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Targeting multidrug resistance in cancer

Key Points

  • The development of simultaneous resistance to multiple drugs, with varying chemical structures and targets, is a major obstacle to effective cancer therapy.

  • Studies indicate that there are three major mechanisms of multidrug resistance (MDR): decreased uptake of water-soluble drugs; various changes in cells that affect the ability of cytotoxic drugs to kill cells; and increased energy-dependent efflux of hydrophobic drugs.

  • Removal of hydrophobic drugs from cells is the most commonly encountered mechanism of multidrug resistance (MDR), and ATP-binding cassette (ABC) transporters have a key role in this process.

  • The ABC transporter family of proteins comprises seven subclasses that are labelled A–G, and these proteins have been shown to be essential for many cellular processes that require transport of substrates across cell membranes, with several members of this family being involved in the absorption, excretion and distribution of drugs.

  • ABC transporters have broad substrate specificity, and the abundance of ABC transporter proteins goes some way to explaining the difficulties faced during the past 20 years when attempting to circumvent ABC-mediated MDR in vivo. Research has focused on the development of drugs that either evade efflux or inhibit the function of efflux transporters, and although progress in this area has been slow, the rationale for this approach is still strong.

  • Several ABC transporters have been found to be overexpressed in cancer cell lines cultured under selective pressure, with at least 12 ABC transporters from four ABC subfamilies implicated in the drug resistance of cells maintained in tissue culture. Studies have shown that the major mechanism of MDR in most cultured cancer cells involves P-glycoprotein (Pgp; MDR1; ABCB1), multidrug resistance associated-protein 1 (MRP1, also known as ABCC1) or ABCG2.

  • Despite significant advances in knowledge of the biochemistry and substrate specificity of ABC transporters since the first description of MDR, translation of this knowledge from the bench to the bedside has proved to be difficult. Only inhibitors of Pgp, and to a lesser extent MRP1 and ABCG2, have been evaluated in clinical trials, and the development of several inhibitors has been discontinued. However, some improved compounds are currently in clinical trials, and it is hoped that the lessons learned from earlier trials will improve the chance of success.

  • Alternative strategies to overcome ABC-transporter-mediated MDR are also emerging, including engaging, evading or exploiting efflux-based resistance mechanisms.

Abstract

Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures — multidrug resistance — has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.

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Figure 1: Summary of the pharmacological role of ATP-binding cassette transporters.
Figure 2: General scheme for evaluating P-glycoprotein susceptibility in early discovery and development of pharmaceutical drugs.
Figure 3: Substrates and inhibitors of ATP-binding cassette transporters.
Figure 4: Targeting multidrug-resistant cancer.

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References

  1. Higgins, C. F. ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8, 67–113 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Ozvegy, C. et al. Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem. Biophys. Res. Commun. 285, 111–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Chang, G. & Roth, C. B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science 293, 1793–1800 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Dean, M., Rzhetsky, A. & Allikmets, R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11, 1156–1166 (2001). Describes the phylogenetic relationship of the 48 human ABC transporters and the diseases caused by mutations in the genes encoding ABC transporters.

    Article  CAS  PubMed  Google Scholar 

  5. Lipinski, C. A., Lombardo, F., Dominy, B. W. & Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev. 46, 3–26 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Schinkel, A. H. et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77, 491–502 (1994). Shows that mice lacking Mdr1a Pgp have altered pharmacokinetics for many drugs. This paper reports the first direct proof of the importance of ABC transporters for drug pharmacokinetics.

    Article  CAS  PubMed  Google Scholar 

  7. Schinkel, A. H. The physiological function of drug-transporting P-glycoproteins. Semin. Cancer Biol. 8, 161–170 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Kwan, P. & Brodie, M. J. Potential role of drug transporters in the pathogenesis of medically intractable epilepsy. Epilepsia 46, 224–235 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Yamazaki, M. et al. In vitro substrate identification studies for P-glycoprotein-mediated transport: species difference and predictability of in vivo results. J. Pharmacol. Exp. Ther. 296, 723–735 (2001).

    CAS  PubMed  Google Scholar 

  10. Ambudkar, S. V. et al. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39, 361–398 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Cordon-Cardo, C. et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J. Histochem. Cytochem. 38, 1277–1287 (1990).

    Article  CAS  PubMed  Google Scholar 

  12. Thiebaut, F. et al. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J. Histochem. Cytochem. 37, 159–164 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Dano, K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim. Biophys. Acta 323, 466–483 (1973).

    Article  CAS  PubMed  Google Scholar 

  14. Tsuruo, T., Iida, H., Tsukagoshi, S. & Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res. 41, 1967–1972 (1981). One of the first demonstrations that non-cytotoxic compounds could be used to reverse the activity of Pgp and formed the basis for the concept of 'engaging' the multidrug transporter to inactivate the protein.

    CAS  PubMed  Google Scholar 

  15. Kellen, J. A. The reversal of multidrug resistance: an update. J. Exp. Ther. Oncol. 3, 5–13 (2003).

    Article  PubMed  Google Scholar 

  16. Childs, S., Yeh, R. L., Georges, E. & Ling, V. Identification of a sister gene to P-glycoprotein. Cancer Res. 55, 2029–2034 (1995).

    CAS  PubMed  Google Scholar 

  17. Gerloff, T. et al. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273, 10046–10050 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. Ruetz, S. & Gros, P. Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell 77, 1071–1081 (1994). Reports that some ABC transporters might be lipid flippases, which is consistent with a major hypothesis for the mechanism of action of Pgp as a drug flippase and extends the biological importance of ABC transporters.

    Article  CAS  PubMed  Google Scholar 

  19. van Helvoort, A. et al. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87, 507–517 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Strautnieks, S. S. et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis. Nature Genet. 20, 233–238 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Childs, S., Yeh, R. L., Hui, D. & Ling, V. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein. Cancer Res. 58, 4160–4167 (1998).

    CAS  PubMed  Google Scholar 

  22. Smith, A. J. et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J. Biol. Chem. 275, 23530–23539 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Bakos, E. et al. Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. J. Biol. Chem. 273, 32167–32175 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Hipfner, D. R., Deeley, R. G. & Cole, S. P. Structural, mechanistic and clinical aspects of MRP1. Biochim. Biophys. Acta 1461, 359–376 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Szakacs, G. et al. Predicting drug sensitivity and resistance: profiling ABC transporter genes in cancer cells. Cancer Cell 6, 129–137 (2004). Applies a global approach to the analysis of the role of ABC transporters in drug resistance in cancer. The authors identified 28 transporters that could have a role in resistance to specific drugs, or classes of drugs. In addition, this paper introduces the concept of 'exploiting' multidrug transporters by identifying drugs that specifically kill Pgp-expressing cells.

    Article  CAS  PubMed  Google Scholar 

  26. Dietrich, C. G. et al. Mrp2-deficiency in the rat impairs biliary and intestinal excretion and influences metabolism and disposition of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Carcinogenesis 22, 805–811 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Paulusma, C. C. et al. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 271, 1126–1128 (1996).

