© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 5, 429-433,
March 3, 1999
© 1999 Oxford University Press
ACCELERATED DISCOVERY |
Atypical Multidrug Resistance: Breast Cancer Resistance Protein Messenger RNA Expression in Mitoxantrone-Selected Cell Lines
Affiliations of authors: D. D. Ross, University of Maryland Greenebaum Cancer Center, Baltimore, Department of Medicine, Division of Hematology/Oncology, University of Maryland School of Medicine, and Baltimore Veterans Medical Center, Department of Veterans Affairs; W. Yang, University of Maryland Greenebaum Cancer Center; L. V. Abruzzo, University of Maryland Greenebaum Cancer Center and Department of Pathology, University of Maryland School of Medicine; W. S. Dalton, Moffitt Cancer Center, University of South Florida, Tampa; E. Schneider, Wadsworth Center, New York State Department of Health, Albany; H. Lage, M. Dietel, Institute of Pathology, University Hospital Charité, Humboldt University, Berlin, Germany; L. Greenberger, Wyeth-Ayerst Research, Pearl River, NY; S. P. C. Cole, Cancer Research Laboratories, Queen's University, Kingston, ON, Canada; L. A. Doyle, University of Maryland Greenebaum Cancer Center and Department of Medicine, Division of Hematology/Oncology, University of Maryland School of Medicine.
Correspondence to: Douglas D. Ross, M.D., Ph.D., Greenebaum Cancer Center of the University of Maryland, Rm. 9-015, Bressler Research Bldg., 655 West Baltimore St., Baltimore, MD 21201 (e-mail: DROSS{at}umcc01.umcc.ab. umd.edu). Reprint requests to: Douglas D. Ross or L. Austin Doyle, Greenebaum Cancer Center of the University of Maryland, Rm. 9-015, Bressler Research Bldg., 655 West Baltimore St., Baltimore, MD 21201.
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ABSTRACT |
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BACKGROUND: Human cancer cell lines grown in the presence of the cytotoxic agent mitoxantrone frequently develop resistance associated with a reduction in intracellular drug accumulation without increased expression of the known drug resistance transporters P-glycoprotein and multidrug resistance protein (also known as multidrug resistance-associated protein). Breast cancer resistance protein (BCRP) is a recently described adenosine triphosphate-binding cassette transporter associated with resistance to mitoxantrone and anthracyclines. This study was undertaken to test the prevalence of BCRP overexpression in cell lines selected for growth in the presence of mitoxantrone. METHODS: Total cellular RNA or poly A+ RNA and genomic DNA were isolated from parental and drug-selected cell lines. Expression of BCRP messenger RNA (mRNA) and amplification of the BCRP gene were analyzed by northern and Southern blot hybridization, respectively. RESULTS: A variety of drug-resistant human cancer cell lines derived by selection with mitoxantrone markedly overexpressed BCRP mRNA; these cell lines included sublines of human breast carcinoma (MCF-7), colon carcinoma(S1 and HT29), gastric carcinoma (EPG85-257), fibrosarcoma (EPF86-079),and myeloma (8226) origins. Analysis of genomic DNA from BCRP-overexpressing MCF-7/MX cells demonstrated that the BCRP gene was also amplified in these cells. CONCLUSIONS: Overexpression of BCRP mRNA is frequently observed in multidrug-resistant cell lines selected with mitoxantrone, suggesting that BCRP is likely to be a major cellular defense mechanism elicited in response to exposure to this drug. It is likely that BCRP is the putative "mitoxantrone transporter" hypothesized to be present in these cell lines.
