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Molecular Imaging and Biology
Published in: Molecular Imaging and Biology 6/2017

01-12-2017 | Research Article

In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2′-deoxy-2′-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models

Authors: James Russell, Nagavarakishore Pillarsetty, Robin M Kramer, Paul B Romesser, Pooja Desai, Adriana Haimovitz-Friedman, Maeve A Lowery, John L Humm

Published in: Molecular Imaging and Biology | Issue 6/2017

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Abstract

Purpose

Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2′-deoxy-2′-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug.

Procedures

[18F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14C]gemcitabine and [18F]FAC were mapped with autoradiography. The inter-tumor correlation between [14C]gemcitabine and [18F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays.
The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18F]FAC and [14C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14C]gemcitabine and [18F]FAC were largely co-localized.

Conclusions

In the lines examined here, [18F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.
Appendix
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Metadata
Title
In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2′-deoxy-2′-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models
Authors
James Russell
Nagavarakishore Pillarsetty
Robin M Kramer
Paul B Romesser
Pooja Desai
Adriana Haimovitz-Friedman
Maeve A Lowery
John L Humm
Publication date
01-12-2017
Publisher
Springer US
Published in
Molecular Imaging and Biology / Issue 6/2017
Print ISSN: 1536-1632
Electronic ISSN: 1860-2002
DOI
https://doi.org/10.1007/s11307-017-1078-6

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