    Article  CAS  PubMed  Google Scholar 

  28. Liedert, B., Materna, V., Schadendorf, D., Thomale, J. & Lage, H. Overexpression of cMOAT (MRP2/ABCC2) is associated with decreased formation of platinum-DNA adducts and decreased G2-arrest in melanoma cells resistant to cisplatin. J. Invest. Dermatol. 121, 172–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Koike, K. et al. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res. 57, 5475–5479 (1997).

    CAS  PubMed  Google Scholar 

  30. Liu, J. et al. Overexpression of glutathione S-transferase II and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. Mol. Pharmacol. 60, 302–309 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Annereau, J. P. et al. Analysis of ATP-binding cassette transporter expression in drug-selected cell lines by a microarray dedicated to multidrug resistance. Mol. Pharmacol. 66, 1397–1405 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Konig, J., Rost, D., Cui, Y. & Keppler, D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 29, 1156–1163 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Scheffer, G. L. et al. Tissue distribution and induction of human multidrug resistant protein 3. Lab. Invest. 82, 193–201 (2002).

    Article  CAS  PubMed  Google Scholar 

  34. Zelcer, N. et al. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. J. Hepatol. 9 Aug 2005 (10.1016/j.jhep.2005.07.022).

  35. Belinsky, M. G. et al. Analysis of the in vivo functions of Mrp3. Mol. Pharmacol. 68, 160–168 (2005).

    CAS  PubMed  Google Scholar 

  36. Kool, M. et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57, 3537–3547 (1997).

    CAS  PubMed  Google Scholar 

  37. Yamada, A., Kawano, K., Koga, M., Matsumoto, T. & Itoh, K. Multidrug resistance-associated protein 3 is a tumor rejection antigen recognized by HLA-A2402-restricted cytotoxic T lymphocytes. Cancer Res. 61, 6459–6466 (2001).

    CAS  PubMed  Google Scholar 

  38. Young, L. C., Campling, B. G., Cole, S. P., Deeley, R. G. & Gerlach, J. H. Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: correlation of protein levels with drug response and messenger RNA levels. Clin. Cancer Res. 7, 1798–1804 (2001).

    CAS  PubMed  Google Scholar 

  39. Le Saux, O. et al. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nature Genet. 25, 223–227 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Belinsky, M. G., Chen, Z. S., Shchaveleva, I., Zeng, H. & Kruh, G. D. Characterization of the drug resistance and transport properties of multidrug resistance protein 6 (MRP6, ABCC6). Cancer Res. 62, 6172–6177 (2002).

    CAS  PubMed  Google Scholar 

  41. Hopper-Borge, E., Chen, Z. S., Shchaveleva, I., Belinsky, M. G. & Kruh, G. D. Analysis of the drug resistance profile of multidrug resistance protein 7 (ABCC10): resistance to docetaxel. Cancer Res. 64, 4927–4930 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Kruh, G. D. & Belinsky, M. G. The MRP family of drug efflux pumps. Oncogene 22, 7537–7552 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Borst, P., Evers, R., Kool, M. & Wijnholds, J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl Cancer Inst. 92, 1295–1302 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Schuetz, J. D. et al. MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nature Med. 5, 1048–1051 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Guo, Y. et al. MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines 2′,3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. J. Biol. Chem. 278, 29509–29514 (2003).

    Article  PubMed  Google Scholar 

  46. Chen, Z. S., Guo, Y., Belinsky, M. G., Kotova, E. & Kruh, G. D. Transport of bile acids, sulfated steroids, estradiol 17-β-D-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Mol. Pharmacol. 67, 545–557 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Abbott, B. L. ABCG2 (BCRP) expression in normal and malignant hematopoietic cells. Hematol. Oncol. 21, 115–130 (2003).

    Article  PubMed  Google Scholar 

  48. Schinkel, A. H. & Jonker, J. W. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55, 3–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Zhao, R. & Goldman, I. D. Resistance to antifolates. Oncogene 22, 7431–7457 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Kawabata, S. et al. Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells. Biochem. Biophys. Res. Commun. 280, 1216–1223 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Ozvegy-Laczka, C., Cserepes, J., Elkind, N. B. & Sarkadi, B. Tyrosine kinase inhibitor resistance in cancer: role of ABC multidrug transporters. Drug Resist. Updat. 8, 15–26 (2005).

    Article  CAS  PubMed  Google Scholar 

  52. Gottesman, M. M., Fojo, T. & Bates, S. E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nature Rev. Cancer 2, 48–58 (2002). A concise review on ABC transporters that confer MDR to cancer cells.

    Article  CAS  Google Scholar 

  53. Leonard, G. D., Fojo, T. & Bates, S. E. The role of ABC transporters in clinical practice. Oncologist 8, 411–424 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Trock, B. J., Leonessa, F. & Clarke, R. Multidrug resistance in breast cancer: a meta-analysis of MDR1/gp170 expression and its possible functional significance. J. Natl Cancer Inst. 89, 917–931 (1997).

    Article  CAS  PubMed  Google Scholar 

  55. Abolhoda, A. et al. Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin. Cancer Res. 5, 3352–3356 (1999).

    CAS  PubMed  Google Scholar 

  56. Szakacs, G., Jakab, K., Antal, F. & Sarkadi, B. Diagnostics of multidrug resistance in cancer. Pathol. Oncol. Res. 4, 251–257 (1998).

    Article  CAS  PubMed  Google Scholar 

  57. Pallis, M. & Das-Gupta, E. Flow cytometric measurement of functional and phenotypic P-glycoprotein. Methods Mol. Med. 111, 167–181 (2005).

    CAS  PubMed  Google Scholar 

  58. Karaszi, E. et al. Calcein assay for multidrug resistance reliably predicts therapy response and survival rate in acute myeloid leukaemia. Br. J. Haematol. 112, 308–314 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Pallis, M. & Russell, N. Strategies for overcoming p-glycoprotein-mediated drug resistance in acute myeloblastic leukaemia. Leukemia 18, 1927–1930 (2004).

    Article  CAS  PubMed  Google Scholar 

  60. van der Holt, B. et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood 106, 2646–2654 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Leith, C. P. et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 94, 1086–1099 (1999).

    CAS  PubMed  Google Scholar 

  62. Berger, W. et al. Multidrug resistance markers P-glycoprotein, multidrug resistance protein 1, and lung resistance protein in non-small cell lung cancer: prognostic implications. J. Cancer Res. Clin. Oncol. 131, 355–363 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Michieli, M. et al. P-glycoprotein (PGP), lung resistance-related protein (LRP) and multidrug resistance-associated protein (MRP) expression in acute promyelocytic leukaemia. Br. J. Haematol. 108, 703–709 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Filipits, M. et al. Clinical role of multidrug resistance protein 1 expression in chemotherapy resistance in early-stage breast cancer: the Austrian Breast and Colorectal Cancer Study Group. J. Clin. Oncol. 23, 1161–1168 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Ross, D. D. Modulation of drug resistance transporters as a strategy for treating myelodysplastic syndrome. Best Pract. Res. Clin. Haematol. 17, 641–651 (2004).

    Article  CAS  PubMed  Google Scholar 

  66. Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nature Rev. Cancer 5, 275–284 (2005).

    Article  CAS  Google Scholar 

  67. Raaijmakers, M. H. et al. Breast cancer resistance protein in drug resistance of primitive CD34+38– cells in acute myeloid leukemia. Clin. Cancer Res. 11, 2436–2444 (2005).

