Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

J H Hooijberg, H J Broxterman, M Kool, Y G Assaraf, G J Peters, P Noordhuis, R J Scheper, P Borst, H M Pinedo, G Jansen

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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)2532-5
Number of pages4
JournalCancer Research
Issue number11
Publication statusPublished - 1 Jun 1999

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