Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

Jan Hendrik Hooijberg, Henk J. Broxterman, Marcel Kool, Yehuda G. Assaraf, Godefridus J. Peters, Paul Noordhuis, Rik J. Scheper, Piet Borst, Herbert M. Pinedo, Gerrit Jansen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

415 Citaten (Scopus)

Samenvatting

Transfection of multidrug resistance proteins (MRPs) MRP1 and MRP2 in human ovarian carcinoma 2008 cells conferred a marked level of resistance to short-term (1-4 h) exposure to the polyglutamatable antifolates methotrexate (MTX; 21-74-fold), ZD1694 (4-138-fold), and GW1843 (101-156-fold). Evidence for MRP-mediated antifolate efflux relies upon the following findings: (a) a 2-3.3-fold lower accumulation of [3H]MTX and subsequent reduced formation of long-chain polyglutamate forms of MTX; (b) reversal of MTX resistance by probenecid in both transfectants, and (c) ATP-dependent uptake of [3H]MTX in inside-out vesicles of MRP1 and MRP2 transfectants. This report provides a mechanistic basis for resistance to polyglutamatable antifolates through an MRP-mediated drug extrusion.

Originele taal-2Engels
Pagina's (van-tot)2532-2535
Aantal pagina's4
TijdschriftCancer Research
Volume59
Nummer van het tijdschrift11
StatusGepubliceerd - 1 jun. 1999
Extern gepubliceerdJa

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