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

Research output: Contribution to journalArticleAcademicpeer-review

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 languageEnglish
Pages (from-to)2532-5
Number of pages4
JournalCancer Research
Volume59
Issue number11
Publication statusPublished - 1 Jun 1999

Cite this

Hooijberg, J H ; Broxterman, H J ; Kool, M ; Assaraf, Y G ; Peters, G J ; Noordhuis, P ; Scheper, R J ; Borst, P ; Pinedo, H M ; Jansen, G. / Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. In: Cancer Research. 1999 ; Vol. 59, No. 11. pp. 2532-5.
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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.",
keywords = "ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors, ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors, ATP-Binding Cassette Transporters/antagonists & inhibitors, Adenosine Triphosphate/metabolism, Antimetabolites, Antineoplastic/metabolism, Drug Resistance, Multiple/genetics, Drug Resistance, Neoplasm/genetics, Female, Folic Acid Antagonists/metabolism, Glutamates/metabolism, Humans, Indoles/metabolism, Isoindoles, Methotrexate/metabolism, Ovarian Neoplasms/genetics, Quinazolines/metabolism, Thiophenes/metabolism, Transfection, Tumor Cells, Cultured/drug effects",
author = "Hooijberg, {J H} and Broxterman, {H J} and M Kool and Assaraf, {Y G} and Peters, {G J} and P Noordhuis and Scheper, {R J} and P Borst and Pinedo, {H M} and G Jansen",
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Hooijberg, JH, Broxterman, HJ, Kool, M, Assaraf, YG, Peters, GJ, Noordhuis, P, Scheper, RJ, Borst, P, Pinedo, HM & Jansen, G 1999, 'Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2' Cancer Research, vol. 59, no. 11, pp. 2532-5.

Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. / Hooijberg, J H; Broxterman, H J; Kool, M; Assaraf, Y G; Peters, G J; Noordhuis, P; Scheper, R J; Borst, P; Pinedo, H M; Jansen, G.

In: Cancer Research, Vol. 59, No. 11, 01.06.1999, p. 2532-5.

Research output: Contribution to journalArticleAcademicpeer-review

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

AU - Hooijberg, J H

AU - Broxterman, H J

AU - Kool, M

AU - Assaraf, Y G

AU - Peters, G J

AU - Noordhuis, P

AU - Scheper, R J

AU - Borst, P

AU - Pinedo, H M

AU - Jansen, G

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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.

KW - ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors

KW - ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors

KW - ATP-Binding Cassette Transporters/antagonists & inhibitors

KW - Adenosine Triphosphate/metabolism

KW - Antimetabolites, Antineoplastic/metabolism

KW - Drug Resistance, Multiple/genetics

KW - Drug Resistance, Neoplasm/genetics

KW - Female

KW - Folic Acid Antagonists/metabolism

KW - Glutamates/metabolism

KW - Humans

KW - Indoles/metabolism

KW - Isoindoles

KW - Methotrexate/metabolism

KW - Ovarian Neoplasms/genetics

KW - Quinazolines/metabolism

KW - Thiophenes/metabolism

KW - Transfection

KW - Tumor Cells, Cultured/drug effects

M3 - Article

VL - 59

SP - 2532

EP - 2535

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 11

ER -

Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P et al. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Research. 1999 Jun 1;59(11):2532-5.