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INTRODUCTION |
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Transport-mediated resistance to anticancer drugs has been a subject of active investigation for a number of years. Currently, two members of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily of transport proteins, P-glycoprotein (Pgp) and multidrug resistance protein (MRP; also known as multidrug resistance-associated protein), are known to cause cultured tumor cell lines to become resistant to multiple anticancer drugs (1,2). However, when the drug mitoxantrone is used as the selecting agent, the resulting drug-resistant cell lines frequently do not overexpress Pgp or MRP, despite a demonstrable reduction in drug accumulation (3-8). This result suggests that a novel transport-mediated drug resistance mechanism(s) is recruited in response to selection with mitoxantrone. The unique mitoxantrone-selected phenotype is characterized by the following: resistance to mitoxantrone, doxorubicin, and daunorubicin; an ATP-dependent reduction in drug accumulation; and sensitivity to vinca alkaloids, paclitaxel, and cisplatin. The drug resistance phenotype typically associated with mitoxantrone selection has also been observed in human breast carcinoma MCF-7/AdrVp cells, which were not selected with mitoxantrone but were selected with doxorubicin in the presence of verapamil, an inhibitor of Pgp (9). Despite the method of selection, MCF-7/AdrVp cells are considerably more resistant to mitoxantrone than to doxorubicin (10).
Recently, MCF-7/AdrVp cells were found to overexpress a novel ABC transport protein designated breast cancer resistance protein, or BCRP (11). Transfection of BCRP complementary DNA (cDNA) into drug-sensitive MCF-7 cells conferred resistance to mitoxantrone, daunorubicin, and doxorubicin but not to vinca alkaloids, paclitaxel, or cisplatin. In addition, lower intracellular accumulation and retention of daunorubicin and an ATP-dependent enhancement of the efflux of rhodamine 123 were observed in the transfected cells (11). Hence, transfection with BCRP cDNA reproduced in MCF-7 cells the drug resistance phenotype typical of mitoxantrone-selected cell lines. This finding suggests that BCRP may be responsible for the novel transport mechanism observed in the mitoxantrone-selected cell lines. This study was undertaken to test the prevalence of BCRP overexpression in mitoxantrone-selected cell lines.
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MATERIALS AND METHODS |
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Cell lines. The cell lines used and the conditions under which they were cultured are given in Table 1
and references listed therein. The S1M1-3.2 colon
carcinoma cells were derived from S1 cells (a subclone of human colon carcinoma cell line
LS174T) by selection for growth in increasing concentrations of mitoxantrone until a final
concentration of 3.2 µM was achieved. The HL-60/MX2 leukemia cells were
purchased from the American Type Culture Collection (Manassas, VA) and were maintained in
culture as described previously (12).
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Northern blot hybridization. Total cellular RNA was used for northern blot hybridization analysis in all cases except for H209 or H69 cells, where poly A+ RNA was used. RNA extraction and northern blotting were performed by standard techniques as described previously (11). A 795-base-pair (bp) fragment of the 3' end of the 2418-bp BCRP cDNA (GenBank database accession number AF098951) was used as the hybridization probe after labeling with [32P]deoxycytidine triphosphate ("Prime-a-Gene" labeling kit; Promega Corp., Madison, WI) as described previously (11). To control for variations in sample loading, the blots were stripped, then rehybridized with 32P-labeled ß-actin or 18S RNA probes as described previously (11). The levels of messenger RNA (mRNA) expression in different cell lines were compared by an arbitrary grading system (Table 1)
based on visual determination of signal intensities. Southern blot hybridization. Genomic DNA was isolated from the MCF-7 cell lines, digested with EcoRI or BamHI, and separated by 0.8% agarose gel electrophoresis. After staining with ethidium bromide, the DNA was transferred and fixed to a nitrocellulose filter by use of standard techniques (13). The filter was hybridized with the 32P-labeled 795-bp BCRP probe described above for northern blot analysis.
Northern or Southern blots were prepared by collaborating authors (S. P. C. Cole, W. S. Dalton, M. Dietel, H. Lage, and E. Schneider) who maintain mitoxantrone-selected and other multidrug-resistant cell lines in their laboratories; the blots were then probed for BCRP expression in the laboratories of D. D. Ross and L. A. Doyle at the University of Maryland Greenebaum Cancer Center.
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RESULTS |
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The drug-resistant cell lines used and their characteristics with respect to the degree of resistance that they exhibit and expression (relative to parental cells) of mRNAs encoding the multidrug resistance transporters Pgp, MRP, and BCRP are summarized in Table 1.
