This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Brangi, M. Articles by Bates, S. E. Search for Related Content PubMed PubMed Citation Articles by Brangi, M. Articles by Bates, S. E.

Camptothecin Resistance

Role of the ATP-binding Cassette (ABC), Mitoxantrone-resistance Half-Transporter (MXR), and Potential for Glucuronidation in MXR-expressing Cells

Medicine Branch [M. B., T. L., K. N., C. T., R. R., T. F., S. E. B] and Laboratory of Molecular Pharmacology, Developmental Therapeutics Program [G. K., Y. P.], Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20892; Heritable Disorders Branch, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland 20892 [M. C.]

The mitoxantrone resistance (MXR) gene encodes a recently characterized ATP-binding cassette half-transporter that confers multidrug resistance. We studied resistance to the camptothecins in two sublines expressing high levels of MXR: S1-M1-80 cells derived from parental S1 colon cancer cells and MCF-7 AdVp3000 isolated from parental MCF-7 breast cancer cells. Both cell lines were 400- to 1000-fold more resistant to topotecan, 9-amino-20(S)-camptothecin, and the active metabolite of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), than their parental cell lines. The cell lines demonstrated much less resistance to camptothecin and to several camptothecin analogues. Reduced accumulation and energy-dependent efflux of topotecan was demonstrated by confocal microscopy. A significant reduction in cleavable complexes in the resistant cells could be observed after SN-38 treatment but not after camptothecin treatment. In addition to topotecan and SN-38, MXR-overexpressing cells are highly resistant to mitoxantrone and epirubicin. Because these compounds are susceptible to glucuronidation, we examined UDP-glucuronosyltransferase (UGT) activity in parental and resistant cells by TLC. Glucuronides were found at equal levels in both parental and resistant colon cancer cell lines for epirubicin and to a lesser extent for SN-38 and mitoxantrone. Low levels of glucuronidation could also be detected in the resistant breast cancer cells. These results were confirmed by analysis of the UGT1A family mRNAs. We thus conclude that colon and breast cancer cells have a capacity for glucuronidation that could contribute to intrinsic drug resistance in colon cancer cells and may be acquired in breast cancer cells. The lack of selection for higher levels of UGT capacity in the colon cells suggests that high levels of expression of MXR alone are sufficient to confer resistance to the camptothecins.

This article has been cited by other articles:

				M. NOWAK, J. A. MADEJ, and P. DZIEGIEL Expression of Breast Cancer Resistance Protein (BCRP-1) in Canine Mammary Adenocarcinomas and Adenomas In Vivo, September 1, 2009; 23(5): 705 - 709. [Abstract] [Full Text] [PDF]

				Y.-W. Zhang, T. L. Jones, S. E. Martin, N. J. Caplen, and Y. Pommier Implication of Checkpoint Kinase-dependent Up-regulation of Ribonucleotide Reductase R2 in DNA Damage Response J. Biol. Chem., July 3, 2009; 284(27): 18085 - 18095. [Abstract] [Full Text] [PDF]

				T. Numbenjapon, J. Wang, D. Colcher, T. Schluep, M. E. Davis, J. Duringer, L. Kretzner, Y. Yen, S. J. Forman, and A. Raubitschek Preclinical Results of Camptothecin-Polymer Conjugate (IT-101) in Multiple Human Lymphoma Xenograft Models Clin. Cancer Res., July 1, 2009; 15(13): 4365 - 4373. [Abstract] [Full Text] [PDF]

				Y. Pommier and M. Cushman The indenoisoquinoline noncamptothecin topoisomerase I inhibitors: update and perspectives Mol. Cancer Ther., May 1, 2009; 8(5): 1008 - 1014. [Abstract] [Full Text] [PDF]

				M. C. D. de la Loza and R. E. Wellinger A novel approach for organelle-specific DNA damage targeting reveals different susceptibility of mitochondrial DNA to the anticancer drugs camptothecin and topotecan Nucleic Acids Res., March 1, 2009; 37(4): e26 - e26. [Abstract] [Full Text] [PDF]

