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

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416 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2532-2535
Number of pages4
JournalCancer Research
Issue number11
Publication statusPublished - 1 Jun 1999
Externally publishedYes


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