All of the mitoxantrone-selected sublines derived from human breast carcinoma MCF-7 cells
overexpressed BCRP mRNA relative to its expression in parental MCF-7 cells. BCRP-positive
cell lines included MCF-7/Mitox cells (3) (Fig. 1, A; lane 2); MCF-7/MXPR cells, partial revertants of MCF-7/MX (5); and two sublines of MCF-7/MX (MCF-7/MXRS250 and
MCF-7/MXRS600) (Mitox = MX = RNOV [see below] = mitoxantrone) that were reselected with higher concentrations of mitoxantrone (6) (Fig. 1, B; lanes 4-6). The MCF-7/MX cells
(Fig. 1, B; lanes 4-6) appeared to express amounts of BCRP mRNA
comparable to or greater than those expressed by the MCF-7/AdrVp1000 cells (Fig. 1, B; lane 10) from which BCRP was originally isolated (Adr =
Adriamycin®) = doxorubicin, and Vp = verapamil) (11). In contrast to BCRP mRNA expression in the mitoxantrone-selected cell lines,
BCRP mRNA was not overexpressed in MCF-7 cells selected with methotrexate
[MCF-7/MTX (13)], etoposide [MCF-7/VP (14)], or doxorubicin [MCF-7/Adr (15)], which derive resistance, at least in part, from the overexpression of dihydrofolate
reductase (DHFR), MRP, or Pgp, respectively (Fig. 1, B; Table 1). Mitoxantrone-selected human breast carcinoma MDA-MB-231RNOV
cells, which are less resistant to mitoxantrone than the MCF-7 sublines, demonstrated only
slightly elevated levels of BCRP mRNA compared with the levels seen in the parental cell line
(Fig. 1, C; lanes 3 and 4).
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Amplification of the BCRP gene was detected in MCF-7/MXPR cells (Fig. 2;
lanes 2 and 8), MCF-7/MXRS250 cells (Fig. 2; lanes 3 and 9), and MCF-7/MXRS600 cells (Fig. 2; lanes 4 and 10). No BCRP gene amplification was observed in etoposide-selected,
MRP-overexpressing MCF-7/VP cells (Fig. 2; lanes 5 and 11) or in
methotrexate-selected, DHFR-amplified MCF-7/MTX cells (Fig. 2; lanes
6 and 12).
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Human myeloma 8226/MR20 cells are capable of sustained growth in 200 nM mitoxantrone (4) and also demonstrated overexpression of BCRP compared with BCRP expression in parental 8226 cells (Fig. 1, A;
lanes
3 and 4). The expression of BCRP mRNA in 8226/MR20 cells was less than the amount of
BCRP mRNA expressed in MCF-7/Mitox cells (Fig. 1, A; lane 2);
however, this may be because the latter cell line is more resistant to mitoxantrone (1208-fold,
Table 1) than is the former (36-fold, Table 1).
Overexpression of BCRP mRNA was also observed in human colon carcinoma S1/M1-3.2 cells
(resistant to 3.2 µM mitoxantrone) (Fig. 1, B; lane 1),
compared with parental S1 cells (Fig. 1, B; lane 2). Another human colon
carcinoma cell line selected with mitoxantrone, HT29RNOV, displayed overexpression of BCRP
compared with the BCRP expression in parental HT29 cells (Fig. 1, C;
lanes 1 and 2).
None of the small-cell lung cancer cell lines tested overexpressed BCRP (data not shown),
including those selected with mitoxantrone (H209/MX2 and H209/MX4) (Table 1). It is of note that these mitoxantrone-selected lines showed only a low degree of
resistance to the drug and also have no demonstrable overexpression of Pgp or MRP.
Etoposide-selected H209/V6 cells appear to derive their resistance from a mutated topoisomerase
II (16); H69/AR cells, selected with doxorubicin, markedly overexpress
MRP (17).
The human gastric carcinoma-derived resistant EPG85-257RNOV cell line was developed by
stepwise selection with mitoxantrone (8). Compared with parental cells,
EPG85-257RNOV cells have no detectable overexpression of Pgp or MRP; they display
decreased mitoxantrone accumulation and cross-resistance to anthracyclines, but they retain
sensitivity to cisplatin and vinca alkaloids (8,18). Northern blot analysis
indicated elevated levels of BCRP mRNA in EPG85-257RNOV cells compared with the levels
in the parental EPG85-257 cells (Fig. 1, C; lanes 7 and 8). In contrast, a
Pgp-overexpressing subline selected with daunorubicin, EPG85-257RDB, did not overexpress
BCRP relative to its expression in parental EPG85-257 cells (Fig. 1, C;
lane 9).