				S. A. Reisman, R. L. Yeager, M. Yamamoto, and C. D. Klaassen Increased Nrf2 Activation in Livers from Keap1-Knockdown Mice Increases Expression of Cytoprotective Genes that Detoxify Electrophiles more than those that Detoxify Reactive Oxygen Species Toxicol. Sci., March 1, 2009; 108(1): 35 - 47. [Abstract] [Full Text] [PDF]

				J. R. Molina, S. H. Kaufmann, J. M. Reid, S. D. Rubin, M. Galvez-Peralta, R. Friedman, K. S. Flatten, K. M. Koch, T. M. Gilmer, R. J. Mullin, et al. Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data Clin. Cancer Res., December 1, 2008; 14(23): 7900 - 7908. [Abstract] [Full Text] [PDF]

				Z. Liao, R. W. Robey, J. Guirouilh-Barbat, K. K. W. To, O. Polgar, S. E. Bates, and Y. Pommier Reduced Expression of DNA Topoisomerase I in SF295 Human Glioblastoma Cells Selected for Resistance to Homocamptothecin and Diflomotecan Mol. Pharmacol., February 1, 2008; 73(2): 490 - 497. [Abstract] [Full Text] [PDF]

				K. Takagi, T. S. Dexheimer, C. Redon, O. Sordet, K. Agama, G. Lavielle, A. Pierre, S. E. Bates, and Y. Pommier Novel E-ring camptothecin keto analogues (S38809 and S39625) are stable, potent, and selective topoisomerase I inhibitors without being substrates of drug efflux transporters Mol. Cancer Ther., December 1, 2007; 6(12): 3229 - 3238. [Abstract] [Full Text] [PDF]

				S. Antony, K. K. Agama, Z.-H. Miao, K. Takagi, M. H. Wright, A. I. Robles, L. Varticovski, M. Nagarajan, A. Morrell, M. Cushman, et al. Novel Indenoisoquinolines NSC 725776 and NSC 724998 Produce Persistent Topoisomerase I Cleavage Complexes and Overcome Multidrug Resistance Cancer Res., November 1, 2007; 67(21): 10397 - 10405. [Abstract] [Full Text] [PDF]

				S. S. Lee, H.-E. Jeong, J.-M. Yi, H.-J. Jung, J.-E. Jang, E.-Y. Kim, S.-J. Lee, and J.-G. Shin Identification and Functional Assessment of BCRP Polymorphisms in a Korean Population Drug Metab. Dispos., April 1, 2007; 35(4): 623 - 632. [Abstract] [Full Text] [PDF]

				J. A. Seamon, C. A. Rugg, S. Emanuel, A. M. Calcagno, S. V. Ambudkar, S. A. Middleton, J. Butler, V. Borowski, and L. M. Greenberger Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol. Cancer Ther., October 1, 2006; 5(10): 2459 - 2467. [Abstract] [Full Text] [PDF]

				C. S. Morrow, C. Peklak-Scott, B. Bishwokarma, T. E. Kute, P. K. Smitherman, and A. J. Townsend Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediates Resistance to Mitoxantrone via Glutathione-Dependent Drug Efflux Mol. Pharmacol., April 1, 2006; 69(4): 1499 - 1505. [Abstract] [Full Text] [PDF]

				C. Marchand, S. Antony, K. W. Kohn, M. Cushman, A. Ioanoviciu, B. L. Staker, A. B. Burgin, L. Stewart, and Y. Pommier A novel norindenoisoquinoline structure reveals a common interfacial inhibitor paradigm for ternary trapping of the topoisomerase I-DNA covalent complex. Mol. Cancer Ther., February 1, 2006; 5(2): 287 - 295. [Abstract] [Full Text] [PDF]

				U. Henriksen, J. U. Fog, T. Litman, and U. Gether Identification of Intra- and Intermolecular Disulfide Bridges in the Multidrug Resistance Transporter ABCG2 J. Biol. Chem., November 4, 2005; 280(44): 36926 - 36934. [Abstract] [Full Text] [PDF]

