Antifolate Resistance Mediated by the Multidrug Resistance Proteins MRP1 and MRP2

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Antifolate Resistance Mediated by the Multidrug Resistance Proteins MRP1 and MRP2¹

Jan Hendrik Hooijberg, Henk J. Broxterman, Marcel Kool, Yehuda G. Assaraf, Godefridus J. Peters, Paul Noordhuis, Rik J. Scheper, Piet Borst, Herbert M. Pinedo and Gerrit Jansen²

Departments of Medical Oncology [J. H. H., H. J. B., G. J. P., P. N., H. M. P., G. J.] and Pathology [R. J. S.], Academisch Ziekenhuis Vrije Universiteit, 1007 MB Amsterdam, the Netherlands; Department of Molecular Biology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands [M. K., P. B.]; and Department of Biology, The Technion, Israel Institute of Technology, Haifa 32000, Israel [Y. G. A.]

Transfection of multidrug resistance proteins (MRPs) MRP1 andMRP2 in human ovarian carcinoma 2008 cells conferred a markedlevel of resistance to short-term (1–4 h) exposure tothe polyglutamatable antifolates methotrexate (MTX; 21–74-fold),ZD1694 (4–138-fold), and GW1843 (101–156-fold).Evidence for MRP-mediated antifolate efflux relies upon thefollowing findings: (a) a 2–3.3-fold lower accumulationof [³H]MTX and subsequent reduced formation of long-chain polyglutamateforms of MTX; (b) reversal of MTX resistance by probenecid inboth transfectants, and (c) ATP-dependent uptake of [³H]MTXin inside-out vesicles of MRP1 and MRP2 transfectants. Thisreport provides a mechanistic basis for resistance to polyglutamatableantifolates through an MRP-mediated drug extrusion.

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Interactions of the Human Multidrug Resistance Proteins MRP1 and MRP2 with Organic Anions
Mol. Pharmacol., April 1, 2000; 57(4): 760 - 768.
[Abstract] [Full Text]

H. Zeng, L. J. Bain, M. G. Belinsky, and G. D. Kruh
Expression of Multidrug Resistance Protein-3 (Multispecific Organic Anion Transporter-D) in Human Embryonic Kidney 293 Cells Confers Resistance to Anticancer Agents
Cancer Res., December 1, 1999; 59(23): 5964 - 5967.
[Abstract] [Full Text] [PDF]

Z.-S. Chen, K. Lee, and G. D. Kruh
Transport of Cyclic Nucleotides and Estradiol 17-beta -D-Glucuronide by Multidrug Resistance Protein 4. RESISTANCE TO 6-MERCAPTOPURINE AND 6-THIOGUANINE
J. Biol. Chem., August 31, 2001; 276(36): 33747 - 33754.
[Abstract] [Full Text] [PDF]

K.-i. Ito, C. J. Oleschuk, C. Westlake, M. Z. Vasa, R. G. Deeley, and S. P. C. Cole
Mutation of Trp1254 in the Multispecific Organic Anion Transporter, Multidrug Resistance Protein 2 (MRP2) (ABCC2), Alters Substrate Specificity and Results in Loss of Methotrexate Transport Activity
J. Biol. Chem., October 5, 2001; 276(41): 38108 - 38114.
[Abstract] [Full Text] [PDF]

J. Wijnholds, C. A. A. M. Mol, L. van Deemter, M. de Haas, G. L. Scheffer, F. Baas, J. H. Beijnen, R. J. Scheper, S. Hatse, E. De Clercq, et al.
Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs
PNAS, June 20, 2000; 97(13): 7476 - 7481.
[Abstract] [Full Text] [PDF]

V. S. Zinchuk, T. Okada, K. Akimaru, and H. Seguchi
Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver
Am J Physiol Gastrointest Liver Physiol, March 1, 2002; 282(3): G540 - G548.
[Abstract] [Full Text] [PDF]