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

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

Research output: Contribution to journal › Article › peer-review

429 Citations (Scopus)

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.

Original language	English
Pages (from-to)	2532-2535
Number of pages	4
Journal	Cancer Research
Volume	59
Issue number	11
Publication status	Published - 1 Jun 1999
Externally published	Yes

Cite this

@article{2704a723814d4885a83c575f6719a18b,

title = "Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2",

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.",

author = "Hooijberg, \{Jan Hendrik\} and Broxterman, \{Henk J.\} and Marcel Kool and Assaraf, \{Yehuda G.\} and Peters, \{Godefridus J.\} and Paul Noordhuis and Scheper, \{Rik J.\} and Piet Borst and Pinedo, \{Herbert M.\} and Gerrit Jansen",

year = "1999",

month = jun,

day = "1",

language = "English",

volume = "59",

pages = "2532--2535",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research Inc.",

number = "11",

}

TY - JOUR

T1 - Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

AU - Hooijberg, Jan Hendrik

AU - Broxterman, Henk J.

AU - Kool, Marcel

AU - Assaraf, Yehuda G.

AU - Peters, Godefridus J.

AU - Noordhuis, Paul

AU - Scheper, Rik J.

AU - Borst, Piet

AU - Pinedo, Herbert M.

AU - Jansen, Gerrit

PY - 1999/6/1

Y1 - 1999/6/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/0033152212

M3 - Article

C2 - 10363967

AN - SCOPUS:0033152212

SN - 0008-5472

VL - 59

SP - 2532

EP - 2535

JO - Cancer Research

JF - Cancer Research

IS - 11

ER -

Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

Abstract

Fingerprint

Cite this