				A. Shafran, I. Ifergan, E. Bram, G. Jansen, I. Kathmann, G. J. Peters, R. W. Robey, S. E. Bates, and Y. G. Assaraf ABCG2 Harboring the Gly482 Mutation Confers High-Level Resistance to Various Hydrophilic Antifolates Cancer Res., September 15, 2005; 65(18): 8414 - 8422. [Abstract] [Full Text] [PDF]

				K. J. Reszka, B. A. Wagner, L. M. Teesch, B. E. Britigan, D. R. Spitz, and C. P. Burns Inactivation of Anthracyclines by Cellular Peroxidase Cancer Res., July 15, 2005; 65(14): 6346 - 6353. [Abstract] [Full Text] [PDF]

				U. Henriksen, U. Gether, and T. Litman Effect of Walker A mutation (K86M) on oligomerization and surface targeting of the multidrug resistance transporter ABCG2 J. Cell Sci., April 1, 2005; 118(7): 1417 - 1426. [Abstract] [Full Text] [PDF]

				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]

				J. Yu, W. D. Shannon, M. A. Watson, and H. L. McLeod Gene Expression Profiling of the Irinotecan Pathway in Colorectal Cancer Clin. Cancer Res., March 1, 2005; 11(5): 2053 - 2062. [Abstract] [Full Text] [PDF]

				L. E. Carlini, N. J. Meropol, J. Bever, M. L. Andria, T. Hill, P. Gold, A. Rogatko, H. Wang, and R. L. Blanchard UGT1A7 and UGT1A9 Polymorphisms Predict Response and Toxicity in Colorectal Cancer Patients Treated with Capecitabine/Irinotecan Clin. Cancer Res., February 1, 2005; 11(3): 1226 - 1236. [Abstract] [Full Text] [PDF]

				J.-P. Annereau, G. Szakacs, C. J. Tucker, A. Arciello, C. Cardarelli, J. Collins, S. Grissom, B. R. Zeeberg, W. Reinhold, J. N. Weinstein, et al. Analysis of ATP-Binding Cassette Transporter Expression in Drug-Selected Cell Lines by a Microarray Dedicated to Multidrug Resistance Mol. Pharmacol., December 1, 2004; 66(6): 1397 - 1405. [Abstract] [Full Text] [PDF]

				S. E. Bates, W. Y. Medina-Perez, G. Kohlhagen, S. Antony, T. Nadjem, R. W. Robey, and Y. Pommier ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 836 - 842. [Abstract] [Full Text] [PDF]

				C. Ozvegy-Laczka, T. Heged""s, G. Varady, O. Ujhelly, J. D. Schuetz, A. Varadi, G. Keri, L. Orfi, K. Nemet, and B. Sarkadi High-Affinity Interaction of Tyrosine Kinase Inhibitors with the ABCG2 Multidrug Transporter Mol. Pharmacol., June 1, 2004; 65(6): 1485 - 1495. [Abstract] [Full Text] [PDF]

				K. Nakayama, A. Kanzaki, K. Terada, M. Mutoh, K. Ogawa, T. Sugiyama, S. Takenoshita, K. Itoh, N. Yaegashi, K. Miyazaki, et al. Prognostic Value of the Cu-Transporting ATPase in Ovarian Carcinoma Patients Receiving Cisplatin-Based Chemotherapy Clin. Cancer Res., April 15, 2004; 10(8): 2804 - 2811. [Abstract] [Full Text] [PDF]

				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]

				H. Minderman, K. L. O'Loughlin, L. Pendyala, and M. R. Baer VX-710 (Biricodar) Increases Drug Retention and Enhances Chemosensitivity in Resistant Cells Overexpressing P-Glycoprotein, Multidrug Resistance Protein, and Breast Cancer Resistance Protein Clin. Cancer Res., March 1, 2004; 10(5): 1826 - 1834. [Abstract] [Full Text] [PDF]

