Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2

Cancer Res. 1999 Jun 1;59(11):2532-5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B / metabolism*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism
  • Antimetabolites, Antineoplastic / metabolism*
  • Antimetabolites, Antineoplastic / pharmacology
  • Drug Resistance, Multiple* / genetics
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Folic Acid Antagonists / metabolism*
  • Folic Acid Antagonists / pharmacology
  • Glutamates / metabolism
  • Humans
  • Indoles / metabolism
  • Indoles / pharmacology
  • Isoindoles
  • Methotrexate / metabolism
  • Methotrexate / pharmacology
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Quinazolines / metabolism
  • Quinazolines / pharmacology
  • Thiophenes / metabolism
  • Thiophenes / pharmacology
  • Transfection
  • Tumor Cells, Cultured / drug effects

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Antimetabolites, Antineoplastic
  • Folic Acid Antagonists
  • Glutamates
  • Indoles
  • Isoindoles
  • Quinazolines
  • Thiophenes
  • 1843U89
  • Adenosine Triphosphate
  • multidrug resistance protein 3
  • raltitrexed
  • Methotrexate