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

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 journal › Article › Academic › peer-review

416 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

Keywords

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

Cite this

@article{ac4690ad7fc34109ba1b2c5076d7196b,

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

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, 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.

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

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

KW - ATP Binding Cassette Transporter, Subfamily B/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

C2 - 10363967

SN - 0008-5472

VL - 59

SP - 2532

EP - 2535

JO - Cancer research

JF - Cancer research

IS - 11

ER -