Abstract
Purpose
We tested the suitability of 99mTc-sestamibi to image the inhibition of P-glycoprotein (Pgp)-mediated multidrug resistance in tumor cells and xenografts after antisense treatment and/or inhibition with a novel Pgp modulator WK-X-34.
Procedure
Pgp inhibition was measured by daunorubicin transport assays and fluorescence microscopy in resistant A2780/Adr cells treated with WK-X-34 and antisense. A2780/Adr xenograft mice were dosed with mdr1 antisense oligodeoxynucleotides intratumorally for three days; next, mice were treated with WK-X-34, followed by 99mTc-sestamibi injection. Mice were imaged, sacrificed, and tissues collected. Images and isolated tissues were analyzed for 99Tc distribution. Pgp expression was analyzed by immunofluorescence and reverse transcription-polymerase chain reaction.
Results
Both WK-X-34 and mdr1 antisense treatments significantly inhibited Pgp activity in vitro and in xenografts. Biodistribution results correlated with results from the 99mTc-sestamibi images. Mdr1 mRNA and Pgp were significantly down-regulated by antisense treatments.
Conclusions
99mTc-sestamibi is a sensitive probe to monitor Pgp inhibition by different mechanisms in vivo in tumor xenografts.
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Acknowledgments
This research was supported by a Canadian Institute of Health Research Grant (MPM), the Deutsche Forschungsgemeinschaft (Graduiertenkolleg 804, University of Bonn, Germany) and the Government of Canada Award (V.J.). The authors wish to thank Shaun Ramdhany and the Department of Nuclear Cardiology, UHN, Toronto, Canada for their cooperation and support in conducting the animal imaging studies.
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Jekerle, V., Wang, JH., Scollard, D.A. et al. 99mTc-Sestamibi, A Sensitive Probe for In Vivo Imaging of P-Glycoprotein Inhibition by Modulators and mdr1 Antisense Oligodeoxynucleotides. Mol Imaging Biol 8, 333–339 (2006). https://doi.org/10.1007/s11307-006-0057-0
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DOI: https://doi.org/10.1007/s11307-006-0057-0