Document Detail

In vivo and in vitro multitracer analyses of P-glycoprotein expression-related multidrug resistance.
MedLine Citation:
PMID:  12830325     Owner:  NLM     Status:  MEDLINE    
P-glycoprotein (Pgp) is an ABC (ATP binding cassette) transporter that is often overexpressed in tumours, contributing significantly to their multidrug resistance. In this study, we explored whether the radiotracers used in tumour diagnostics can be used for in vivo visualisation of Pgp-related multidrug resistance. We also examined the effects of different Pgp modulators on the accumulation of these radioligands in tumours with or without Pgp expression. In a SCID BC-17 mouse model, cells of the drug-sensitive KB-3-1 (MDR(-)) and the KB-V1 Pgp-expressing (MDR(+)) human epidermoid carcinoma cell lines were inoculated to yield tumours in opposite flanks. For in vivo scintigraphic (biodistribution) and positron emission tomography (PET) examinations, the mice were injected with technetium-99m hexakis-2-methoxybutylisonitrile ((99m)Tc-MIBI), carbon-11 labelled methionine and fluorine-18 fluoro-2-deoxy- d-glucose ((18)FDG). For validation, in vitro cell studies with (99m)Tc-MIBI,( 99m)Tc-tetrofosmin, [(11)C]methionine and (18)FDG were carried out using a gamma counter. The expression and function of the MDR product were proved by immunohistochemistry and spectrofluorimetry. (99m)Tc-MIBI uptake was significantly lower in KB-V1 cells as compared with KB-3-1-derived tumours in vivo (Pgp(+)/Pgp(-) =0.61+/-0.13; P<0.01) and cells in vitro (Pgp(+)/Pgp(-) =0.08+/-0.01; P<0.001).()Cyclosporin A reversed (99m)Tc-MIBI uptake in the Pgp+ cells, while verapamil failed to modify it. (18)FDG uptake was significantly higher in KB-V1 tumours (Pgp(+)/Pgp(-) =1.36+/-0.05; P<0.01) and cells (Pgp(+)/Pgp(- )=1.52+/-0.12; P<0.001). Whereas cyclosporin A eliminated the difference between FDG uptake in MDR(+) and MDR(-) cell lines, verapamil significantly increased it. When the animals were treated with verapamil, the ratio of (99m)Tc-MIBI uptake in the MDR(+) tumours to that in the MDR(-) tumours decreased to 0.38+/-0.05 ( P<0.01), while the ratio of (18)FDG uptake increased to 2.1+/-0.3 ( P<0.001). There were no significant differences in the [(11)C]methionine uptake in the MDR(+) and MDR(-) tumours and cell lines, nor was [(11)C]methionine accumulation modified by cyclosporin A. Parallel administration of (18)FDG and (99m)Tc-MIBI combined with verapamil treatment seems to be a good candidate as a non-invasive marker for the diagnosis of MDR-related Pgp expression in tumours.
Teréz Márián; Gábor Szabó; Katalin Goda; Henrietta Nagy; Nóra Szincsák; István Juhász; László Galuska; László Balkay; Pál Mikecz; Lajos Trón; Zoltán Krasznai
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Publication Detail:
Type:  Comparative Study; Evaluation Studies; Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-06-27
Journal Detail:
Title:  European journal of nuclear medicine and molecular imaging     Volume:  30     ISSN:  1619-7070     ISO Abbreviation:  Eur. J. Nucl. Med. Mol. Imaging     Publication Date:  2003 Aug 
Date Detail:
Created Date:  2003-08-04     Completed Date:  2004-05-25     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  101140988     Medline TA:  Eur J Nucl Med Mol Imaging     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  1147-54     Citation Subset:  IM    
PET Center, University of Debrecen, Hungary.
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MeSH Terms
Antineoplastic Agents / therapeutic use
Carcinoma, Squamous Cell / drug therapy,  metabolism*,  radionuclide imaging*
Cell Line, Tumor
Cyclosporine / therapeutic use
Drug Resistance, Multiple
Drug Resistance, Neoplasm*
Fluorodeoxyglucose F18 / diagnostic use*,  pharmacokinetics*
Metabolic Clearance Rate
Mice, SCID
P-Glycoprotein / metabolism*
Radioisotope Dilution Technique
Radiopharmaceuticals / diagnostic use,  pharmacokinetics
Technetium Tc 99m Sestamibi / diagnostic use*,  pharmacokinetics*
Tissue Distribution
Tomography, Emission-Computed / methods
Verapamil / therapeutic use
Reg. No./Substance:
0/Antineoplastic Agents; 0/P-Glycoprotein; 0/Radiopharmaceuticals; 109581-73-9/Technetium Tc 99m Sestamibi; 52-53-9/Verapamil; 59865-13-3/Cyclosporine; 63503-12-8/Fluorodeoxyglucose F18

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