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Cancer Research Laboratories [C. E. G., G. V., D. R. H., K. C. A., S. P. C. C., R. G. D.] and Department of Pathology [D. R. H., K. C. A., S. P. C. C., R. G. D.], Queen's University, Kingston, Ontario, Canada K7L 3N6
2 To whom reprint requests should be addressed.
Amplification of the gene encoding multidrug resistance-associated protein (MRP) and overexpression of its cognate mRNA have been detected in multidrug-resistant cell lines derived from several different tumor types. To establish whether or not the increase in MRP is responsible for drug resistance in these cell lines, we have transfected HeLa cells with MRP expression vectors. The transfectants display an increase in resistance to doxorubicin that is proportional to the levels of a Mr 190,000, integral membrane protein recognized by anti-MRP antibodies. The transfectants are also resistant to vincristine and VP-16 but not to cisplatin. The results demonstrate that MRP overexpression confers a multidrug resistance phenotype similar to that formerly associated exclusively with elevated levels of P-glycoprotein.
1 This work was supported by grants from the Medical Research Council of Canada and the Cancer Research Society (S. P. C. C. and R. G. D.). C. E. G. is a recipient of a Medical Research Council postdoctoral fellowship; D. R. H. is the recipient of a Queen's University graduate award; and G. V. and K. C. A. were supported by the Ontario Cancer Treatment and Research Foundation. S. P. C. C. is a Career Scientist of the Ontario Cancer Treatment and Research Foundation, and R. G. D. is the Stauffer Research Professor of Queen's University.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 10/28/93. Accepted 11/26/93.
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 K. Toth, M. M. Vaughan, G. Schwartz, J. S. Winston, B. S. Skenderis II, H. K. Slocum, and Y. M. Rustum Expression of the MRP and MDRI Multidrug Resistance Gene Products in 160 Untreated Human Carcinomas Studied by Immunohistochemical Methods in Formalin-Paraffin Sections International Journal of Surgical Pathology, July 1, 1998; 6(3): 145 - 154. [Abstract] [PDF]
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O. Legrand, G. Simonin, J.-Y. Perrot, R. Zittoun, and J.-P. Marie Pgp and MRP Activities Using Calcein-AM Are Prognostic Factors in Adult Acute Myeloid Leukemia Patients Blood, June 15, 1998; 91(12): 4480 - 4488. [Abstract] [Full Text] [PDF]
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M. Gao, M. Yamazaki, D. W. Loe, C. J. Westlake, C. E. Grant, S. P. C. Cole, and R. G. Deeley Multidrug Resistance Protein. IDENTIFICATION OF REGIONS REQUIRED FOR ACTIVE TRANSPORT OF LEUKOTRIENE C4 J. Biol. Chem., April 24, 1998; 273(17): 10733 - 10740. [Abstract] [Full Text] [PDF]
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V. A. Kickhoefer, K. S. Rajavel, G. L. Scheffer, W. S. Dalton, R. J. Scheper, and L. H. Rome Vaults Are Up-regulated in Multidrug-resistant Cancer Cell Lines J. Biol. Chem., April 10, 1998; 273(15): 8971 - 8974. [Abstract] [Full Text] [PDF]
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M. Filipits, G. Pohl, T. Stranzl, R. W. Suchomel, R. J. Scheper, U. Jager, K. Geissler, K. Lechner, and R. Pirker Expression of the Lung Resistance Protein Predicts Poor Outcome in De Novo Acute Myeloid Leukemia Blood, March 1, 1998; 91(5): 1508 - 1513. [Abstract] [Full Text] [PDF]
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X.-B. Chang, Y.-X. Hou, and J. R. Riordan ATPase Activity of Purified Multidrug Resistance-associated Protein J. Biol. Chem., December 5, 1997; 272(49): 30962 - 30968. [Abstract] [Full Text] [PDF]
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C. Kast and P. Gros Topology Mapping of the Amino-terminal Half of Multidrug Resistance-associated Protein by Epitope Insertion and Immunofluorescence J. Biol. Chem., October 17, 1997; 272(42): 26479 - 26487. [Abstract] [Full Text] [PDF]
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C. D. Jennings and K. A. Foon Recent Advances in Flow Cytometry: Application to the Diagnosis of Hematologic Malignancy Blood, October 15, 1997; 90(8): 2863 - 2892. [Full Text] [PDF]
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D. R. Hipfner, K. C. Almquist, E. M. Leslie, J. H. Gerlach, C. E. Grant, R. G. Deeley, and S. P. C. Cole Membrane Topology of the Multidrug Resistance Protein (MRP). A STUDY OF GLYCOSYLATION-SITE MUTANTS REVEALS AN EXTRACYTOSOLIC NH2 TERMINUS J. Biol. Chem., September 19, 1997; 272(38): 23623 - 23630. [Abstract] [Full Text] [PDF]
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B. D. Stride, C. E. Grant, D. W. Loe, D. R. Hipfner, S. P. C. Cole, and R. G. Deeley Pharmacological Characterization of the Murine and Human Orthologs of Multidrug-Resistance Protein in Transfected Human Embryonic Kidney Cells Mol. Pharmacol., September 1, 1997; 52(3): 344 - 353. [Abstract] [Full Text]