BCRP mRNA was not overexpressed in human pancreatic carcinoma EPP85-181 cells selected
in mitoxantrone (EPP85-181RNOV) or daunorubicin (EPP85-181RDB) (19) (Fig. 1, C; lanes 10-12). The baseline expression of BCRP
in the parental EPP85-181 pancreatic carcinoma cells appeared to be lower than that in the
parental EPG85-257 gastric carcinoma cells (Fig. 1, C; lanes 7 and 10).
Mitoxantrone-selected EPF86-079RNOV human fibrosarcoma cells displayed overexpression of
BCRP mRNA compared with the BCRP mRNA expression in parental EPF86-079 cells (Fig. 1,
C; lanes 5 and 6).
A mitoxantrone-selected subline of human acute myeloid leukemia HL-60 cells [HL-60/MX2 (12)] did not overexpress BCRP mRNA (data not shown). However, these resistant cells do not display the typical phenotype displayed by mitoxantrone-selected cells that overexpress BCRP, since HL-60/MX2 cells do not have diminished accumulation of mitoxantrone and are cross-resistant to etoposide. HL-60/MX2 cells have altered catalytic activity of DNA topoisomerase II and reduced levels of topoisomerase II alpha and beta proteins (12).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Elevated expression of the novel ABC transporter BCRP is a common feature of many cancer cell lines selected with mitoxantrone and is consistently associated with a phenotype that includes high-level resistance to mitoxantrone, lower resistance to anthracyclines, and sensitivity to vinca alkaloids, paclitaxel, and cisplatin. ATP-dependent export of mitoxantrone, anthracyclines, and rhodamine 123 has been observed in several BCRP-positive, mitoxantrone-resistant cell lines and BCRP-transfected breast cancer cells (7,11). Cross-resistance to topoisomerase I-directed agents has been reported in some mitoxantrone-resistant cell lines (20), but resistance to these agents has not yet been confirmed in BCRP-transfected cells.
The BCRP peptide has the characteristics of a "half-transporter," having only a single ATP-binding domain and a single lipophilic region containing transmembrane domains (11). Hence, it is possible that the most efficient transmembrane conductance channel contains BCRP as a dimer or multimer either with itself or with another heretofore undescribed "half-transporter" (11). Although the transfection studies suggest that the enforced overexpression of BCRP cDNA is sufficient to confer drug resistance to the transfected cells (11), it is possible that another transporter(s) may be involved in a dimeric or a multimeric complex with BCRP, which may contribute to the resistance of the mitoxantrone-selected cell lines. The identification of other transporters that may participate in the BCRP transmembrane conductance channel is currently under active investigation in our laboratory.
The finding of elevated expression of BCRP mRNA in the human colon carcinoma S1M1-3.2 cells suggests that BCRP is the "non-Pgp, non-MRP" drug transporter manifested by this multidrug-resistant cell line. This is of particular importance because of the recent report (7) of a novel and specific inhibitor of the transporter identified in S1M1-3.2 cells. This inhibitor, fumitremorgin C, does not reverse resistance in cells that overexpress Pgp or MRP. In preliminary studies in our laboratory, fumitremorgin C is able to enhance the accumulation and inhibit the efflux of BBR 3390 (an aza-anthrapyrazole drug that is effluxed by BCRP) in BCRP-transfected MCF-7 cells [data not shown; (11)]. Further development of fumitremorgin C is warranted for use in functional assays of BCRP activity and possibly as a clinical adjunct to chemotherapy, should BCRP protein/activity levels be shown to be elevated in human cancers.
BCRP expression is associated with multidrug resistance in mitoxantrone-selected cell lines derived from human breast, gastric, and colon cancers, as well as from fibrosarcoma and multiple myeloma cells. High levels of BCRP expression are not associated with strong expression of MRP or Pgp in mitoxantrone-selected cell lines or in multidrug-resistant cell lines known to overexpress MRP or Pgp.
