Experimental modulation of MRP (multidrug resistanceassociated protein)-mediated resistance

Twentyman, Peter R.; Versantvoort, C. H. M.

doi:10.1016/0959-8049(96)00067-6

Cited by 37 publications

(24 citation statements)

References 33 publications

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“…For P-gp, several blockers are known, such as verapamil and cyclosporin A, which enables the study of the functional efflux inhibition of 99mTc-MIBI by these blockers from P-gp-positive tumours. We are aware of the fact that verapamil and cyclosporin A are not specific inhibitors for P-gp and affect to some extent MRP (Twentyman et al, 1996). For MRP, it is suggested that probenecid and sulfinpyrazone may be useful as specific reversal agents for MRP-mediated drug resistance (Evers et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein

Hendrikse¹,

Franssen²,

Graaf³

et al. 1998

Br J Cancer

130

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Summary 9gmTc-sestamibi (SSmTc-MIBI) is a substrate for the P-glycoprotein (P-gp) pump but it is not known whether it is a substrate for the multidrug resistance-associated protein (MRP) pump. Therefore, 99mTc-MIBI was evaluated in the GLC4 cell line and its doxorubicin-resistant MRP-, but not P-gp-, overexpressing GLC4/ADR sublines as well as in the Si cell line and its MRP-transfected subline Sl-MRR 99mTc-MIBI concentration decreased in the GLC4/ADR sublines with increasing MRP overexpression and was lower in S1-MRP than in Si. 99mTc-MIBI plus vincristine increased 99mTc-MIBI concentration in GLC4 lines compared with 99,"Tc-MIBI alone. 99,"Tc-MIBI efflux raised with increasing MRP expression in the GLC4 lines. Glutathione depletion elevated 99mTc-MIBI concentration in GLC4/ADR15,x. Cross resistance for 99Tc-MIBI, used to test cytotoxicity of the Tc compound, was observed in GLC4/ADR,50X vs GLC4. 99Tc-MIBI induced a synergistic effect on vincristine cytotoxicity in GLC4/ADR15oX. These results show that 99mTc-MIBI is involved in MRP-mediated efflux. The fact that 99mTc-MIBI efflux is influenced by MDR1 and MRP expression must be taken into account when this y-rays-emitting complex is tested for tumour efflux measurements.Keywords: multidrug resistance; P-glycoprotein; multidrug resistance-associated protein; 99mTc-sestamibi; drug transportResistance of tumours to chemotherapeutic compounds is an important problem in the clinic. Drugs such as anthracyclines, vinca alkaloids and epipodophyllotoxins are involved in the socalled multidrug resistance (MDR) Bradley et al, 1988;De Vries et al, 1989;De Jong et al, 1990;Meijer et al, 1990;Cole et al, 1992;Versantvoort et al, 1992; Scheper et al, 1993).One of the mechanisms involved in MDR is the overexpression, in tumour cells, of the ATP-dependent 170-kDa P-glycoprotein (P-gp) encoded by the MDR] gene (Endicott and Ling, 1989). P-gp acts as a transmembrane efflux pump that transports chemotherapeutic compounds out of the cell, resulting in drug resistance. P-gp is also expressed in many normal human tissues, such as the liver (bile canaliculi), pancreas, colon, jejunum and kidney (Thiebaut et al, 1987;Sugawara et al, 1988). In normal tissues, P-gp is considered to act as a transporter of toxins.Drugs that are substrates for P-gp are hydrophobic and mostly positively charged at neutral pH. Piwnica-Worms et al (1993) have shown that 99mTc-sestamibi (99mTc-MIBI), a lipophilic cationic radiopharmaceutical, is also a substrate for P-gp-mediated transport (Piwnica-Worms et al, 1993;Vallabhaneni et al, 1994;Ballinger et al, 1995). Consequently, 99-Tc-MIBI allowed visualization of P-gp-mediated efflux in tumours in the animal model (Piwnica-Worms et al, 1993).Apart from P-gp, another pump, the multidrug resistance-associated protein (MRP), is involved in MDR. The MRP pump was identified and characterized as a member of the ATP-binding cassette superfamily (Cole et al, 1992;Ishikawa, 1992 Correspondence to: EGE de Vries 1994). In MRP-transfected cell lines, it was shown that t...

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Section: Discussionmentioning

confidence: 99%

99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein

Hendrikse¹,

Franssen²,

Graaf³

et al. 1998

Br J Cancer

130

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“…This protein, termed multidrug resistance-associated protein (MRP), was found to be highly expressed in several non-P-gp-expressing MDR cell models including several lung cancer cell lines (Cole et al, 1992;Zaman et al, 1993). Most of these were characterized by an ATP-dependent reduction of drug accumulation, which was reversible by different substances including organic anion transport inhibitors and glutathione-depleting agents (review: Twentyman and Versantvoort, 1996). Transfection studies have revealed that MRP mediates resistance against a broad spectrum of antineoplastic drugs, which is similar although not identical to that mediated by P-gp (Cole et al, 1994).…”

mentioning

confidence: 99%

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells

Berger¹,

Elbling²,

Hauptmann³

et al. 1997

Int. J. Cancer

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“…by calcium channel blockers, calmodulin antagonists, cyclosporin, steroids, monoclonal antibodies, inhibitors of PGPmodifying enzymes, etc. (e.g Kellen, 1993;Goldstein, 1995;Ford, 1996;Twentyman and Versantvoort, 1996). Although some of these substances have been examined for reversal of MDR in experimental models and even in clinical trials, their usefulness remains controversial (e.g.…”

Section: Introductionmentioning

confidence: 99%

Cytokine-mediated reversal of multidrug resistance

Stein¹,

Walther²

1998

Multiple Drug Resistance in Cancer 2

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The occurrence of the multidrug resistance phenotype still represents a limiting factor for successful cancer chemotherapy. Numerous efforts have been made to develop strategies for reversal and/or modulation of this major therapy obstacle through targeting at different levels of intervention. The phenomenon of MDR is often associated with overexpression of resistance-associated genes. Since the classical type of MDR in human cancers is mainly mediated by the P-glycoprotein encoded by the multidrug resistance gene 1, mdr1, the majority of reversal approaches target the expression and/or function of the mdr1 gene/P-glycoprotein. Due to the fact that the multidrug phenotype always represents the net effect of a panel of resistance-associated genes/gene products, other resistance genes, e.g. those encoding the multidrug resistance-associated protein MRP or the lung resistance protein LRP, were included in the studies. Cytokines such as tumor necrosis factor α and interleukin-2 have been shown to modulate the MDR phenotype in different experimental settings in vitro and in vivo. Several studies have been performed to evaluate their potential as chemosensitizers of tumor cells in the context of a combined application of MDR-associated anticancer drugs like doxorubicin and vincristine with cytokines. Moreover, the capability of cytokines to modulate the expression of MDR-associated genes was demonstrated, either by external addition or by transduction of the respective cytokine gene. Knowledge of the combination effects of cytokines and cytostatics and its link to their MDR-modulating capacity may contribute to a more efficient and to a more individualized immuno-chemotherapy of human malignancies.

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Experimental modulation of MRP (multidrug resistanceassociated protein)-mediated resistance

Cited by 37 publications

References 33 publications

99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein

99mTc-sestamibi is a substrate for P-glycoprotein and the multidrug resistance-associated protein

Expression of the multidrug resistance-associated protein (MRP) and chemoresistance of human non-small-cell lung cancer cells

Cytokine-mediated reversal of multidrug resistance

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