99mTc-Sestamibi, a sensitive probe for in vivo imaging of P-glycoprotein inhibition by modulators and mdr1 antisense oligodeoxynucleotides.
OBJECTIVE
We tested the suitability of (99m)Tc-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.


METHODS
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 (99m)Tc-sestamibi injection. Mice were imaged, sacrificed, and tissues collected. Images and isolated tissues were analyzed for (99)Tc 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 (99m)Tc-sestamibi images. Mdr1 mRNA and Pgp were significantly down-regulated by antisense treatments.


CONCLUSIONS
(99m)Tc-sestamibi is a sensitive probe to monitor Pgp inhibition by different mechanisms in vivo in tumor xenografts.
Jekerle
Veronika
V
Department of Pharmaceutical Sciences, University of Toronto, 144 College St., Toronto, Ontario, Canada, M5S 3M2.
Wang
Jing-Hung
JH
Scollard
Deborah A
DA
Reilly
Raymond M
RM
Wiese
Michael
M
Piquette-Miller
Micheline
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D045744:Cell Line, Tumor; D016373:DNA, Antisense / Q000494:pharmacology*; D015536:Down-Regulation; D018432:Drug Resistance, Multiple; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015345:Oligonucleotide Probes / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000494:pharmacology; D017256:Technetium Tc 99m Sestamibi / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001549:Benzamides; D016373:DNA, Antisense; D015345:Oligonucleotide Probes; D019275:Radiopharmaceuticals; C511688:WK-X-34; D017256:Technetium Tc 99m Sestamibi