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[Cancer Research 59, 4559-4563, September 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 4559-4563, September 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Overexpression of the BCRP/MXR/ABCP Gene in a Topotecan-selected Ovarian Tumor Cell Line1

Marc Maliepaard2, Margôt A. van Gastelen, Laurina A. de Jong, Dick Pluim, Robert C. A. M. van Waardenburg, Marjan C. Ruevekamp-Helmers, Ben G. J. Floot and Jan H. M. Schellens

Divisions of Experimental Therapy [M. M., M. v. G., L. d. J., D. P., R. v. W., M. R.-H., B. F., J. S.] and Medical Oncology, [J. S.] The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

Topotecan- or mitoxantrone-selected cell lines (T8 and MX3, respectively), derived from the human IGROV1 ovarian cancer cell line, were resistant to the topoisomerase I inhibitors topotecan, SN-38 (the active metabolite of irinotecan), and 9-aminocamptothecin, as well as to the topoisomerase II drug mitoxantrone. In both resistant cell lines, decreased accumulation of topotecan and mitoxantrone was observed, caused by enhanced energy-dependent efflux of the drugs involved. In both cell lines, we found that the breast cancer resistance protein/mitoxantrone resistance/placenta-specific ATP binding cassette (BCRP/MXR/ABCP) gene was overexpressed. Furthermore, BCRP/MXR/ABCP expression levels in various partially revertant T8 cells correlated with the levels of resistance to topotecan, SN-38, and mitoxantrone, strongly suggesting BCRP/MXR/ABCP to be the transporter responsible for the enhanced efflux. Pharmacodynamic analysis demonstrated that BCRP/MXR/ABCP is a very efficient transporter of topotecan; in vitro, 70% of the intracellular topotecan pool was transported out of the T8 or MX3 cells within 30 s. In conclusion, we report for the first time that BCRP/MXR/ABCP can also be up-regulated upon exposure of tumor cells to the clinically important drug topotecan, and that BCRP-mediated efflux of topotecan is very efficient. This highly efficient efflux of topotecan by BCRP/MXR/ABCP may have clinical relevance for patients being treated with topotecan.




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C.M.F. Kruijtzer, J.H. Beijnen, and J.H.M. Schellens
Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview
Oncologist, December 1, 2002; 7(6): 516 - 530.
[Abstract] [Full Text] [PDF]

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 Proc. Natl. Acad. Sci. USAHome page
J. W. Jonker, M. Buitelaar, E. Wagenaar, M. A. van der Valk, G. L. Scheffer, R. J. Scheper, T. Plosch, F. Kuipers, R. P. J. O. Elferink, H. Rosing, et al.
The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria
PNAS, November 26, 2002; 99(24): 15649 - 15654.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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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 JCOHome page
C. M.F. Kruijtzer, J. H. Beijnen, H. Rosing, W. W. ten Bokkel Huinink, M. Schot, R. C. Jewell, E. M. Paul, and J. H.M. Schellens
Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918
J. Clin. Oncol., July 1, 2002; 20(13): 2943 - 2950.
[Abstract] [Full Text] [PDF]

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 Molecular Cancer TherapeuticsHome page
Y. Imai, M. Nakane, K. Kage, S. Tsukahara, E. Ishikawa, T. Tsuruo, Y. Miki, and Y. Sugimoto
C421A Polymorphism in the Human Breast Cancer Resistance Protein Gene Is Associated with Low Expression of Q141K Protein and Low-Level Drug Resistance
Mol. Cancer Ther., June 1, 2002; 1(8): 611 - 616.
[Abstract] [Full Text] [PDF]

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 BloodHome page
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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 J. Clin. Pathol.Home page
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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 Cancer Res.Home page
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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 Molecular Cancer TherapeuticsHome page
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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 Molecular Cancer TherapeuticsHome page
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.
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 Clin. Cancer Res.Home page
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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 Clin. Cancer Res.Home page
R. Garcia-Carbonero and J. G. Supko
Current Perspectives on the Clinical Experience, Pharmacology, and Continued Development of the Camptothecins
Clin. Cancer Res., March 1, 2002; 8(3): 641 - 661.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
M. H. Woo, J. R. Vance, A. R. O. Marcos, C. Bailly, and M.-A. Bjornsti
Active Site Mutations in DNA Topoisomerase I Distinguish the Cytotoxic Activities of Camptothecin and the Indolocarbazole, Rebeccamycin
J. Biol. Chem., February 1, 2002; 277(6): 3813 - 3822.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
M. De Cesare, G. Pratesi, P. Perego, N. Carenini, S. Tinelli, L. Merlini, S. Penco, C. Pisano, F. Bucci, L. Vesci, et al.
Potent Antitumor Activity and Improved Pharmacological Profile of ST1481, a Novel 7-substituted Camptothecin
Cancer Res., October 1, 2001; 61(19): 7189 - 7195.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Cancer Res.Home page
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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 Clin. Cancer Res.Home page
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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 JCOHome page
U. Vanhoefer, A. Harstrick, W. Achterrath, S. Cao, S. Seeber, and Y. M. Rustum
Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview
J. Clin. Oncol., March 1, 2001; 19(5): 1501 - 1518.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
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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 JNCI J Natl Cancer InstHome page
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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 BloodHome page
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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 Cancer Res.Home page
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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