    Article  CAS  PubMed  Google Scholar 

  68. List, A. F. et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia: a Southwest Oncology Group study. Blood 98, 3212–3220 (2001). The first study to show that addition of cyclosporine to AML (known to be Pgp positive) therapy improves response in poor-risk patients.

    Article  CAS  PubMed  Google Scholar 

  69. Wattel, E. et al. Quinine improves results of intensive chemotherapy (IC) in myelodysplastic syndromes (MDS) expressing P-glycoprotein (PGP). Updated results of a randomized study. Groupe Français des Myélodysplasies (GFM) and Groupe GOELAMS. Adv. Exp. Med. Biol. 457, 35–46 (1999).

    Article  CAS  PubMed  Google Scholar 

  70. Daenen, S. et al. Addition of cyclosporin A to the combination of mitoxantrone and etoposide to overcome resistance to chemotherapy in refractory or relapsing acute myeloid leukaemia; a randomised phase II trial from HOVON, the Dutch-Belgian Haemato-Oncology Working Group for adults. Leuk. Res. 28, 1057–1067 (2004).

    Article  CAS  PubMed  Google Scholar 

  71. Hollt, V., Kouba, M., Dietel, M. & Vogt, G. Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Biochem. Pharmacol. 43, 2601–2608 (1992).

    Article  CAS  PubMed  Google Scholar 

  72. Baer, M. R. et al. Phase 3 study of the multidrug resistance modulator PSC-833 in previously untreated patients 60 years of age and older with acute myeloid leukemia: Cancer and Leukemia Group B Study 9720. Blood 100, 1224–1232 (2002).

    CAS  PubMed  Google Scholar 

  73. Kolitz, J. E. et al. Dose escalation studies of cytarabine, daunorubicin, and etoposide with and without multidrug resistance modulation with PSC-833 in untreated adults with acute myeloid leukemia younger than 60 years: final induction results of Cancer and Leukemia Group B Study 9621. J. Clin. Oncol. 22, 4290–4301 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Goldman, B. Multidrug resistance: can new drugs help chemotherapy score against cancer? J. Natl Cancer Inst. 95, 255–257 (2003).

    Article  PubMed  Google Scholar 

  75. Product Development Pipeline — November 2004 [online], <http://www.glaxosmithkline.de/content/forschung/pipeline-dec2004.pdf> (2004).

  76. Guns, E. S., Denyssevych, T., Dixon, R., Bally, M. B. & Mayer, L. Drug interaction studies between paclitaxel (Taxol) and OC144-093 — a new modulator of MDR in cancer chemotherapy. Eur. J. Drug Metab. Pharmacokinet. 27, 119–126 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Stewart, A. et al. Phase I trial of XR9576 in healthy volunteers demonstrates modulation of P-glycoprotein in CD56+ lymphocytes after oral and intravenous administration. Clin. Cancer Res. 6, 4186–4191 (2000). Uses a surrogate marker for inhibition of Pgp (Pgp-positive CD56 lymphocytes) to show activity of a third-generation Pgp inhibitor (XR9576) in vivo.

    CAS  PubMed  Google Scholar 

  78. Minderman, H., O'Loughlin, K. L., Pendyala, L. & Baer, M. R. 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. 10, 1826–1834 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Xenova Group Limited Tariquidar [online], &lt;http://www.xenova.co.uk/dc_xr9576.html&gt; (2006).

  80. van Zuylen, L., Nooter, K., Sparreboom, A. & Verweij, J. Development of multidrug-resistance convertors: sense or nonsense? Invest. New Drugs 18, 205–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  81. Dantzig, A. H., de Alwis, D. P. & Burgess, M. Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv. Drug Deliv. Rev. 55, 133–150 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Loo, T. W. & Clarke, D. M. Blockage of drug resistance in vitro by disulfiram, a drug used to treat alcoholism. J. Natl Cancer Inst. 92, 898–902 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Zhou, S., Lim, L. Y. & Chowbay, B. Herbal modulation of P-glycoprotein. Drug Metab. Rev. 36, 57–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  84. Seelig, A. & Gatlik-Landwojtowicz, E. Inhibitors of multidrug efflux transporters: their membrane and protein interactions. Mini Rev. Med. Chem. 5, 135–151 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Pleban, K. & Ecker, G. F. Inhibitors of p-glycoprotein — lead identification and optimisation. Mini Rev. Med. Chem. 5, 153–163 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Sharom, F. J. et al. Interaction of the P-glycoprotein multidrug transporter (MDR1) with high affinity peptide chemosensitizers in isolated membranes, reconstituted systems, and intact cells. Biochem. Pharmacol. 58, 571–586 (1999).

    Article  CAS  PubMed  Google Scholar 

  87. Tarasova, N. I., Rice, W. G. & Michejda, C. J. Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions. J. Biol. Chem. 274, 34911–34915 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. George, S. R. et al. Blockade of G protein-coupled receptors and the dopamine transporter by a transmembrane domain peptide: novel strategy for functional inhibition of membrane proteins in vivo. J. Pharmacol. Exp. Ther. 307, 481–489 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Tarasova, N. I. et al. Transmembrane inhibitors of P-glycoprotein, an ABC transporter. J. Med. Chem. 48, 3768–3775 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Mechetner, E. B. & Roninson, I. B. Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody. Proc. Natl Acad. Sci. USA 89, 5824–5828 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Pawlak-Roblin, C. et al. Inhibition of multidrug resistance by immunisation with synthetic P-glycoprotein-derived peptides. Eur. J. Cancer 40, 606–613 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Scotto, K. W. Transcriptional regulation of ABC drug transporters. Oncogene 22, 7496–7511 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Kang, H. et al. Inhibition of MDR1 gene expression by chimeric HNA antisense oligonucleotides. Nucleic Acids Res. 32, 4411–4419 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bartsevich, V. V. & Juliano, R. L. Regulation of the MDR1 gene by transcriptional repressors selected using peptide combinatorial libraries. Mol. Pharmacol. 58, 1–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Xu, D., Ye, D., Fisher, M. & Juliano, R. L. Selective inhibition of P-glycoprotein expression in multidrug-resistant tumor cells by a designed transcriptional regulator. J. Pharmacol. Exp. Ther. 302, 963–971 (2002).

    Article  CAS  PubMed  Google Scholar 

  96. Synold, T. W., Dussault, I. & Forman, B. M. The orphan nuclear receptor SXR coordinately regulates drug metabolism and efflux. Nature Med. 7, 584–590 (2001).

    Article  CAS  PubMed  Google Scholar 

  97. Xu, D., Kang, H., Fisher, M. & Juliano, R. L. Strategies for inhibition of MDR1 gene expression. Mol. Pharmacol. 66, 268–275 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Pichler, A., Zelcer, N., Prior, J. L., Kuil, A. J. & Piwnica-Worms, D. In vivo RNA interference-mediated ablation of MDR1 P-glycoprotein. Clin. Cancer Res. 11, 4487–4494 (2005).