				M. D. Prados, W.K.A. Yung, K. A. Jaeckle, H. I. Robins, M. P. Mehta, H. A. Fine, P. Y. Wen, T. F. Cloughesy, S. M. Chang, M. K. Nicholas, et al. Phase 1 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study Neuro-oncol, January 1, 2004; 6(1): 44 - 54. [Abstract] [PDF]

				J. Cummings, B. T. Ethell, L. Jardine, G. Boyd, J. S. Macpherson, B. Burchell, J. F. Smyth, and D. I. Jodrell Glucuronidation as a Mechanism of Intrinsic Drug Resistance in Human Colon Cancer: Reversal of Resistance by Food Additives Cancer Res., December 1, 2003; 63(23): 8443 - 8450. [Abstract] [Full Text] [PDF]

				G. D. Leonard, T. Fojo, and S. E. Bates The Role of ABC Transporters in Clinical Practice Oncologist, October 1, 2003; 8(5): 411 - 424. [Abstract] [Full Text] [PDF]

				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]

				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]

				T. Janvilisri, H. Venter, S. Shahi, G. Reuter, L. Balakrishnan, and H. W. van Veen Sterol Transport by the Human Breast Cancer Resistance Protein (ABCG2) Expressed in Lactococcus lactis J. Biol. Chem., May 30, 2003; 278(23): 20645 - 20651. [Abstract] [Full Text] [PDF]

				E. J. Licitra, V. Vyas, K. Nelson, R. Musanti, S. Beers, C. Thomas, E. Poplin, S. Smith, Y. Lin, Larry. J. Schaaf, et al. Phase I Evaluation of Sequential Topoisomerase Targeting with Irinotecan/Cisplatin Followed by Etoposide in Patients with Advanced Malignancy Clin. Cancer Res., May 1, 2003; 9(5): 1673 - 1679. [Abstract] [Full Text] [PDF]

				S. Zhou, J. J. Morris, Y. Barnes, L. Lan, J. D. Schuetz, and B. P. Sorrentino Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo PNAS, September 17, 2002; 99(19): 12339 - 12344. [Abstract] [Full Text] [PDF]

				J. M. Mariadason, D. Arango, G. A. Corner, M. J. Aranes, K. A. Hotchkiss, W. Yang, and L. H. Augenlicht A Gene Expression Profile That Defines Colon Cell Maturation in Vitro Cancer Res., August 15, 2002; 62(16): 4791 - 4804. [Abstract] [Full Text] [PDF]

				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]

				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]

				M. P. Gamcsik, M. S. Kasibhatla, D. J. Adams, J. L. Flowers, O. M. Colvin, G. Manikumar, M. Wani, M. E. Wall, G. Kohlhagen, and Y. Pommier Dual Role of Glutathione in Modulating Camptothecin Activity: Depletion Potentiates Activity, but Conjugation Enhances the Stability of the Topoisomerase I-DNA Cleavage Complex Mol. Cancer Ther., November 1, 2001; 1(1): 11 - 20. [Abstract] [Full Text] [PDF]

				S. Jacob, M. Aguado, D. Fallik, and F. Praz The Role of the DNA Mismatch Repair System in the Cytotoxicity of the Topoisomerase Inhibitors Camptothecin and Etoposide to Human Colorectal Cancer Cells Cancer Res., September 1, 2001; 61(17): 6555 - 6562. [Abstract] [Full Text] [PDF]

				Y. Honjo, C. A. Hrycyna, Q.-W. Yan, W. Y. Medina-Perez, R. W. Robey, A. van de Laar, T. Litman, M. Dean, and S. E. Bates Acquired Mutations in the MXR/BCRP/ABCP Gene Alter Substrate Specificity in MXR/BCRP/ABCP-overexpressing Cells Cancer Res., September 1, 2001; 61(18): 6635 - 6639. [Abstract] [Full Text] [PDF]

				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]

				R. H. J. Mathijssen, R. J. van Alphen, J. Verweij, W. J. Loos, K. Nooter, G. Stoter, and A. Sparreboom Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11) Clin. Cancer Res., August 1, 2001; 7(8): 2182 - 2194. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				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]

				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]