Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview

Advanced Drug Delivery Reviews

Volumn 55, Issue 1, 2003, Pages 3-29

  Schinkel, Alfred H ^a   Jonker, Johan W ^a  

^a NETHERLANDS CANCER INSTITUTE   (Netherlands)

Author keywords

ATP binding cassette; Blood brain barrier; Drug efflux transporter; Drug excretion; Multidrug resistance; Oral bioavailability; Pharmacokinetics; Placenta; Sanctuary sites; Toxicology

Indexed keywords

ADENOSINETRIPHOSPHATE; CARCINOGENS; CELLS; DRUG PRODUCTS; METABOLITES; PROTEINS; TISSUE; TOXICITY;

DRUG EFFLUX TRANSPORTERS;

DRUG THERAPY;

7 ETHYL 10 HYDROXYCAMPTOTHECIN; ABC TRANSPORTER; ASIMADOLINE; BISANTRENE; BREAST CANCER RESISTANCE PROTEIN; DAUNORUBICIN; DOCETAXEL; DOXORUBICIN; ELACRIDAR; EPIRUBICIN; ETOPOSIDE; GLYCOPROTEIN P; MITOXANTRONE; MORPHINE; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 2; MULTIDRUG RESISTANCE PROTEIN 3; MULTIDRUG RESISTANCE PROTEIN 4; MULTIDRUG RESISTANCE PROTEIN 5; OC 144 093; PACLITAXEL; PROTEIN INHIBITOR; SAQUINAVIR; TARIQUIDAR; TOPOTECAN; UNCLASSIFIED DRUG; UNINDEXED DRUG; VALSPODAR; VINBLASTINE; VINCRISTINE; ZOSUQUIDAR;

ATAXIA; BLOOD BRAIN BARRIER; BLOOD TESTIS BARRIER; CLINICAL TRIAL; DRUG BIOAVAILABILITY; DRUG CONJUGATION; DRUG DEGRADATION; DRUG EXCRETION; DRUG PENETRATION; DRUG TRANSPORT; FETOMATERNAL TRANSFUSION; HEPATOBILIARY SYSTEM; HUMAN; INTESTINE ABSORPTION; KIDNEY; NONHUMAN; PRIORITY JOURNAL; PROTEIN FAMILY; PROTEIN FUNCTION; PROTEIN LOCALIZATION; REVIEW; RISK FACTOR; TISSUE DISTRIBUTION; TOXICITY; TRANSPORT KINETICS; URINARY EXCRETION;

EID: 0037457802     PISSN: 0169409X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0169-409X(02)00169-2     Document Type: Article

References (169)