In conclusion, our study indicates that elevated expression of BCRP is frequently observed in mitoxantrone-selected cell lines derived from human multiple myeloma and a number of solid tumors. Considered together with results from BCRP transfection studies (11), these data demonstrate that BCRP is a novel ABC protein responsible for mediating resistance to mitoxantrone and other important chemotherapeutic agents in a wide variety of human cancer cell lines.
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NOTES |
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L. Greenberger owns stock in, and is an employee of, American Home Products, which fully owns Wyeth-Ayerst Research, the company that manufactures and sells mitoxantrone.
Supported in part by Public Health Service grant CA52178 (D. D. Ross) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by a merit review grant (D. D. Ross) from the Department of Veterans Affairs.
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Manuscript received January 13, 1999; accepted January 27, 1999.
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M. H.G.P. Raaijmakers, E. P.L.M. de Grouw, L. H.H. Heuver, B. A. van der Reijden, J. H. Jansen, R. J. Scheper, G. L. Scheffer, T. J.M. de Witte, and R. A.P. Raymakers Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38- Cells in Acute Myeloid Leukemia Clin. Cancer Res., March 15, 2005; 11(6): 2436 - 2444. [Abstract] [Full Text] [PDF]
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N. B. Elkind, Z. Szentpetery, A. Apati, C. Ozvegy-Laczka, G. Varady, O. Ujhelly, K. Szabo, L. Homolya, A. Varadi, L. Buday, et al. Multidrug Transporter ABCG2 Prevents Tumor Cell Death Induced by the Epidermal Growth Factor Receptor Inhibitor Iressa (ZD1839, Gefitinib) Cancer Res., March 1, 2005; 65(5): 1770 - 1777. [Abstract] [Full Text] [PDF]
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Z. Benderra, A.-M. Faussat, L. Sayada, J.-Y. Perrot, D. Chaoui, J.-P. Marie, and O. Legrand Breast Cancer Resistance Protein and P-Glycoprotein in 149 Adult Acute Myeloid Leukemias Clin. Cancer Res., December 1, 2004; 10(23): 7896 - 7902. [Abstract] [Full Text] [PDF]
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K. Yoh, G. Ishii, T. Yokose, Y. Minegishi, K. Tsuta, K. Goto, Y. Nishiwaki, T. Kodama, M. Suga, and A. Ochiai Breast Cancer Resistance Protein Impacts Clinical Outcome in Platinum-Based Chemotherapy for Advanced Non-Small Cell Lung Cancer Clin. Cancer Res., March 1, 2004; 10(5): 1691 - 1697. [Abstract] [Full Text] [PDF]
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P. L. R. Ee, S. Kamalakaran, D. Tonetti, X. He, D. D. Ross, and W. T. Beck Identification of a Novel Estrogen Response Element in the Breast Cancer Resistance Protein (ABCG2) Gene Cancer Res., February 15, 2004; 64(4): 1247 - 1251. [Abstract] [Full Text] [PDF]
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 J van der Heijden, M C de Jong, B A C Dijkmans, W F Lems, R Oerlemans, I Kathmann, G L Scheffer, R J Scheper, Y G Assaraf, and G Jansen Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs Ann Rheum Dis, February 1, 2004; 63(2): 131 - 137. [Abstract] [Full Text] [PDF]
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J van der Heijden, M C de Jong, B A C Dijkmans, W F Lems, R Oerlemans, I Kathmann, C G Schalkwijk, G L Scheffer, R J Scheper, and G Jansen Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNF{alpha} Ann Rheum Dis, February 1, 2004; 63(2): 138 - 143. [Abstract] [Full Text] [PDF]
