Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2.
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.
Hooijberg
J H
JH
Department of Medical Oncology, Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.
Broxterman
H J
HJ
Kool
M
M
Assaraf
Y G
YG
Peters
G J
GJ
Noordhuis
P
P
Scheper
R J
RJ
Borst
P
P
Pinedo
H M
HM
Jansen
G
G
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005493:Folic Acid Antagonists / Q000378:metabolism* / Q000494:pharmacology; D005971:Glutamates / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D054833:Isoindoles; D008727:Methotrexate / Q000378:metabolism / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology; D013876:Thiophenes / Q000378:metabolism / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D007211:Indoles; D054833:Isoindoles; D011799:Quinazolines; D013876:Thiophenes; C079601:1843U89; D000255:Adenosine Triphosphate; C095122:multidrug resistance protein 3; C068874:raltitrexed; D008727:Methotrexate