title: Comparison of the accumulation and efflux kinetics of technetium-99m sestamibi and technetium-99m tetrofosmin in an MRP-expressing tumour cell line.
abstract: The potential clinical use of technetium-99m labeled sestamibi (Tc-MIBI) and tetrofosmin (Tc-Tfos) to image tumours is currently being evaluated. In this study. the accumulation and efflux of Tc-MIBI and Tc-Tfos in the nasopharyngeal carcinoma cell line CNE-1 were examined in the presence or absence of various inhibitors of P-glycoprotein (PGP) and/or multidrug resistance associated protein (MRP) activity [GG918, PSC833, verapamil (Vrp), cyclosporin A (CsA) and buthionine sulfoximine (BSO)]. Reverse-transcriptase polymerase chain reaction analysis and immunodetection of the CNE-1 cells detected expression of MRP, MRPI and MRP2 but not PGP. Tc-MIBI and Tc-Tfos accumulation was increased (P < 0.0001) and efflux decreased (P < 0.05) in the presence of BSO, CsA, Vrp and PSC833 but not GG918, which is a specific inhibitor of PGP. The absolute accumulation of Tc-MIBI was approximately twofold higher than that seen with Tc-Tfos, whereas the addition of inhibitors caused a much greater suppression of Tc-Tfos transport (>2 times greater than for Tc-MIBI). However, no qualitative differences in inhibitors were seen between Tc-MIBI and Tc-Tfos. These results suggest that both Tc-MIBI and Tc-Tfos are substrates for the MRP transporter and that PSC833, Vrp, CsA and BSO but not GG918 can inhibit MRP activity. These results indicate that Tc-MIBI and Tc-Tfos may be suitable imaging agents for detecting MRP-mediated drug resistance in human cancers.
authors.affiliation: Nuclear Medicine, Mount Sinai Hospital, Medical Imaging, University of Toronto, Ontario, Canada.
authors.forename: K
authors.initials: K
authors.lastname: Utsunomiya
authors.forename: J R
authors.initials: JR
authors.lastname: Ballinger
authors.forename: M
authors.initials: M
authors.lastname: Piquette-Miller
authors.forename: A M
authors.initials: AM
authors.lastname: Rauth
authors.forename: W
authors.initials: W
authors.lastname: Tang
authors.forename: Z F
authors.initials: ZF
authors.lastname: Su
authors.forename: M
authors.initials: M
authors.lastname: Ichise
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism*; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D007202:Indicators and Reagents; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000493:pharmacokinetics*; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017256:Technetium Tc 99m Sestamibi / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007202:Indicators and Reagents; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D019275:Radiopharmaceuticals; C078700:technetium tc-99m tetrofosmin; D017256:Technetium Tc 99m Sestamibi