Selective modulation of P-glycoprotein-mediated drug resistance

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dc.contributor.author Bebawy, Mary en_US
dc.contributor.author Morris, M B en_US
dc.contributor.author Roufogalis, Basil en_US
dc.contributor.editor en_US
dc.date.accessioned 2012-02-10T06:09:14Z
dc.date.available 2012-02-10T06:09:14Z
dc.date.issued 2001 en_US
dc.identifier 2010004308 en_US
dc.identifier.citation Bebawy Mary, Morris M B, and Roufogalis Basil 2001, 'Selective modulation of P-glycoprotein-mediated drug resistance', Nature Publishing Group, vol. 85, no. 12, pp. 1998-2003. en_US
dc.identifier.issn 0007-0920 en_US
dc.identifier.other C1UNSUBMIT en_US
dc.identifier.uri http://hdl.handle.net/10453/16960
dc.description.abstract Multidrug resistance associated with the overexpression of the multidrug transporter P-glycoprotein is a serious impediment to successful cancer treatment. We found that verapamil reversed resistance of CEM/VLB100 cells to vinblastine and fluorescein-colchicine, but not to colchicine. Chlorpromazine reversed resistance to vinblastine but not to fluorescein-colchicine, and it increased resistance to colchicine. Initial influx rates of fluorescein-colchicine were similar in resistant and parental cells, whereas vinblastine uptake was about 10- fold lower in the resistant cells. These results provide indirect evidence that fluorescein-colchicine is transported from the inner leaflet of the membrane and vinblastine from the outer membrane leaflet. Verapamil inhibited luorescein-colchicine transport in inside-out vesicles made from resistant cells, whilst chlorpromazine was found to activate the transport of fluorescein-colchicine. The chlorpromazine-induced activation of fluorescein-colchicine transport was temperature-dependent and may reflect its interaction with phospholipids localised in the same bilayer leaflet. Conversely, chlorpromazine localisation in this leaflet may be responsible for its allosteric inhibition of vinblastine transport from the opposing membrane leaflet. The proposed relationship between the selectivity of modulation of P-glycoprotein and the membrane localisation of the cytotoxic drug substrates and modulators may have important implications in the rational design of regimes for the circumvention of multidrug resistance clinically. en_US
dc.language en_US
dc.publisher Nature Publishing Group en_US
dc.relation.isbasedon http://dx.doi.org/10.1054/bjoc.2001.2184 en_US
dc.title Selective modulation of P-glycoprotein-mediated drug resistance en_US
dc.parent British Journal Of Cancer en_US
dc.journal.volume 85 en_US
dc.journal.number 12 en_US
dc.publocation London en_US
dc.identifier.startpage 1998 en_US
dc.identifier.endpage 2003 en_US
dc.cauo.name GSH.Pharmacy en_US
dc.conference Verified OK en_US
dc.for 111200 en_US
dc.personcode 112474 en_US
dc.personcode 0000069522 en_US
dc.personcode X000240 en_US
dc.percentage 100 en_US
dc.classification.name Oncology and Carcinogenesis en_US
dc.classification.type FOR-08 en_US
dc.edition en_US
dc.custom en_US
dc.date.activity en_US
dc.location.activity WOS:000173373000026 en_US
dc.description.keywords Multidrug resistance associated with the overexpression of the multidrug transporter P-glycoprotein is a serious impediment to successful cancer treatment. We found that verapamil reversed resistance of CEM/VLB100 cells to vinblastine and fluorescein-colchicine, but not to colchicine. Chlorpromazine reversed resistance to vinblastine but not to fluorescein-colchicine, and it increased resistance to colchicine. Initial influx rates of fluorescein-colchicine were similar in resistant and parental cells, whereas vinblastine uptake was about 10- fold lower in the resistant cells. These results provide indirect evidence that fluorescein-colchicine is transported from the inner leaflet of the membrane and vinblastine from the outer membrane leaflet. Verapamil inhibited fluorescein-colchicine transport in inside-out vesicles made from resistant cells, whilst chlorpromazine was found to activate the transport of fluorescein-colchicine. The chlorpromazine-induced activation of fluorescein-colchicine transport was temperature-dependent and may reflect its interaction with phospholipids localised in the same bilayer leaflet. Conversely, chlorpromazine localisation in this leaflet may be responsible for its allosteric inhibition of vinblastine transport from the opposing membrane leaflet. The proposed relationship between the selectivity of modulation of P-glycoprotein and the membrane localisation of the cytotoxic drug substrates and modulators may have important implications in the rational design of regimes for the circumvention of multidrug resistance clinically. en_US


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