1. Higgins C.F. ABC transporters: from microorganisms to man. Annu. Rev. Cell Biol. 8:1992;67-113.
2. Borst P., Evers R., Kool M., Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J. Natl. Cancer Inst. 92:2000;1295-1302.
3. Hipfner D.R., Deeley R.G., Cole S.P.C. Structural, mechanistic, and clinical aspects of MRP1. Biochim. Biophys. Acta. 1461:1999;359-376.
4. König J., Nies A.T., Cui Y., Leier I., Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim. Biophys. Acta. 1461:1999;377-394.
5. Senior A.E., Gadsby D.C. ATP hydrolysis cycles and mechanism in P-glycoprotein and CFTR. Semin. Cancer Biol. 8:1997;143-150.
6. Ambudkar S.V., Dey S., Hrycyna C.A., Ramachandra M., Pastan I., Gottesman M.M. Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu. Rev. Pharmacol. Toxicol. 39:1999;361-398.
7. Schinkel A.H. The physiological function of drug-transporting P-glycoproteins. Semin. Cancer Biol. 8:1997;161-170.
8. Schinkel A.H. P-glycoprotein, a gatekeeper in the blood-brain barrier. Adv. Drug Deliv. Rev. 36:1999;179-194.
9. Ayrton A., Morgan P. Role of transport proteins in drug absorption, distribution and excretion. Xenobiotica. 31:2001;469-497.
10. Maliepaard M., Scheffer G.L., Faneyte I.F., van Gastelen M.A., Pijnenborg A.C.L.M., Schinkel A.H., van de Vijver M.J., Scheper R.J., Schellens J.H.M. Subcellular localization and distribution of the breast cancer resistance protein in normal human tissues. Cancer Res. 61:2001;3458-3464.
11. van Veen H.W., Margolles A., Müller M., Higgins C.F., Konings W.N. The homodimeric ATP-binding cassette transporter LmrA mediates multidrug transport by an alternating two-site (two-cylinder engine) mechanism. EMBO J. 19:2000;2503-2514.
12. Chang G., Roth C.B. Structure of MsbA from E. coli: a homolog of the multidrug resistance ATP binding cassette (ABC) transporters. Science. 293:2001;1793-1800.
13. Özvegy C., Litman T., Szakacs G., Nagy Z., Bates S., Varadi A., Sarkadi B. Functional characterization of the human multidrug transporter, abcg2, expressed in insect cells. Biochem. Biophys. Res. Commun. 285:2001;111-117.
14. Honjo Y., Hrycyna C.A., Robey R.W., Medina-Pérez W.Y., Yan Q.-W., van de Laar A., Litman T., Dean M., Bates S.E. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 61:2001;6635-6639.
15. Kage K., Tsukahara S., Sugiyama T., Asada S., Ishikawa E., Tsuruo T., Sugimoto Y. Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S homodimerization. Int. J. Cancer. 97:2002;626-630.
16. Schinkel A.H., Kemp S., Dollé M., Rudenko G., Wagenaar E. N-glycosylation and deletion mutants of the human MDR1 P-glycoprotein. J. Biol. Chem. 268:1993;7474-7481.
17. Juliano R.L., Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta. 455:1976;152-162.
18. Huisman M.T., Smit J.W., Schinkel A.H. Significance of P-glycoprotein for the pharmacology and clinical use of HIV protease inhibitors. AIDS. 14:2000;237-242.
19. Sikic B.I. Modulation of multidrug resistance: a paradigm for translational clinical research. Oncology (Huntingt.). 13:1999;183-187.
20. Litman T., Druley T.E., Stein W.D., Bates S.E. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell. Mol. Life Sci. 58:2001;931-959.
21. Higgins C.F., Gottesman M.M. Is the multidrug transporter a flippase? Trends Biochem. Sci. 17:1992;18-21.
22. Smit J.J.M., Schinkel A.H., Oude Elferink R.P.J., Groen A.K., Wagenaar E., van Deemter L., Mol C.A.A.M., Ottenhoff R., van der Lugt N.M.T., van Roon M.A., van der Valk M.A., Offerhaus G.J.A., Berns A.J.M., Borst P. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell. 75:1993;451-462.
23. Smith A.J., Timmermans-Hereijgers J.L.P.M., Roelofsen B., Wirtz K.W.A., van Blitterswijk W.J., Smit J.J.M., Schinkel A.H., Borst P. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett. 354:1994;263-266.
24. van Helvoort A., Smith A.J., Sprong H., Fritsche I., Schinkel A.H., Borst P., van Meer G. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell. 87:1996;507-517.
25. 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. 41:1981;1967-1972.
26. Boesch D., Gavériaux C., Jachez B., Pourtier-Manzanedo A., Bollinger P., Loor F. In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res. 51:1991;4226-4233.
