title: In vitro comparison of sestamibi, tetrofosmin, and furifosmin as agents for functional imaging of multidrug resistance in tumors.
abstract: Sestamibi, tetrofosmin, and furifosmin are 99mTc-labeled myocardial perfusion imaging agents which have been shown to be substrates for P-glycoprotein (Pgp), the multidrug-resistance transporter which is overexpressed in some tumors. The three tracers were directly compared in vitro in the human breast cancer cell line MCF7-WT and two multidrug-resistant variants, MCF7-BC19 (MDR1 gene transfected) and MCF7-AdrR (doxorubicin selected). Tracer accumulation over the course of 60 minutes was determined. Dose-response curves were generated for two modulators of Pgp function, GG918 and PSC833. The general shape of accumulation curves for the three tracers in MCF7-WT cells was similar, with accumulation levels being sestamibi > tetrofosmin > furifosmin. Accumulation of sestamibi and furifosmin in MCF7-BC19 cells was reduced to 10% and 21% of MCF7-WT levels, respectively, but this accumulation deficit could be completely reversed by addition of 0.1 microM GG918 or 2 microM PSC833. Accumulation of sestamibi and tetrofosmin in MCF7-AdrR cells was 1.6% and 12% of MCF7-WT levels, respectively, and could only be enhanced to 30% and 45% of MCF7-WT levels by addition of GG918 or PSC833. In contrast, furifosmin showed similar levels of accumulation in MCF7-WT and MCF7-BC19 cells, slightly lower levels in MCF7-AdrR cells, and no consistent response to Pgp modulators. These results support the continued investigation of sestamibi and tetrofosmin as agents for functional imaging of multidrug resistance in human cancer.
authors.affiliation: Department of Pharmaceutical Sciences, University of Toronto, Canada.
authors.forename: T
authors.initials: T
authors.lastname: Muzzammil
authors.forename: M J
authors.initials: MJ
authors.lastname: Moore
authors.forename: J R
authors.initials: JR
authors.lastname: Ballinger
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000166:Acridines / Q000378:metabolism*; D003524:Cyclosporins / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005663:Furans / Q000378:metabolism*; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D009943:Organophosphorus Compounds / Q000378:metabolism*; D015609:Organotechnetium Compounds / Q000378:metabolism*; D017256:Technetium Tc 99m Sestamibi / Q000378:metabolism*; D044005:Tetrahydroisoquinolines; D015899:Tomography, Emission-Computed, Single-Photon; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000166:Acridines; D003524:Cyclosporins; D005663:Furans; D007546:Isoquinolines; D009943:Organophosphorus Compounds; D015609:Organotechnetium Compounds; D044005:Tetrahydroisoquinolines; C078496:technetium Tc 99m Q12; C078700:technetium tc-99m tetrofosmin; D017256:Technetium Tc 99m Sestamibi; C083501:Elacridar; C070272:valspodar