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) | 2532-5 |
| Number of pages | 4 |
| Journal | Cancer Research |
| Volume | 59 |
| Issue number | 11 |
| Publication status | Published - 1 Jun 1999 |
Cite this
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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 journal › Article › Academic › peer-review
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/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 -