    Article  CAS  PubMed  Google Scholar 

  99. Perego, P. 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. 61, 6034–6037 (2001).

    CAS  PubMed  Google Scholar 

  100. Lampidis, T. J. et al. Circumvention of P-GP MDR as a function of anthracycline lipophilicity and charge. Biochemistry 36, 2679–2685 (1997).

    Article  CAS  PubMed  Google Scholar 

  101. Byrne, J. L. et al. Early allogeneic transplantation for refractory or relapsed acute leukaemia following remission induction with FLAG. Leukemia 13, 786–791 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Vail, D. M. et al. Pegylated liposomal doxorubicin: proof of principle using preclinical animal models and pharmacokinetic studies. Semin. Oncol. 31, 16–35 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Krishna, R., St-Louis, M. & Mayer, L. D. Increased intracellular drug accumulation and complete chemosensitization achieved in multidrug-resistant solid tumors by co-administering valspodar (PSC 833) with sterically stabilized liposomal doxorubicin. Int. J. Cancer 85, 131–141 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Fracasso, P. M. et al. Phase I study of pegylated liposomal doxorubicin and the multidrug-resistance modulator, valspodar. Br. J. Cancer 93, 46–53 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Gao, Z., Fain, H. D. & Rapoport, N. Ultrasound-enhanced tumor targeting of polymeric micellar drug carriers. Mol. Pharm. 1, 317–330 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Mahadevan, D. & List, A. F. Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies. Blood 104, 1940–1951 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Licht, T., Goldenberg, S. K., Vieira, W. D., Gottesman, M. M. & Pastan, I. Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice. Gene Ther. 7, 348–358 (2000).

    Article  CAS  PubMed  Google Scholar 

  108. Blagosklonny, M. V. How cancer could be cured by 2015. Cell Cycle 4, 269–278 (2005).

    CAS  PubMed  Google Scholar 

  109. Blagosklonny, M. V. Treatment with inhibitors of caspases, that are substrates of drug transporters, selectively permits chemotherapy-induced apoptosis in multidrug-resistant cells but protects normal cells. Leukemia 15, 936–941 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. FitzGerald, D. J. et al. A monoclonal antibody–Pseudomonas toxin conjugate that specifically kills multidrug-resistant cells. Proc. Natl Acad. Sci. USA 84, 4288–4292 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Heike, Y. et al. Monoclonal anti-P-glycoprotein antibody-dependent killing of multidrug-resistant tumor cells by human mononuclear cells. Jpn. J. Cancer Res. 81, 1155–1161 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Morizono, K. et al. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Nature Med. 11, 346–352 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Warr, J. R., Quinn, D., Elend, M. & Fenton, J. A. Gain and loss of hypersensitivity to resistance modifiers in multidrug resistant Chinese hamster ovary cells. Cancer Lett. 98, 115–120 (1995).

    Article  CAS  PubMed  Google Scholar 

  114. Lehne, G., De Angelis, P., den Boer, M. & Rugstad, H. E. Growth inhibition, cytokinesis failure and apoptosis of multidrug-resistant leukemia cells after treatment with P-glycoprotein inhibitory agents. Leukemia 13, 768–778 (1999).

    Article  CAS  PubMed  Google Scholar 

  115. Lehne, G. et al. The cyclosporin PSC 833 increases survival and delays engraftment of human multidrug-resistant leukemia cells in xenotransplanted NOD-SCID mice. Leukemia 16, 2388–2394 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Kaplan, O. et al. The multidrug resistance phenotype: 31P nuclear magnetic resonance characterization and 2-deoxyglucose toxicity. Cancer Res. 51, 1638–1644 (1991).

    CAS  PubMed  Google Scholar 

  117. Bell, S. E., Quinn, D. M., Kellett, G. L. & Warr, J. R. 2-Deoxy-D-glucose preferentially kills multidrug-resistant human KB carcinoma cell lines by apoptosis. Br. J. Cancer 78, 1464–1470 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Bentley, J., Quinn, D. M., Pitman, R. S., Warr, J. R. & Kellett, G. L. The human KB multidrug-resistant cell line KB-C1 is hypersensitive to inhibitors of glycosylation. Cancer Lett. 115, 221–227 (1997).

    Article  CAS  PubMed  Google Scholar 

  119. Warr, J. R., Bamford, A. & Quinn, D. M. The preferential induction of apoptosis in multidrug-resistant KB cells by 5-fluorouracil. Cancer Lett. 175, 39–44 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Monks, A. et al. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl Cancer Inst. 83, 757–766 (1991).

    Article  CAS  PubMed  Google Scholar 

  121. Johnstone, R. W., Ruefli, A. A. & Smyth, M. J. Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem. Sci. 25, 1–6 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Turzanski, J., Grundy, M., Shang, S., Russell, N. & Pallis, M. P-glycoprotein is implicated in the inhibition of ceramide-induced apoptosis in TF-1 acute myeloid leukemia cells by modulation of the glucosylceramide synthase pathway. Exp. Hematol. 33, 62–72 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Lucci, A., Han, T. Y., Liu, Y. Y., Giuliano, A. E. & Cabot, M. C. Multidrug resistance modulators and doxorubicin synergize to elevate ceramide levels and elicit apoptosis in drug-resistant cancer cells. Cancer 86, 300–311 (1999).

    Article  CAS  PubMed  Google Scholar 

  124. Trompier, D. et al. Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1. Cancer Res. 64, 4950–4956 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. Meerum Terwogt, J. M. et al. Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. Clin. Cancer Res. 5, 3379–3384 (1999).

    CAS  PubMed  Google Scholar 

  126. Lepper, E. R. et al. Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics 6, 115–138 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Juliano, R. L. & Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 455, 152–162 (1976).

    Article  CAS  PubMed  Google Scholar 

  128. Chen, C. J. et al. Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell 47, 381–389 (1986). Includes the sequence of the first cloned human ABC transporter, MDR1 (Pgp) and shows its homology to two known nutrient transporters in bacteria, MalK (maltose transporter ATP-binding subunit) and HisP (histidine transporter ATP-binding subunit).

    Article  CAS  PubMed  Google Scholar 

  129. Ueda, K., Cardarelli, C., Gottesman, M. M. & Pastan, I. Expression of a full-length cDNA for the human 'MDR1' gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc. Natl Acad. Sci. USA 84, 3004–3008 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Gerlach, J. H. et al. Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature 324, 485–489 (1986).

    Article  CAS  PubMed  Google Scholar 

  131. Shen, D. W. et al. Multiple drug-resistant human KB carcinoma cells independently selected for high-level resistance to colchicine, adriamycin, or vinblastine show changes in expression of specific proteins. J. Biol. Chem. 261, 7762–7770 (1986).

    CAS  PubMed  Google Scholar 

  132. Gros, P., Croop, J. & Housman, D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 47, 371–380 (1986).

    Article  CAS  PubMed  Google Scholar 

  133. McGrath, T. & Center, M. S. Mechanisms of multidrug resistance in HL60 cells: evidence that a surface membrane protein distinct from P-glycoprotein contributes to reduced cellular accumulation of drug. Cancer Res. 48, 3959–3963 (1988).

    CAS  PubMed  Google Scholar 

  134. Mirski, S. E., Gerlach, J. H. & Cole, S. P. Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Res. 47, 2594–2598 (1987).

