Comparison of99mTc-sestamibi and doxorubicin to monitor inhibition of P-glycoprotein function

Abstract

P-glycoprotein (Pgp) overexpression is a well-recognized factor in resistance to chemotherapy. Doxorubicin flow cytometry is used to monitor Pgp function in haematological specimens and biopsies from other cancers, and radionuclide imaging with sestamibi has recently shown promise for non-invasive monitoring. In the present study the two methods were directly compared in single-cell suspensions of three variants of the human breast carcinoma cell line MCF7: sensitive MCF7/WT, doxorubicin-selected MCF7/AdrR, and MDR1 -gene-transfected MCF7/BC19 cells with doxorubicin resistance factors of 1, 192, and 14, respectively. Accumulation of sestamibi and mean fluorescence of doxorubicin (5.5 μM) were assessed over 60 min in the presence and absence of Pgp modulators GG918 (0.01 to 0.2 μM) and PSC833 (0.05 to 2.0 μM). Accumulation curves for sestamibi and doxorubicin differed among the cell variants under control conditions, with sestamibi showing a significantly greater difference between WT and resistant cells than doxorubicin. Both GG918 and PSC833 reversed uptake deficits to WT levels for sestamibi in MCF7/BC19 cells and doxorubicin in MCF7/BC19 and MCF7/AdrR cells, but failed to show the same effect for sestamibi in MCF7/AdrR cells (∼30% of MCF7/WT level). Thus, both methods clearly distinguished sensitive from resistant MCF7 variants, with the radionuclide method showing greater sensitivity. © 2001 Cancer Research Campaign http://www.bjcancer.com

Imaging recognition of inhibition of multidrug resistance in human breast cancer xenografts using 99mTc-labeled sestamibi and tetrofosmin

“…Examples of modulators include verapamil, cyclosporin A, GG918 (elacridar) and PSC833 (valspodar). PSC833 is a cyclosporine derivative that lacks immunosuppressive and nephrotoxic effects and has been reported to be a powerful MDR modulator in animal studies and clinical trials [8][9][10][11][12][13][14]. It was also conceived that PSC833 could inhibit the development of cancer by compromising Pgp function [15].…”

Predicting Early Chemotherapy Response with Technetium-99m Methoxyisobutylisonitrile SPECT/CT in Advanced Non-Small Cell Lung Cancer

“…It has been demonstrated that the retention of 99m Tc-MIBI in cells depends on the activity of Pgp, an ATPdependent efflux pump for many cytotoxic substances, encoded on the MDR1 gene. Accumulation of 99m Tc-MIBI, a substrate for MDR-Pgp, in cells has been found to inversely relate to the level of Pgp as a result of enhanced efflux by these membrane transporters [14,16,24,25]. More recently, a distinction has been argued between 99m Tc-MIBI uptake and clearance, as uptake is governed by the level of antiapoptotic proteins and clearance is governed by the level of Pgp expression as described above.…”

“…A possible explanation for the lower MIBI counts with poor responders is the overexpression of the multidrug resistance gene (MDR1) in chemotherapy resistant tumors. MDR1 encodes P-glycoprotein (Pgp), a transmembrane protein which acts as an efflux pump to a wide range of cytotoxic drugs and 99m Tc-labeled lipophilic radiopharmaceuticals such as 99m Tc-MIBI [12][13][14][15][16][17].…”

Does the Clearance of Inhaled99mTc-Sestamibi Correlate with Multidrug Resistance Protein 1 Expression in the Human Lung?

“…Many in vitro and in vivo studies have demonstrated correlation between the uptake and/or retention of these radiopharmaceuticals and the expression levels of P-gp and/or MRP1 in tumor cells (17,(20)(21)(22). Therefore, Tcsestamibi and 99m Tc-tetrofosmin have been proposed as imaging probes for multidrug resistance assessment and to monitor the efficacy of multidrug resistance modulators (23,24). All these studies have studied the handling of the radiopharmaceutical after intravenous injection but none have specifically looked at the cellular handling of inhaled aerosols.…”