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D. W. Loe, R. K. Stewart, T. E. Massey, R. G. Deeley, and S. P. C. Cole ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene Mol. Pharmacol., June 1, 1997; 51(6): 1034 - 1041. [Abstract] [Full Text]
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Z. Zhan, V. A. Sandor, E. Gamelin, J. Regis, B. Dickstein, W. Wilson, A. T. Fojo, and S. E. Bates Expression of the Multidrug Resistance-Associated Protein Gene in Refractory Lymphoma: Quantitation by a Validated Polymerase Chain Reaction Assay Blood, May 15, 1997; 89(10): 3795 - 3800. [Abstract] [Full Text] [PDF]
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M. Gao, D. W. Loe, C. E. Grant, S. P.C. Cole, and R. G. Deeley Reconstitution of ATP-dependent Leukotriene C4 Transport by Co-expression of Both Half-molecules of Human Multidrug Resistance Protein in Insect Cells J. Biol. Chem., November 1, 1996; 271(44): 27782 - 27787. [Abstract] [Full Text] [PDF]
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D. W. Loe, K. C. Almquist, R. G. Deeley, and S. P. C. Cole Multidrug Resistance Protein (MRP)-mediated Transport of Leukotriene C(4) and Chemotherapeutic Agents in Membrane Vesicles J. Biol. Chem., April 19, 1996; 271(16): 9675 - 9682. [Abstract] [Full Text] [PDF]
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D. W. Loe, K. C. Almquist, S. P. C. Cole, and R. G. Deeley ATP-dependent 17beta-Estradiol 17-(beta-D-Glucuronide) Transport by Multidrug Resistance Protein (MRP) J. Biol. Chem., April 19, 1996; 271(16): 9683 - 9689. [Abstract] [Full Text] [PDF]
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S. Ruetz, M. Brault, C. Kast, C. Hemenway, J. Heitman, C. E. Grant, S. P. C. Cole, R. G. Deeley, and P. Gros Functional Expression of the Multidrug Resistance-associated Protein in the Yeast Saccharomyces cerevisiae J. Biol. Chem., February 23, 1996; 271(8): 4154 - 4160. [Abstract] [Full Text] [PDF]
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 M. D. Norris, S. B. Bordow, G. M. Marshall, P. S. Haber, S. L. Cohn, and M. Haber Expression of the Gene for Multidrug-Resistance-Associated Protein and Outcome in Patients with Neuroblastoma N. Engl. J. Med., January 25, 1996; 334(4): 231 - 238. [Abstract] [Full Text] [PDF]
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 S. Michealis and C. Berkower Sequence Comparison of Yeast ATP-binding Cassette Proteins Cold Spring Harb Symp Quant Biol, January 1, 1995; 60(0): 291 - 307. [Abstract] [PDF]
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K. Nagata, M. Nishitani, M. Matsuo, N. Kioka, T. Amachi, and K. Ueda Nonequivalent Nucleotide Trapping in the Two Nucleotide Binding Folds of the Human Multidrug Resistance Protein MRP1 J. Biol. Chem., June 2, 2000; 275(23): 17626 - 17630. [Abstract] [Full Text] [PDF]
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T. C. Hallstrom and W. S. Moye-Rowley Multiple Signals from Dysfunctional Mitochondria Activate the Pleiotropic Drug Resistance Pathway in Saccharomyces cerevisiae J. Biol. Chem., November 22, 2000; 275(48): 37347 - 37356. [Abstract] [Full Text] [PDF]
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Y.-M. Qian, W.-C. Song, H. Cui, S. P. C. Cole, and R. G. Deeley Glutathione Stimulates Sulfated Estrogen Transport by Multidrug Resistance Protein 1 J. Biol. Chem., February 23, 2001; 276(9): 6404 - 6411. [Abstract] [Full Text] [PDF]
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D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of an Amino Acid Residue in Multidrug Resistance Protein 1 Critical for Conferring Resistance to Anthracyclines J. Biol. Chem., April 13, 2001; 276(16): 13231 - 13239. [Abstract] [Full Text] [PDF]
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K.-i. Ito, S. L. Olsen, W. Qiu, R. G. Deeley, and S. P. C. Cole Mutation of a Single Conserved Tryptophan in Multidrug Resistance Protein 1 (MRP1/ABCC1) Results in Loss of Drug Resistance and Selective Loss of Organic Anion Transport J. Biol. Chem., May 4, 2001; 276(19): 15616 - 15624. [Abstract] [Full Text] [PDF]
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E. M. Leslie, K.-i. Ito, P. Upadhyaya, S. S. Hecht, R. G. Deeley, and S. P. C. Cole Transport of the beta -O-Glucuronide Conjugate of the Tobacco-specific Carcinogen 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the Multidrug Resistance Protein 1 (MRP1). REQUIREMENT FOR GLUTATHIONE OR A NON-SULFUR-CONTAINING ANALOG J. Biol. Chem., July 20, 2001; 276(30): 27846 - 27854. [Abstract] [Full Text] [PDF]
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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]
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D.-W. Zhang, S. P. C. Cole, and R. G. Deeley Identification of a Nonconserved Amino Acid Residue in Multidrug Resistance Protein 1 Important for Determining Substrate Specificity. EVIDENCE FOR FUNCTIONAL INTERACTION BETWEEN TRANSMEMBRANE HELICES 14 AND 17 J. Biol. Chem., September 7, 2001; 276(37): 34966 - 34974. [Abstract] [Full Text] [PDF]
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