    CAS  PubMed  Google Scholar 

  135. Cole, S. P. Patterns of cross-resistance in a multidrug-resistant small-cell lung carcinoma cell line. Cancer Chemother. Pharmacol. 26, 250–256 (1990).

    Article  CAS  PubMed  Google Scholar 

  136. Cole, S. P. et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650–1654 (1992). Describes the characterization of the second member of the ABC transporter family that can confer MDR (MRP1 or ABCC1), changing the paradigm of MDR.

    Article  CAS  PubMed  Google Scholar 

  137. Doyle, L. A. et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl Acad. Sci. USA 95, 15665–15670 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V. & Dean, M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res. 58, 5337–5339 (1998).

    CAS  PubMed  Google Scholar 

  139. Miyake, K. et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res. 59, 8–13 (1999).

    CAS  PubMed  Google Scholar 

  140. Sarkadi, B., Price, E. M., Boucher, R. C., Germann, U. A. & Scarborough, G. A. Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J. Biol. Chem. 267, 4854–4858 (1992).

    CAS  PubMed  Google Scholar 

  141. Garrigues, A., Nugier, J., Orlowski, S. & Ezan, E. A high-throughput screening microplate test for the interaction of drugs with P-glycoprotein. Anal. Biochem. 305, 106–114 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Robert, J. & Jarry, C. Multidrug resistance reversal agents. J. Med. Chem. 46, 4805–4817 (2003).

    Article  CAS  PubMed  Google Scholar 

  143. Lin, J. H. & Yamazaki, M. Clinical relevance of P-glycoprotein in drug therapy. Drug Metab. Rev. 35, 417–454 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Relling, M. V. Are the major effects of P-glycoprotein modulators due to altered pharmacokinetics of anticancer drugs? Ther. Drug Monit. 18, 350–356 (1996).

    Article  CAS  PubMed  Google Scholar 

  145. Benet, L. Z., Cummins, C. L. & Wu, C. Y. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int. J. Pharm. 277, 3–9 (2004).

    Article  CAS  PubMed  Google Scholar 

  146. Bohme, M., Buchler, M., Muller, M. & Keppler, D. Differential inhibition by cyclosporins of primary-active ATP-dependent transporters in the hepatocyte canalicular membrane. FEBS Lett. 333, 193–196 (1993).

    Article  CAS  PubMed  Google Scholar 

  147. Liscovitch, M. & Lavie, Y. Cancer multidrug resistance: a review of recent drug discovery research. IDrugs 5, 349–355 (2002).

    CAS  PubMed  Google Scholar 

  148. Hegewisch-Becker, S. MDR1 reversal: criteria for clinical trials designed to overcome the multidrug resistance phenotype. Leukemia 10 (Suppl. 3), 32–38 (1996).

    Google Scholar 

  149. Beck, W. T. & Grogan, T. M. Methods to detect P-glycoprotein and implications for other drug resistance-associated proteins. Leukemia 11, 1107–1109 (1997).

    Article  CAS  PubMed  Google Scholar 

  150. Marie, J. P. et al. Measuring multidrug resistance expression in human malignancies: elaboration of consensus recommendations. Semin. Hematol. 34, 63–71 (1997).

    CAS  PubMed  Google Scholar 

  151. Agrawal, M. et al. Increased 99mTc-sestamibi accumulation in normal liver and drug-resistant tumors after the administration of the glycoprotein inhibitor, XR9576. Clin. Cancer Res. 9, 650–656 (2003).

    CAS  PubMed  Google Scholar 

  152. Leslie, E. M., Deeley, R. G. & Cole, S. P. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 204, 216–237 (2005).

    Article  CAS  PubMed  Google Scholar 

  153. Maliepaard, M. et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 61, 3458–3464 (2001).

    CAS  PubMed  Google Scholar 

  154. Mottino, A. D., Hoffman, T., Jennes, L. & Vore, M. Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J. Pharmacol. Exp. Ther. 293, 717–723 (2000).

    CAS  PubMed  Google Scholar 

  155. Thiebaut, F. et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc. Natl Acad. Sci. USA 84, 7735–7738 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Scheffer, G. L. et al. Multidrug resistance related molecules in human and murine lung. J. Clin. Pathol. 55, 332–339 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Peng, K. C. et al. Tissue and cell distribution of the multidrug resistance-associated protein (MRP) in mouse intestine and kidney. J. Histochem. Cytochem. 47, 757–768 (1999).

    Article  CAS  PubMed  Google Scholar 

  158. Chandra, P. & Brouwer, K. L. The complexities of hepatic drug transport: current knowledge and emerging concepts. Pharm. Res. 21, 719–735 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Ros, J. E., Libbrecht, L., Geuken, M., Jansen, P. L. & Roskams, T. A. High expression of MDR1, MRP1, and MRP3 in the hepatic progenitor cell compartment and hepatocytes in severe human liver disease. J. Pathol. 200, 553–560 (2003).

    Article  CAS  PubMed  Google Scholar 

  160. Ros, J. E. et al. ATP binding cassette transporter gene expression in rat liver progenitor cells. Gut 52, 1060–1067 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Mizuno, N. et al. Impaired renal excretion of 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole (E3040) sulfate in breast cancer resistance protein (BCRP1/ABCG2) knockout mice. Drug Metab. Dispos. 32, 898–901 (2004).

    CAS  PubMed  Google Scholar 

  162. Atkinson, D. E., Greenwood, S. L., Sibley, C. P., Glazier, J. D. & Fairbairn, L. J. Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer. Am. J. Physiol. Cell Physiol. 285, C584–C591 (2003).

    Article  CAS  PubMed  Google Scholar 

  163. Ronaldson, P. T., Bendayan, M., Gingras, D., Piquette-Miller, M. & Bendayan, R. Cellular localization and functional expression of P-glycoprotein in rat astrocyte cultures. J. Neurochem. 89, 788–800 (2004).

    Article  CAS  PubMed  Google Scholar 

  164. Rao, V. V. et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood–cerebrospinal-fluid drug-permeability barrier. Proc. Natl Acad. Sci. USA 96, 3900–3905 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sugiyama, D., Kusuhara, H., Lee, Y. J. & Sugiyama, Y. Involvement of multidrug resistance associated protein 1 (Mrp1) in the efflux transport of 17β estradiol-D-17β-glucuronide (E217βG) across the blood–brain barrier. Pharm. Res. 20, 1394–1400 (2003).

    Article  CAS  PubMed  Google Scholar 

  166. Zhang, Y., Schuetz, J. D., Elmquist, W. F. & Miller, D. W. Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells. J. Pharmacol. Exp. Ther. 311, 449–455 (2004).

    Article  CAS  PubMed  Google Scholar 

  167. Leggas, M. et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol. Cell Biol. 24, 7612–7621 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Dombrowski, S. M. et al. Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42, 1501–1506 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Potschka, H., Fedrowitz, M. & Loscher, W. Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR-rats. Epilepsia 44, 1479–1486 (2003).

    Article  CAS  PubMed  Google Scholar 

  170. Potschka, H., Fedrowitz, M. & Loscher, W. Multidrug resistance protein MRP2 contributes to blood–brain barrier function and restricts antiepileptic drug activity. J. Pharmacol. Exp. Ther. 306, 124–131 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Jonker, J. W. et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl Cancer Inst. 92, 1651–1656 (2000).

