sdz-psc-833 and technetium-tc-99m-tetrofosmin

The multidrug resistance (MDR) phenotype in cancer is closely related with the overexpression of P-glycoprotein (Pgp) and multidrug resistance protein-1 (MRP1). Although conferring resistance to a similar spectrum of drugs, these proteins present distinct transport mechanisms and have their own substrates. In this work, we compared the functional properties of Pgp and MRP1 in the transport kinetics of two cationic lipophilic tracers, [(99m)Tc]sestamibi and [(99m)Tc]tetrofosmin, in cellular models of resistance. Cellular transport kinetics of both tracers was evaluated in Small-cell lung cancer cell line H69 and in its drug-resistant sublines, H69LX4 and H69AR, overexpressing Pgp and MRP1, respectively. Studies were performed in the absence and in the presence of MDR modulators. Kinetic parameters extracted from time-activity curves were analyzed through receiver-operating characteristics curve analysis. The uptake and the efflux rate of both radiotracers were significantly higher (p < 0.05) in sensitive cells. However, MRP1 was more effective than Pgp in removing tracers from the intracellular medium. The addition of verapamil and PSC833 significantly reduced the efflux rate and restored the accumulation of both tracers in H69LX4 cells. Only verapamil was effective in the inhibition of MRP1; however, the effects were more pronounced with [(99m)Tc]sestamibi, when compared to [(99m)Tc]tetrofosmin. Outward transport of radiotracers by MRP1 was dependent on the intracellular glutathione levels. We concluded that both tracers can detect Pgp- and MRP1-mediated drug resistance, based on transport kinetics; however, MRP1 is more effective than Pgp on outward transport of radiotracers. We postulate that this finding can be useful to distinguish between the two resistance mechanisms.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Transport; Cell Line, Tumor; Cyclosporins; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Multidrug Resistance-Associated Proteins; Organophosphorus Compounds; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; ROC Curve; Small Cell Lung Carcinoma; Technetium Tc 99m Sestamibi; Tumor Cells, Cultured; Verapamil

(99m)Tc-sestamibi (MIBI) and (99m)Tc-tetrofosmin (TF) are avid transport substrates recognized by the multidrug resistance (MDR) P-glycoprotein (Pgp). This study was designed to compare the properties of MIBI and TF in assessing the inhibition of Pgp by PSC833 in severe combined immunodeficient mice bearing MCF7 human breast tumors using SPECT imaging.. Animals with drug-sensitive (MCF/WT) and drug-resistant (MCF7/AdrR) tumors were treated by PSC833 and by carrier vehicle 1 h before imaging, respectively. Dynamic images were acquired for 30 min after intravenous injection of MIBI/TF using a SPECT system, FastSPECT. The biodistribution of MIBI and TF was determined at the end of the imaging session.. MCF7/WT in the absence and presence of PSC833 could be visualized by MIBI and TF imaging within 5 min and remained detectable for 30 min postinjection. MCF7/AdrR could be visualized only 2-5 min without PSC833 treatment but could be detected for 30 min with PSC833, very similar to MCF7/WT. MCF7/AdrR without PSC833 showed significantly greater radioactive washout than MCF7/WT and MCF7/AdrR with PSC833 treatment. PSC833 increased the accumulation (%ID/g) in MCF7/AdrR 3.0-fold (1.62+/-0.15 vs. 0.55+/-0.05, P<.05) for TF and 1.9-fold (1.21+/-0.04 vs. 0.64+/-0.05, P<.05) for MIBI but did not affect MCF7/WT.. The feasibility of MIBI and TF for assessment of MDR expression and inhibition was demonstrated in mice through FastSPECT imaging. The results indicate that TF may be at least comparable with MIBI in recognizing Pgp expression and modulation.

Topics: Adenocarcinoma; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blotting, Western; Breast Neoplasms; Cyclosporins; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Humans; Metabolic Clearance Rate; Mice; Mice, SCID; Organ Specificity; Organophosphorus Compounds; Organotechnetium Compounds; Radiopharmaceuticals; Technetium Tc 99m Sestamibi; Tissue Distribution; Tomography, Emission-Computed, Single-Photon; Transplantation, Heterologous; Tumor Cells, Cultured

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.

Topics: Acridines; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Neoplasm; Furans; Humans; Isoquinolines; Neoplasms; Organophosphorus Compounds; Organotechnetium Compounds; Technetium Tc 99m Sestamibi; Tetrahydroisoquinolines; Tomography, Emission-Computed, Single-Photon; Tumor Cells, Cultured

There has been a preliminary report that furifosmin, like the other lipophilic 99mTc cations sestamibi and tetrofosmin, is a substrate for P-glycoprotein, the membrane transporter that is a mechanism of multidrug resistance (MDR) in tumors. This has been further investigated in the rat mammary carcinoma cell line MatB/WT and its doxorubicin-selected resistant variant MatB/AdrR.. In vitro studies were performed by adding furifosmin to stirred single-cell suspensions of MatB/WT and MatB/AdrR in the presence or absence of the Pgp-modulating drug PSC833. Dynamic imaging studies over 30 min were performed in rats bearing MatB/WT or MatB/AdrR tumors growing in the leg.. Accumulation of furifosmin in MatB/AdrR cells in vitro was much lower than that in MatB/WT cells. The addition of 1 microM PSC833 increased the plateau accumulation in MatB/AdrR cells 2.4-fold, but did not affect accumulation in MatB/WT cells. In rats, furifosmin accumulated rapidly in MatB/WT tumors and washed out with a mean t3 of 78 min. Washout from MAtB/AdrR tumors was more rapid, with a t3 of 46 min (p < 0.025). Following dissection of animals at 30 min, mean tumor-to-muscle ratios were 1.57 and 1.05 in MatB/WT and MatB/ AdrR tumors, respectively (p < 0.025).. Furifosmin is suitable for functional imaging of multidrug resistance in tumors.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cyclosporins; Drug Resistance, Neoplasm; Female; Furans; Mammary Neoplasms, Experimental; Neoplasm Transplantation; Organophosphorus Compounds; Organotechnetium Compounds; Radionuclide Imaging; Radiopharmaceuticals; Rats; Rats, Inbred F344; Technetium Tc 99m Sestamibi; Tumor Cells, Cultured