Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

Transfection of multidrug resistance proteins (MRPs) MRP1 and MRP2, in huma n ovarian carcinoma 2008 cells conferred a marked level of resistance to sh ort-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 [3(H)]MTX and subsequent reduced format ion of long-chain polyglutamate forms of MTX; br reversal of MTX resistance by probenecid in both transfectants, and (c) ATP-dependent uptake of [H-3] MTX in inside-out vesicles of MRP1 and MRP2 transfectants. This report prov ides a mechanistic basis for resistance to polyglutamatable antifolates thr ough an MRP-mediated drug extrusion.