    Article  CAS  PubMed  Google Scholar 

  172. St-Pierre, M. V. et al. Expression of members of the multidrug resistance protein family in human term placenta. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1495–R1503 (2000).

    Article  CAS  PubMed  Google Scholar 

  173. Madon, J., Hagenbuch, B., Landmann, L., Meier, P. J. & Stieger, B. Transport function and hepatocellular localization of mrp6 in rat liver. Mol. Pharmacol. 57, 634–641 (2000).

    Article  CAS  PubMed  Google Scholar 

  174. Jonker, J. W. et al. The breast cancer resistance protein BCRP (ABCG2) concentrates drugs and carcinogenic xenotoxins into milk. Nature Med. 11, 127–129 (2005). Analysis of Abcg2 -knockout mice that reveals a surprising role of ABCG2 (BCRP) in concentrating drugs and carcinogenic xenotoxins into breast milk.

    Article  CAS  PubMed  Google Scholar 

  175. Haimeur, A., Conseil, G., Deeley, R. G. & Cole, S. P. The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation. Curr. Drug Metab. 5, 21–53 (2004).

    Article  CAS  PubMed  Google Scholar 

  176. Tribull, T. E., Bruner, R. H. & Bain, L. J. The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. Toxicol. Lett. 142, 61–70 (2003).

    Article  CAS  PubMed  Google Scholar 

  177. Melaine, N. et al. Multidrug resistance genes and p-glycoprotein in the testis of the rat, mouse, Guinea pig, and human. Biol. Reprod. 67, 1699–1707 (2002).

    Article  CAS  PubMed  Google Scholar 

  178. Zhou, S. et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Med. 7, 1028–1034 (2001).

    Article  CAS  PubMed  Google Scholar 

  179. Van Aubel, R. A., Smeets, P. H., van den Heuvel, J. J. & Russel, F. G. Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am. J. Physiol. Renal Physiol. 288, F327–F333 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Rius, M., Nies, A. T., Hummel-Eisenbeiss, J., Jedlitschky, G. & Keppler, D. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology 38, 374–384 (2003).

    Article  CAS  PubMed  Google Scholar 

  181. Laing, N. M. et al. Amplification of the ATP-binding cassette 2 transporter gene is functionally linked with enhanced efflux of estramustine in ovarian carcinoma cells. Cancer Res. 58, 1332–1337 (1998).

    CAS  PubMed  Google Scholar 

  182. Vulevic, B. et al. Cloning and characterization of human adenosine 5′-triphosphate-binding cassette, sub-family A, transporter 2 (ABCA2). Cancer Res. 61, 3339–3347 (2001).

    CAS  PubMed  Google Scholar 

  183. Boonstra, R. et al. Mitoxantrone resistance in a small cell lung cancer cell line is associated with ABCA2 upregulation. Br. J. Cancer 90, 2411–2417 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Tanigawara, Y. et al. Transport of digoxin by human P-glycoprotein expressed in a porcine kidney epithelial cell line (LLC-PK1). J. Pharmacol. Exp. Ther. 263, 840–845 (1992).

    CAS  PubMed  Google Scholar 

  185. Kim, R. B. et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J. Clin. Invest. 101, 289–294 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Norris, M. D. et al. Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate. Int. J. Cancer 65, 613–619 (1996).

    Article  CAS  PubMed  Google Scholar 

  187. Lee, C. G. et al. HIV-1 protease inhibitors are substrates for the MDR1 multidrug transporter. Biochemistry 37, 3594–3601 (1998).

    Article  CAS  PubMed  Google Scholar 

  188. Hegedus, T. et al. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim. Biophys. Acta 1587, 318–325 (2002).

    Article  CAS  PubMed  Google Scholar 

  189. Zhang, X. P. et al. P-glycoprotein mediates profound resistance to bisantrene. Oncol. Res. 6, 291–301 (1994).

    CAS  PubMed  Google Scholar 

  190. Hooijberg, J. H. et al. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 59, 2532–2535 (1999).

    CAS  PubMed  Google Scholar 

  191. Cui, Y. et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. 55, 929–937 (1999).

    CAS  PubMed  Google Scholar 

  192. Bakos, E. et al. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol. Pharmacol. 57, 760–768 (2000).

    Article  CAS  PubMed  Google Scholar 

  193. Zeng, H., Chen, Z. S., Belinsky, M. G., Rea, P. A. & Kruh, G. D. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res. 61, 7225–7232 (2001).

    CAS  PubMed  Google Scholar 

  194. Renes, J., de Vries, E. G., Nienhuis, E. F., Jansen, P. L. & Muller, M. ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. Br. J. Pharmacol. 126, 681–688 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Klappe, K., Hinrichs, J. W., Kroesen, B. J., Sietsma, H. & Kok, J. W. MRP1 and glucosylceramide are coordinately over expressed and enriched in rafts during multidrug resistance acquisition in colon cancer cells. Int. J. Cancer 110, 511–522 (2004).

    Article  CAS  PubMed  Google Scholar 

  196. Zaman, G. J. et al. Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc. Natl Acad. Sci. USA 92, 7690–7694 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Luo, F. R., Paranjpe, P. V., Guo, A., Rubin, E. & Sinko, P. Intestinal transport of irinotecan in Caco-2 cells and MDCK II cells overexpressing efflux transporters Pgp, cMOAT, and MRP1. Drug Metab. Dispos. 30, 763–770 (2002).

    Article  CAS  PubMed  Google Scholar 

  198. Chu, X. Y. et al. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J. Pharmacol. Exp. Ther. 281, 304–314 (1997).

    CAS  PubMed  Google Scholar 

  199. Chu, X. Y. et al. Biliary excretion mechanism of CPT-11 and its metabolites in humans: involvement of primary active transporters. Cancer Res. 58, 5137–5143 (1998).

    CAS  PubMed  Google Scholar 

  200. Norris, M. D. et al. Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. Mol. Cancer Ther. 4, 547–553 (2005).

    Article  CAS  PubMed  Google Scholar 

  201. Yang, C. J., Horton, J. K., Cowan, K. H. & Schneider, E. Cross-resistance to camptothecin analogues in a mitoxantrone-resistant human breast carcinoma cell line is not due to DNA topoisomerase I alterations. Cancer Res. 55, 4004–4009 (1995).

    CAS  PubMed  Google Scholar 

  202. Tian, Q. et al. Human multidrug resistance associated protein 4 confers resistance to camptothecins. Pharm. Res. 22, 1837–1853 (2005).

    Article  CAS  PubMed  Google Scholar 

  203. Yang, C. H. et al. BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem. Pharmacol. 60, 831–837 (2000).

    Article  CAS  PubMed  Google Scholar 

  204. Chu, X. Y. et al. Active efflux of CPT-11 and its metabolites in human KB-derived cell lines. J. Pharmacol. Exp. Ther. 288, 735–741 (1999).

    CAS  PubMed  Google Scholar 

  205. Chen, Z. S., Lee, K. & Kruh, G. D. Transport of cyclic nucleotides and estradiol 17-β-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J. Biol. Chem. 276, 33747–33754 (2001).