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T. Nakanishi, L. A. Doyle, B. Hassel, Y. Wei, K. S. Bauer, S. Wu, D. W. Pumplin, H.-B. Fang, and D. D. Ross Functional Characterization of Human Breast Cancer Resistance Protein (BCRP, ABCG2) Expressed in the Oocytes of Xenopus laevis Mol. Pharmacol., December 1, 2003; 64(6): 1452 - 1462. [Abstract] [Full Text] [PDF]
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 H. H. Yang, M. H. Ma, R. A. Vescio, and J. R. Berenson Overcoming Drug Resistance in Multiple Myeloma: The Emergence of Therapeutic Approaches to Induce Apoptosis J. Clin. Oncol., November 15, 2003; 21(22): 4239 - 4247. [Abstract] [Full Text] [PDF]
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E. L. Volk and E. Schneider Wild-Type Breast Cancer Resistance Protein (BCRP/ABCG2) is a Methotrexate Polyglutamate Transporter Cancer Res., September 1, 2003; 63(17): 5538 - 5543. [Abstract] [Full Text] [PDF]
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S. Kawabata, M. Oka, H. Soda, K. Shiozawa, K. Nakatomi, J. Tsurutani, Y. Nakamura, S. Doi, T. Kitazaki, K. Sugahara, et al. Expression and Functional Analyses of Breast Cancer Resistance Protein in Lung Cancer Clin. Cancer Res., August 1, 2003; 9(8): 3052 - 3057. [Abstract] [Full Text] [PDF]
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A. C. Lockhart, R. G. Tirona, and R. B. Kim Pharmacogenetics of ATP-binding Cassette Transporters in Cancer and Chemotherapy Mol. Cancer Ther., July 1, 2003; 2(7): 685 - 698. [Abstract] [Full Text] [PDF]
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R. Rajendra, M. K. Gounder, A. Saleem, J. H. M. Schellens, D. D. Ross, S. E. Bates, P. Sinko, and E. H. Rubin Differential Effects of the Breast Cancer Resistance Protein on the Cellular Accumulation and Cytotoxicity of 9-Aminocamptothecin and 9-Nitrocamptothecin Cancer Res., June 15, 2003; 63(12): 3228 - 3233. [Abstract] [Full Text] [PDF]
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 C. Ozvegy, A. Varadi, and B. Sarkadi Characterization of Drug Transport, ATP Hydrolysis, and Nucleotide Trapping by the Human ABCG2 Multidrug Transporter. MODULATION OF SUBSTRATE SPECIFICITY BY A POINT MUTATION J. Biol. Chem., December 6, 2002; 277(50): 47980 - 47990. [Abstract] [Full Text] [PDF]
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E. L. Volk, K. M. Farley, Y. Wu, F. Li, R. W. Robey, and E. Schneider Overexpression of Wild-Type Breast Cancer Resistance Protein Mediates Methotrexate Resistance Cancer Res., September 1, 2002; 62(17): 5035 - 5040. [Abstract] [Full Text] [PDF]
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D. M. van der Kolk, E. Vellenga, G. L. Scheffer, M. Muller, S. E. Bates, R. J. Scheper, and E. G. E. de Vries Expression and activity of breast cancer resistance protein (BCRP) in de novo and relapsed acute myeloid leukemia Blood, May 15, 2002; 99(10): 3763 - 3770. [Abstract] [Full Text] [PDF]
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 G L Scheffer, A C L M Pijnenborg, E F Smit, M Muller, D S Postma, W Timens, P van der Valk, E G E de Vries, and R J Scheper Multidrug resistance related molecules in human and murine lung J. Clin. Pathol., May 1, 2002; 55(5): 332 - 339. [Abstract] [Full Text] [PDF]
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J. D. Allen, S. C. Jackson, and A. H. Schinkel A Mutation Hot Spot in the Bcrp1 (Abcg2) Multidrug Transporter in Mouse Cell Lines Selected for Doxorubicin Resistance Cancer Res., April 1, 2002; 62(8): 2294 - 2299. [Abstract] [Full Text] [PDF]
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J. D. Allen, A. van Loevezijn, J. M. Lakhai, M. van der Valk, O. van Tellingen, G. Reid, J. H. M. Schellens, G.-J. Koomen, and A. H. Schinkel Potent and Specific Inhibition of the Breast Cancer Resistance Protein Multidrug Transporter in Vitro and in Mouse Intestine by a Novel Analogue of Fumitremorgin C Mol. Cancer Ther., April 1, 2002; 1(6): 417 - 425. [Abstract] [Full Text] [PDF]
