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Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography

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Publication Date
2006-09-01
ICR Author
Forster, Martin
Mitchell, Fraser
Author
Perumal, M
Pillai, RG
Barthel, H
Leyton, J
Latigo, JR
Forster, M
Mitchell, F
Jackman, AL
Aboagye, EO
Type
Journal Article
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Abstract
Thymidylate synthase (EC 2.1.1.45) is a key enzyme for the de novo synthesis of DNA and as such a target for anticancer drug development. There is a need to develop noninvasive methods for assessing thymidylate synthase inhibition in tumors. The aim of this study was to assess the potential of 3’-deoxy-3’-[F-18]fluorothymidine ([F-18]FLT) positron emission tomography (PET) for early measurement of thymidylate synthase inhibition and to elucidate the cellular mechanisms involved. Radiation-induced fibrosarcoma-1 tumor-bearing mice were injected with a single i.p. dose of the thymidylate synthase inhibitor 5-fluorouracil (5-FU; 165 mg/kg) and imaged by [F-18]FLT-PET at 1 to 2 hours after treatment. Deoxyuridine, thymidine kinase 1 (cytoplasmic thymidine kinase; EC2.7.1.21), and ATP levels in excised tumors were measured. Cellular assays for membrane transport were also done. There was a 1.8-fold increase in the 60-minute [F-18]FLT tumor/heart radioactivity ratio in drug-treated mice compared with vehicle controls (P = 0.0016). Plasma and tumor deoxyuridine levels increased significantly but thymidine kinase and ATP levels were unchanged. Whole-cell assays implicated a (low level) functional role for the type-1 equilibrative nucleoside transporter (ENT). There was an increase in type-1 ENT-binding sites per cell from 49,110 in untreated cells to 73,142 (P = 0.03) in cells treated with 10 mu g/mL 5-FU for 2 hours, without a change in transporter affinity (P = 0.41). We conclude that [F-18]FLT-PET can be used to measure thymidylate synthase inhibition as early as 1 to 2 hours after treatment with 5-FU by a mechanism involving redistribution of nucleoside transporters to the plasma membrane.
URL
https://repository.icr.ac.uk/handle/internal/2511
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Version of record
10.1158/0008-5472.CAN-06-0898
Language
English
License start date
2006-09-01
Citation
CANCER RESEARCH, 2006, 66 pp. 8558 - 8564
Publisher
AMER ASSOC CANCER RESEARCH

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