    Article  CAS  PubMed  Google Scholar 

  206. Huisman, M. T., Chhatta, A. A., van Tellingen, O., Beijnen, J. H. & Schinkel, A. H. MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int. J. Cancer 116, 824–829 (2005).

    Article  CAS  PubMed  Google Scholar 

  207. Dietrich, C. G., Ottenhoff, R., de Waart, D. R. & Oude Elferink, R. P. Role of MRP2 and GSH in intrahepatic cycling of toxins. Toxicology 167, 73–81 (2001).

    Article  CAS  PubMed  Google Scholar 

  208. Jorajuria, S. et al. ATP binding cassette multidrug transporters limit the anti-HIV activity of zidovudine and indinavir in infected human macrophages. Antivir. Ther. 9, 519–528 (2004).

    CAS  PubMed  Google Scholar 

  209. Sampath, J. et al. Role of MRP4 and MRP5 in biology and chemotherapy. AAPS PharmSci [online], &lt;http://www.aapsj.org/view.asp?art=ps040314&gt; (2002).

    Google Scholar 

  210. Staud, F. & Pavek, P. Breast cancer resistance protein (BCRP/ABCG2). Int. J. Biochem. Cell Biol. 37, 720–725 (2005).

    Article  CAS  PubMed  Google Scholar 

  211. Han, B. & Zhang, J. T. Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2. Curr. Med. Chem. Anti-Canc. Agents 4, 31–42 (2004).

    Article  CAS  Google Scholar 

  212. Litman, T. et al. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J. Cell Sci. 113 (Pt 11), 2011–2021 (2000).

    CAS  PubMed  Google Scholar 

  213. Kool, M. et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc. Natl Acad. Sci. USA 96, 6914–6919 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Zelcer, N., Saeki, T., Reid, G., Beijnen, J. H. & Borst, P. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J. Biol. Chem. 276, 46400–46407 (2001).

    Article  CAS  PubMed  Google Scholar 

  215. Wielinga, P. et al. The human multidrug resistance protein MRP5 transports folates and can mediate cellular resistance against antifolates. Cancer Res. 65, 4425–4430 (2005).

    Article  CAS  PubMed  Google Scholar 

  216. Pratt, S. et al. The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol. Cancer Ther. 4, 855–863 (2005).

    Article  CAS  PubMed  Google Scholar 

  217. Wang, X. et al. Breast cancer resistance protein (BCRP/ABCG2) induces cellular resistance to HIV-1 nucleoside reverse transcriptase inhibitors. Mol. Pharmacol. 63, 65–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  218. Haimeur, A., Conseil, G., Deeley, R. G. & Cole, S. P. Mutations of charged amino acids in or near the transmembrane helices of the second membrane spanning domain differentially affect the substrate specificity and transport activity of the multidrug resistance protein MRP1 (ABCC1). Mol. Pharmacol. 65, 1375–1385 (2004).

    Article  CAS  PubMed  Google Scholar 

  219. Bradshaw, D. M. & Arceci, R. J. Clinical relevance of transmembrane drug efflux as a mechanism of multidrug resistance. J. Clin. Oncol. 16, 3674–3690 (1998).

    Article  CAS  PubMed  Google Scholar 

  220. Vastag, B. Almost serendipity: alcoholism drug reverses drug resistance in vitro. J. Natl Cancer Inst. 92, 864–865 (2000).

    Article  CAS  PubMed  Google Scholar 

  221. Evers, R. et al. Inhibitory effect of the reversal agents V-104, GF120918 and Pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport. Br. J. Cancer 83, 366–374 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Robey, R. W. et al. Pheophorbide A is a specific probe for ABCG2 function and inhibition. Cancer Res. 64, 1242–1246 (2004).

    Article  CAS  PubMed  Google Scholar 

  223. Dantzig, A. H. et al. Evaluation of the binding of the tricyclic isoxazole photoaffinity label LY475776 to multidrug resistance associated protein 1 (MRP1) orthologs and several ATP- binding cassette (ABC) drug transporters. Biochem. Pharmacol. 67, 1111–1121 (2004).

    Article  CAS  PubMed  Google Scholar 

  224. Shepard, R. L., Cao, J., Starling, J. J. & Dantzig, A. H. Modulation of P-glycoprotein but not MRP1- or BCRP-mediated drug resistance by LY335979. Int. J. Cancer 103, 121–125 (2003).

    Article  CAS  PubMed  Google Scholar 

  225. van Zuylen, L. et al. The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel. Clin. Cancer Res. 6, 1365–1371 (2000).

    CAS  PubMed  Google Scholar 

  226. Martin, C. et al. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br. J. Pharmacol. 128, 403–411 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Hofmann, J. et al. Reversal of multidrug resistance by B859–35, a metabolite of B859–35, niguldipine, verapamil and nitrendipine. J. Cancer Res. Clin. Oncol. 118, 361–366 (1992).

    Article  CAS  PubMed  Google Scholar 

  228. Norman, B. H. et al. Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1). Bioorg. Med. Chem. Lett. 15, 5526–5530 (2005).

    Article  CAS  PubMed  Google Scholar 

  229. Wishart, G. C. et al. Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial. J. Clin. Oncol. 12, 1771–1777 (1994).

    Article  CAS  PubMed  Google Scholar 

  230. Millward, M. J. et al. Oral verapamil with chemotherapy for advanced non-small cell lung cancer: a randomised study. Br. J. Cancer 67, 1031–1035 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. Milroy, R. A randomised clinical study of verapamil in addition to combination chemotherapy in small cell lung cancer. West of Scotland Lung Cancer Research Group, and the Aberdeen Oncology Group. Br. J. Cancer 68, 813–818 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Dalton, W. S. et al. A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A Southwest Oncology Group study. Cancer 75, 815–820 (1995).

    Article  CAS  PubMed  Google Scholar 

  233. Wood, L. et al. Results of a phase III, double-blind, placebo-controlled trial of megestrol acetate modulation of P-glycoprotein-mediated drug resistance in the first-line management of small-cell lung carcinoma. Br. J. Cancer 77, 627–631 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  234. Liu Yin, J. A., Wheatley, K., Rees, J. K. & Burnett, A. K. Comparison of 'sequential' versus 'standard' chemotherapy as re-induction treatment, with or without cyclosporine, in refractory/relapsed acute myeloid leukaemia (AML): results of the UK Medical Research Council AML-R trial. Br. J. Haematol. 113, 713–726 (2001).

    Article  CAS  PubMed  Google Scholar 

  235. van der Holt, B. et al. The value of the MDR1 reversal agent PSC-833 in addition to daunorubicin and cytarabine in the treatment of elderly patients with previously untreated acute myeloid leukemia (AML), in relation to MDR1 status at diagnosis. Blood 106, 2646–2654 (2005).

    Article  CAS  PubMed  Google Scholar 

  236. Wattel, E. et al. Quinine improves the results of intensive chemotherapy in myelodysplastic syndromes expressing P glycoprotein: results of a randomized study. Br. J. Haematol. 102, 1015–1024 (1998).

    Article  CAS  PubMed  Google Scholar 

  237. Sonneveld, P. et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma: an EORTC-HOVON randomized phase III study (06914). Br. J. Haematol. 115, 895–902 (2001).

