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Permanent link (DOI): https://doi.org/10.7939/R33363

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Characterization of transport of positron emission tomography tracer 3′-deoxy-3′-fluorothymidine by nucleoside transporters Open Access

Descriptions

Other title
Subject/Keyword
positron emission tomography
3′-deoxy-3′-fluorothymidine
nucleoside transporters
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Paproski, Robert Joseph
Supervisor and department
Cass, Carol (Oncology)
Examining committee member and department
Hitt, Mary (Oncology)
Cheeseman, Chris (Physiology)
Cass, Carol (Oncology)
Young, James (Physiology)
Hammond, James (Physiology and Pharmacology)
Department
Department of Oncology
Specialization

Date accepted
2010-01-07T22:44:02Z
Graduation date
2012-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Positron emission tomography (PET) tracer 3′-fluoro-3′-deoxythymidine (FLT) is used for imaging tumor proliferation. Prior to this work, human equilibrative nucleoside transporter 1 (hENT1) was the only known human nucleoside transporter (hNT) capable of FLT transport. The aim of this research was to determine if other hNTs, including hENT2, human concentrative nucleoside transporter 1 (hCNT1), hCNT2 and hCNT3, were capable/important of/for FLT transport in mammalian cells. Transport assays performed in Xenopus laevis oocytes producing recombinant hNTs demonstrated that hENT1/2 and hCNT1/3 were capable of FLT transport. FLT uptake assays with or without hENT1 inhibitor nitrobenzylmercaptopurine ribonucleoside (NBMPR) in various cultured cancer cell lines demonstrated that hENT1 was responsible for the majority of mediated FLT uptake in all tested cell lines, suggesting that hENT1 was important for FLT uptake. The in vivo role of hENT1 in FLT uptake was determined by performing [18F]FLT PET on wild-type and ENT1 knockout mice. One hour after [18F]FLT injection, ENT1 knockout mice displayed significantly reduced [18F]FLT accumulation in the blood, heart, brain, kidney, liver, and lungs compared to wild-type mice. Interestingly, ENT1 knockout mice displayed increased [18F]FLT accumulation in the bone marrow and spleen which both have high CNT expression, suggesting that loss of ENT1 significantly alters FLT biodistribution in mice. hENT1 is a predictive marker of gemcitabine response in pancreatic cancers. Since FLT uptake and gemcitabine toxicity are dependent on hENT1, FLT uptake may predict gemcitabine response in pancreatic cancers. To test this hypothesis, six different pancreatic cancer cell lines were analyzed for FLT uptake and gemcitabine toxicity. hENT1/2 inhibition in cells decreased FLT uptake and gemcitabine sensitivity. In five of six cell lines, a positive correlation was observed between FLT uptake and gemcitabine toxicity, suggesting that FLT PET may be clinically useful for predicting gemcitabine response in pancreatic cancers. The results from this research suggest that hNTs, especially hENT1, are important for FLT uptake in mammalian cells and that FLT uptake can predict gemcitabine response in most cultured pancreatic cancer cells. The results warrant FLT PET clinical trials in pancreatic cancer patients to determine the potential of FLT PET in predicting gemcitabine response.
Language
English
DOI
doi:10.7939/R33363
Rights
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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