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J. D. Allen and A. H. Schinkel Multidrug Resistance and Pharmacological Protection Mediated by the Breast Cancer Resistance Protein (BCRP/ABCG2) Mol. Cancer Ther., April 1, 2002; 1(6): 427 - 434. [Full Text] [PDF]
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I. F. Faneyte, P. M. P. Kristel, M. Maliepaard, G. L. Scheffer, R. J. Scheper, J. H. M. Schellens, and M. J. van de Vijver Expression of the Breast Cancer Resistance Protein in Breast Cancer Clin. Cancer Res., April 1, 2002; 8(4): 1068 - 1074. [Abstract] [Full Text] [PDF]
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M. Kim, H. Turnquist, J. Jackson, M. Sgagias, Y. Yan, M. Gong, M. Dean, J. G. Sharp, and K. Cowan The Multidrug Resistance Transporter ABCG2 (Breast Cancer Resistance Protein 1) Effluxes Hoechst 33342 and Is Overexpressed in Hematopoietic Stem Cells Clin. Cancer Res., January 1, 2002; 8(1): 22 - 28. [Abstract] [Full Text] [PDF]
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P. Perego, M. De Cesare, P. De Isabella, N. Carenini, G. Beggiolin, G. Pezzoni, M. Palumbo, L. Tartaglia, G. Pratesi, C. Pisano, et al. A Novel 7-modified Camptothecin Analog Overcomes Breast Cancer Resistance Protein-associated Resistance in a Mitoxantrone-selected Colon Carcinoma Cell Line Cancer Res., August 1, 2001; 61(16): 6034 - 6037. [Abstract] [Full Text] [PDF]
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S. K. Diah, P. K. Smitherman, J. Aldridge, E. L. Volk, E. Schneider, A. J. Townsend, and C. S. Morrow Resistance to Mitoxantrone in Multidrug-resistant MCF7 Breast Cancer Cells: Evaluation of Mitoxantrone Transport and the Role of Multidrug Resistance Protein Family Proteins Cancer Res., July 1, 2001; 61(14): 5461 - 5467. [Abstract] [Full Text] [PDF]
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H. Komatani, H. Kotani, Y. Hara, R. Nakagawa, M. Matsumoto, H. Arakawa, and S. Nishimura Identification of Breast Cancer Resistant Protein/Mitoxantrone Resistance/Placenta-Specific, ATP-binding Cassette Transporter as a Transporter of NB-506 and J-107088, Topoisomerase I Inhibitors with an Indolocarbazole Structure Cancer Res., April 1, 2001; 61(7): 2827 - 2832. [Abstract] [Full Text]
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M. Maliepaard, G. L. Scheffer, I. F. Faneyte, M. A. van Gastelen, A. C. L. M. Pijnenborg, A. H. Schinkel, M. J. van de Vijver, R. J. Scheper, and J. H. M. Schellens Subcellular Localization and Distribution of the Breast Cancer Resistance Protein Transporter in Normal Human Tissues Cancer Res., April 1, 2001; 61(8): 3458 - 3464. [Abstract] [Full Text]
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M. Maliepaard, M. A. van Gastelen, A. Tohgo, F. H. Hausheer, R. C. A. M. van Waardenburg, L. A. de Jong, D. Pluim, J. H. Beijnen, and J. H. M. Schellens Circumvention of Breast Cancer Resistance Protein (BCRP)-mediated Resistance to Camptothecins in Vitro Using Non-Substrate Drugs or the BCRP Inhibitor GF120918 Clin. Cancer Res., April 1, 2001; 7(4): 935 - 941. [Abstract] [Full Text]
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C. Erlichman, S. A. Boerner, C. G. Hallgren, R. Spieker, X.-Y. Wang, C. D. James, G. L. Scheffer, M. Maliepaard, D. D. Ross, K. C. Bible, et al. The HER Tyrosine Kinase Inhibitor CI1033 Enhances Cytotoxicity of 7-Ethyl-10-hydroxycamptothecin and Topotecan by Inhibiting Breast Cancer Resistance Protein-mediated Drug Efflux Cancer Res., January 1, 2001; 61(2): 739 - 748. [Abstract] [Full Text]
