. All rights reserved.
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