    Article  CAS  PubMed  Google Scholar 

  238. Solary, E. et al. Combination of quinine as a potential reversing agent with mitoxantrone and cytarabine for the treatment of acute leukemias: a randomized multicenter study. Blood 88, 1198–1205 (1996).

    CAS  PubMed  Google Scholar 

  239. Solary, E. et al. Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Blood 102, 1202–1210 (2003).

    Article  CAS  PubMed  Google Scholar 

  240. Robert, J. MS-209 Schering. Curr. Opin. Investig. Drugs 5, 1340–1347 (2004).

    CAS  PubMed  Google Scholar 

  241. Joly, F. J. C. et al. A phase 3 study of PSC 833 in combination with paclitaxel and carboplatin (PC-PSC) versus paclitaxel and carboplatin (PC) alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary cancer of the peritoneum. Proc. Am. Soc. Clin. Oncol. 21, Abstract 806 (2002).

    Google Scholar 

  242. Belpomme, D. et al. Verapamil increases the survival of patients with anthracycline-resistant metastatic breast carcinoma. Ann. Oncol. 11, 1471–1476 (2000).

    Article  CAS  PubMed  Google Scholar 

  243. Greenberg, P. L. et al. Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J. Clin. Oncol. 22, 1078–1086 (2004).

    Article  CAS  PubMed  Google Scholar 

  244. Cooray, H. C. et al. Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport 13, 2059–2063 (2002).

    Article  CAS  PubMed  Google Scholar 

  245. Keppler, D. & Konig, J. Hepatic secretion of conjugated drugs and endogenous substances. Semin. Liver Dis. 20, 265–272 (2000).

    Article  CAS  PubMed  Google Scholar 

  246. Consoli, U. et al. Cellular pharmacology of mitoxantrone in p-glycoprotein-positive and-negative human myeloid leukemic cell lines. Leukemia 11, 2066–2074 (1997).

    Article  CAS  PubMed  Google Scholar 

  247. Morrow, C. S. et al. Multidrug resistance protein 1 (MRP1, ABCC1) mediates resistance to mitoxantrone via glutathione-dependent drug efflux. Mol. Pharmacol. 24 Jan 2006 [epubd ahead of print].

  248. Williams, G. C., Liu, A., Knipp, G. & Sinko, P. J. Direct evidence that saquinavir is transported by multidrug resistance-associated protein (MRP1) and canalicular multispecific organic anion transporter (MRP2). Antimicrob. Agents Chemother. 46, 3456–3462 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Chen, Z. S. et al. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 62, 3144–3150 (2002).

    CAS  PubMed  Google Scholar 

  250. Reid, G. et al. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol. Pharmacol. 63, 1094–1103 (2003)

    Article  CAS  PubMed  Google Scholar 

  251. Allen, J. D., Van Dort, S. C., Buitelaar, M., van Tellingen, O. & Schinkel, A. H. Mouse breast cancer resistance protein (Bcrp1/Abcg2) mediates etoposide resistance and transport, but etoposide oral availability is limited primarily by P-glycoprotein. Cancer Res. 63, 1339–1344 (2003)

    CAS  PubMed  Google Scholar 

  252. Robey, R. W. et al. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (Mxr/BCrp/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin. Cancer Res. 7, 145–152 (2001).

    CAS  PubMed  Google Scholar 

  253. Volk, E. L. et al. Overexpression of wild-type breast cancer resistance protein mediates methotrexate resistance. Cancer Res. 62, 5035–5040 (2002).

    CAS  PubMed  Google Scholar 

  254. Twentyman, P. R. Cyclosporins as drug resistance modifiers. Biochem. Pharmacol. 43, 109–117 (1992).

    Article  CAS  PubMed  Google Scholar 

  255. Hyafil, F., Vergely, C., Du Vignaud, P. & Grand-Perret, T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 53, 4595–4602 (1993).

    CAS  PubMed  Google Scholar 

  256. Venne, A., Li, S., Mandeville, R., Kabanov, A. & Alakhov, V. Hypersensitizing effect of pluronic L61 on cytotoxic activity, transport, and subcellular distribution of doxorubicin in multiple drug-resistant cells. Cancer Res. 56, 3626–3629 (1996).

    CAS  PubMed  Google Scholar 

  257. Germann, U. A., Ford, P. J., Shlyakhter, D., Mason, V. S. & Harding, M. W. Chemosensitization and drug accumulation effects of VX-710, verapamil, cyclosporin A, MS-209 and GF120918 in multidrug resistant HL60/ADR cells expressing the multidrug resistance-associated protein MRP. Anticancer Drugs 8, 141–155 (1997).

    Article  CAS  PubMed  Google Scholar 

  258. Sauna, Z. E., Peng, X. H., Nandigama, K., Tekle, S. & Ambudkar, S. V. The molecular basis of the action of disulfiram as a modulator of the multidrug resistance-linked ATP binding cassette transporters MDR1 (ABCB1) and MRP1 (ABCC1). Mol. Pharmacol. 65, 675–684 (2004).

    Article  CAS  PubMed  Google Scholar 

  259. Chen, Z. S. et al. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol. Pharmacol. 56, 1219–1228 (1999).

    Article  CAS  PubMed  Google Scholar 

  260. Qadir, M. et al. Cyclosporin A is a broad-spectrum multidrug resistance modulator. Clin. Cancer Res. 11, 2320–2326 (2005).

    Article  CAS  PubMed  Google Scholar 

  261. de Bruin, M., Miyake, K., Litman, T., Robey, R. & Bates, S. E. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 146, 117–126 (1999).

    Article  CAS  PubMed  Google Scholar 

  262. Rabindran, S. K., Ross, D. D., Doyle, L. A., Yang, W. & Greenberger, L. M. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res. 60, 47–50 (2000).

    CAS  PubMed  Google Scholar 

  263. Lecureur, V. et al. Cloning and expression of murine sister of P-glycoprotein reveals a more discriminating transporter than MDR1/P-glycoprotein. Mol. Pharmacol. 57, 24–35 (2000).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Leiman for his excellent editorial assistance.

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Glossary

AUC

The AUC is a measure of drug exposure, derived from the plasma drug concentration depicted as a function of time. It is used to determine pharmacokinetic parameters, such as clearance or bioavailability, and provides guidelines for dosing and comparing the relative efficiency of different drugs.

Phase II metabolic products

Cellular defence mechanisms against toxins are usually divided into several steps. ABC proteins hinder the cellular uptake of compounds (Phase 0). Should toxins enter the cells, they are subject to chemical modification (Phase I), and subsequent conjugation (Phase II). As a result of Phase I–II metabolism, toxins become more hydrophilic, and are expelled from the cells via mechanisms that involve ABC transporters (Phase III).

Enterohepatic circulation

Before entering systemic circulation, orally ingested drugs are directed to the liver via the portal vein. In the liver, drugs can be metabolized and sequestered to the gut. The enterohepatic circulation is an excretion–reabsorption cycle, in which drugs sequestered through the bile are reabsorbed in the gut.

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Szakács, G., Paterson, J., Ludwig, J. et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov 5, 219–234 (2006). https://doi.org/10.1038/nrd1984

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