Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2
JH Hooijberg, HJ Broxterman, M Kool, YG Assaraf… - Cancer research, 1999 - AACR
Cancer research, 1999•AACR
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 …
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 …
Abstract
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.
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