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R. W. Robey, W. Y. Medina-Pérez, K. Nishiyama, T. Lahusen, K. Miyake, T. Litman, A. M. Senderowicz, D. D. Ross, and S. E. Bates Overexpression of the ATP-binding Cassette Half-Transporter, ABCG2 (MXR/BCRP/ABCP1), in Flavopiridol-resistant Human Breast Cancer Cells Clin. Cancer Res., January 1, 2001; 7(1): 145 - 152. [Abstract] [Full Text]
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 M. J. Egorin Adenosine Triphosphate-Binding Cassette Proteins and Bioavailability: "We Can Pump You Up (or Out)" J Natl Cancer Inst, October 18, 2000; 92(20): 1628 - 1629. [Full Text] [PDF]
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J. W. Jonker, J. W. Smit, R. F. Brinkhuis, M. Maliepaard, J. H. Beijnen, J. H. M. Schellens, and A. H. Schinkel Role of Breast Cancer Resistance Protein in the Bioavailability and Fetal Penetration of Topotecan J Natl Cancer Inst, October 18, 2000; 92(20): 1651 - 1656. [Abstract] [Full Text] [PDF]
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G. L. Scheffer, M. Kool, M. Heijn, Marcel de Haas, A. C. L. M. Pijnenborg, J. Wijnholds, A. van Helvoort, M. C. de Jong, J. H. Hooijberg, C. A. A. M. Mol, et al. Specific Detection of Multidrug Resistance Proteins MRP1, MRP2, MRP3, MRP5, and MDR3 P-Glycoprotein with a Panel of Monoclonal Antibodies Cancer Res., September 1, 2000; 60(18): 5269 - 5277. [Abstract] [Full Text]
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E. L. Volk, K. Rohde, M. Rhee, J. J. McGuire, L. A. Doyle, D. D. Ross, and E. Schneider Methotrexate Cross-Resistance in a Mitoxantrone-selected Multidrug-resistant MCF7 Breast Cancer Cell Line Is Attributable to Enhanced Energy-dependent Drug Efflux Cancer Res., July 1, 2000; 60(13): 3514 - 3521. [Abstract] [Full Text]
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D. D. Ross, J. E. Karp, T. T. Chen, and L. A. Doyle Expression of breast cancer resistance protein in blast cells from patients with acute leukemia Blood, July 1, 2000; 96(1): 365 - 368. [Abstract] [Full Text] [PDF]
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G. L. Scheffer, M. Maliepaard, A. C. L. M. Pijnenborg, M. A. van Gastelen, M. C. de Jong, A. B. Schroeijers, D. M. van der Kolk, J. D. Allen, D. D. Ross, P. van der Valk, et al. Breast Cancer Resistance Protein Is Localized at the Plasma Membrane in Mitoxantrone- and Topotecan-resistant Cell Lines Cancer Res., May 1, 2000; 60(10): 2589 - 2593. [Abstract] [Full Text]
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S. K. Rabindran, D. D. Ross, L. A. Doyle, W. Yang, and L. M. Greenberger Fumitremorgin C Reverses Multidrug Resistance in Cells Transfected with the Breast Cancer Resistance Protein Cancer Res., January 1, 2000; 60(1): 47 - 50. [Abstract] [Full Text]
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J. D. Allen, R. F. Brinkhuis, J. Wijnholds, and A. H. Schinkel The Mouse Bcrp1/Mxr/Abcp Gene: Amplification and Overexpression in Cell Lines Selected for Resistance to Topotecan, Mitoxantrone, or Doxorubicin Cancer Res., September 1, 1999; 59(17): 4237 - 4241. [Abstract] [Full Text] [PDF]
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M. Maliepaard, M. A. van Gastelen, L. A. de Jong, D. Pluim, R. C. A. M. van Waardenburg, M. C. Ruevekamp-Helmers, B. G. J. Floot, and J. H. M. Schellens Overexpression of the BCRP/MXR/ABCP Gene in a Topotecan-selected Ovarian Tumor Cell Line Cancer Res., September 1, 1999; 59(18): 4559 - 4563. [Abstract] [Full Text] [PDF]
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