Effects of MDR1 and MDR3 P-glycoproteins, MRP1, and BCRP/MXR/ABCP on the transport of 99mTc-tetrofosmin

doi:10.1016/S0006-2952(00)00341-5

Biochemical Pharmacology

Volume 60, Issue 3, 1 August 2000, Pages 413-426

https://doi.org/10.1016/S0006-2952(00)00341-5 Get rights and content

Abstract

Multidrug resistance (MDR1) P-glycoprotein (Pgp), multidrug resistance-associated protein (MRP1), and breast cancer resistance protein (BCRP/MXR/ABCP) are members of the ATP-binding-cassette (ABC) superfamily of membrane transporters and are thought to function as energy-dependent efflux pumps of a variety of structurally diverse chemotherapeutic agents. We herein report the characterization of ^99mTc-Tetrofosmin, a candidate radiopharmaceutical substrate of ABC transporters. ^99mTc-Tetrofosmin showed high membrane potential-dependent accumulation in drug-sensitive KB 3–1 cells and low antagonist-reversible accumulation in MDR KB 8–5 and KB 8–5-11 cells in proportion to levels of MDR1 Pgp expression. In KB 8–5 cells, ec₅₀ values of the potent MDR antagonists N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979), and (3′-keto-Bmt′)-[Val²]-cyclosporin A (PSC 833) were 40, 66, and 986 nM, respectively. Furthermore, only baculoviruses carrying human MDR1, but not MDR3, conferred both a decrease in accumulation of ^99mTc-Tetrofosmin in host Spodoptera frugiperda (Sf9) cells and a GF120918-induced enhancement. Transport studies with a variety of stably transfected and drug-selected tumor cell lines were performed with ^99mTc-Tetrofosmin and compared with ^99mTc-Sestamibi, a previously validated MDR imaging agent. MDR1 Pgp readily transported each agent. To a lesser extent, MRP1 also transported each agent, likely as co-transport substrates with GSH; neither agent was a substrate for the BCRP/MXR/ABCP half-transporter. In mdr1a(−/−) and mdr1a/1b(−/−) mice, ^99mTc-Tetrofosmin showed ∼3.5-fold greater brain uptake and retention compared with wild-type, with no net change in blood pharmacokinetics, consistent with transport in vivo by Pgp expressed at the capillary blood–brain barrier. Molecular imaging of the functional transport activity of ABC transporters in vivo with ^99mTc-Tetrofosmin and related radiopharmaceuticals may enable non-invasive monitoring of chemotherapeutic and MDR gene therapy protocols.

Section snippets

Solutions and reagents

Stock solutions of N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918; gift of Glaxo-Wellcome), (2R)-anti-5-{3-[4-(10,11-difluoromethanodibenzo-suber-5-yl)piperazin-1-yl]-2-hydroxypropoxy}quinoline trihydrochloride (LY335979; gift of Eli Lilly & Co.), (3′-keto-Bmt′)-[Val²]-cyclosporin A (PSC 833; gift of Mallinckrodt, Inc.), methotrexate, and cisplatin were prepared in DMSO. The final concentration of DMSO in

Validation of Tc-tetrofosmin as a substrate for MDR1 Pgp: Transport analysis in KB cells

To validate the transport of ^99mTc-Tetrofosmin by MDR1 Pgp, cell accumulation of the tracer was determined in drug-sensitive KB 3–1 and MDR derivative cell lines. KB 3–1 cell lines expressed no immunodetectable MDR1 Pgp, whereas KB 8–5 and KB 8–5-11 expressed moderate and high levels of Pgp, respectively (Fig. 2). Time–activity curves show large differences in accumulation of Tc-Tetrofosmin between KB 3–1 and KB 8–5 cells (Fig. 3). Cell-associated counts were normalized to total

Cellular mechanisms of localization of Tc-tetrofosmin

The mechanisms of uptake and retention of selected hydrophobic cationic Tc-based complexes analogous to Tc-Tetrofosmin have been studied extensively in a variety of cellular and subcellular preparations in vitro. Net cell content of these Tc-based agents generally is a function of both passive potential-dependent influx and transporter-mediated efflux. For example, biophysical analysis has shown that Tc-Sestamibi is a high fidelity probe of transmembrane potential 50, 62, with passive inward

Acknowledgements

This work was supported by grants from the U.S. Department of Energy (DE-FG02–94ER61885), U.S. National Institutes of Health (RO1 CA83059), Mallinckrodt, Inc., and a Howard Hughes Medical Institute Summer Research Fellowship to W. S. C. We thank Mary Marmion and Elizabeth Webb, Mallinckrodt, Inc., for synthesis of radiolabeled Tc-Tetrofosmin and Carolyn Crankshaw for technical assistance.

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Chemotherapy and metabolic inhibitorsEffects of MDR1 and MDR3 P-glycoproteins, MRP1, and BCRP/MXR/ABCP on the transport of 99mTc-tetrofosmin

Abstract

Section snippets

Solutions and reagents

Validation of Tc-tetrofosmin as a substrate for MDR1 Pgp: Transport analysis in KB cells

Cellular mechanisms of localization of Tc-tetrofosmin

Acknowledgements

Biochim Biophys Acta

Biochem Pharmacol

Eur J Cancer

Blood

J Biol Chem

Anal Biochem

J Nucl Cardiol

Biochim Biophys Acta

Magn Reson Imaging

J Biol Chem

Cell

J Nucl Cardiol

Cell

Ben Neriah Y, Croop JM and Housman DE, Isolation and expression of a complementary DNA that confers multidrug resistance

Nature

Human multidrug-resistant cell linesIncreased mdr1 expression can precede gene amplification

Science

Biochemistry of multidrug resistance mediated by the multidrug transporter

Annu Rev Biochem

Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line

Science

Tissue distribution of multidrug resistance protein

Am J Pathol

Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2

Biol Chem

A multidrug resistance transporter from human MCF-7 breast cancer cells

Proc Natl Acad Sci USA

Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cellsDemonstration of homology to ABC transport genes

Cancer Res

A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance

Cancer Res

Pharmacology of drugs that alter multidrug resistance in cancer

Pharmacol Rev

Kinetic evidence suggesting that the multidrug transporter differentially handles influx and efflux of its substrates

Mol Pharmacol

Mechanisms of multidrug resistance in HL60 cellsDetection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequence of P-glycoprotein

Cancer Res

Human MDR1 protein overexpression delays the apoptotic cascade in Chinese hamster ovary fibroblasts

Biochemistry

The drug efflux protein P-glycoprotein additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis

Proc Natl Acad Sci USA

In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative

Cancer Res

Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979

Cancer Res

Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209, and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP

Anticancer Drugs

Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C

Cancer Res

Selection of drug-resistant bone marrow cells in vivo after retroviral transfer of human MDR1

Science

Transfer and expression of the human multiple drug resistance gene into live mice

Proc Natl Acad Sci USA

Resistance to taxol chemotherapy produced in mouse marrow cells by safety-modified retroviruses containing a human MDR-1 transcription unit

Gene Ther

Functional imaging of multidrug-resistant P-glycoprotein with an organotechnetium complex

Cancer Res

Characterization of multidrug-resistance P-glycoprotein transport function with an organotechnetium cation

Biochemistry

99mTc-Sestamibi as an agent for imaging P-glycoprotein-mediated multi-drug resistanceIn vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant

Nucl Med Commun

Differences between accumulation of Tc-99m-MIBI and Tl-201-thallous chloride in tumor cellsRole of P-glycoprotein

Q J Nucl Med

Technetium-99m-sestamibi uptake by human benign and malignant breast tumor cellsCorrelation with mdr gene expression

J Nucl Med

In vivo detection of multidrug resistance (MDR1) phenotype by technetium-99m sestamibi scan in untreated breast cancer patients

Eur J Nucl Med

Fractional retention of technetium-99m-sestamibi as an index of P-glycoprotein expression in untreated breast cancer patients

J Nucl Med

Chemotherapy and metabolic inhibitors
Effects of MDR1 and MDR3 P-glycoproteins, MRP1, and BCRP/MXR/ABCP on the transport of ^99mTc-tetrofosmin

^99mTc-Sestamibi as an agent for imaging P-glycoprotein-mediated multi-drug resistanceIn vitro and in vivo studies in a rat breast tumour cell line and its doxorubicin-resistant variant