27. Smith A.J., Mayer U., Schinkel A.H., Borst P. Availability of PSC833, a substrate and inhibitor of P-glycoproteins, in various concentrations of serum. J. Natl. Cancer Inst. 90:1998;1161-1166.
28. Fischer V., Rodríguez-Gascón A., Heitz F., Tynes R., Hauck C., Cohen D., Vickers A.E.M. The multidrug resistance modulator valspodar (PSC 833) is metabolized by human cytochrome P450 3A. Drug Met. Disp. 26:1998;802-811.
29. Hyafil F., Vergely C., Du Vigneaud P., Grand-Perret T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 53:1993;4595-4602.
30. Malingré M.M., Beijnen J.H., Rosing H., Koopman F.J., Jewell R.C., Paul E.M., ten Bokkel Huinink W.W., Schellens J.H.M. Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients. Br. J. Cancer. 84:2001;42-47.
31. de Bruin M., Miyake K., Litman T., Robey R., Bates S.E. Reversal of drug resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett. 146:1999;117-126.
32. Dantzig A.H., Shepard R.L., Cao J., Law K.L., Ehlhardt W.J., Baughmann T.M., Bumol T.F., Starling J.J. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res. 56:1996;4171-4179.
33. Dantzig A.H., Law K.L., Cao J., Starling J.J. Reversal of multidrug resistance by the P-glycoprotein modulator, LY335979, from the bench to the clinic. Curr. Med. Chem. 8:2001;39-50.
34. Mistry P., Stewart A.J., Dangerfield W., Okiji S., Liddle C., Bootle D., Plumb J.A., Templeton D., Charlton P. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. 61:2001;749-758.
35. Newman M.J., Rodarte J.C., Benbatoul K.D., Romano S.J., Zhang C., Krane S., Moran E.J., Uyeda R.T., Dixon R., Guns E.S., Mayer L.D. Discovery and characterization of OC144-093, a novel inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Res. 60:2000;2964-2972.
36. Thiebaut F., Tsuruo T., Hamada H., Gottesman M.M., Pastan I., Willingham M.C. Cellular localization of the multidrug resistance gene product in normal human tissues. Proc. Natl. Acad. Sci. USA. 84:1987;7735-7738.
37. Cordon-Cardo C., O'Brien J.P., Casals D., Rittman-Grauer L., Biedler J.L., Melamed M.R., Bertino J.R. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc. Natl. Acad. Sci. USA. 86:1989;695-698.
38. Schinkel A.H., Smit J.J.M., van Tellingen O., Beijnen J.H., Wagenaar E., van Deemter L., Mol C.A.A.M., van der Valk M.A., Robanus Maandag E.C., te Riele H.P.J., Berns A.J.M., Borst P. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 77:1994;491-502.
39. Schinkel A.H., Wagenaar E., van Deemter L., Mol C.A.A.M., Borst P. Absence of the mdr1a P-glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J. Clin. Invest. 96:1995;1698-1705.
40. Schinkel A.H., Wagenaar E., Mol C.A.A.M., van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 97:1996;2517-2524.
41. Choo E.F., Leake B., Wandel C., Imamura H., Wood A.J.J., Wilkinson G.R., Kim R.B. Pharmacological inhibition of P-glycoprotein transport enhances the distribution of HIV-1 protease inhibitors into brain and testes. Drug Metab. Disp. 28:2000;655-660.
42. Saito T., Zhang Z.J., Ohtsubo T., Noda I., Shibamori Y., Yamamoto T., Saito H. Homozygous disruption of the mdr1a P-glycoprotein gene affects blood-nerve barrier function in mice administered with neurotoxic drugs. Acta Otolaryngol. 121:2001;735-742.
43. Lankas G.R., Wise L.D., Cartwright M.E., Pippert T., Umbenhauer D.R. Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reprod. Toxicol. 12:1998;457-463.
44. Sugawara I., Kataoka I., Morishita Y., Hamada H., Tsuruo T., Itoyama S., Mori S. Tissue distribution of P-glycoprotein encoded by a multidrug-resistant gene as revealed by a monoclonal antibody, MRP16. Cancer Res. 48:1988;1926-1929.
45. Smit J.W., Huisman M.T., van Tellingen O., Wiltshire H.R., Schinkel A.H. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J. Clin. Invest. 104:1999;1441-1447.
46. Huisman M.T., Smit J.W., Wiltshire H.R., Hoetelmans R.M., Beijnen J.H., Schinkel A.H. P-glycoprotein limits oral availability, brain, and fetal penetration of saquinavir even with high doses of ritonavir. Mol. Pharmacol. 59:2001;806-813.
47. Mayer U., Wagenaar E., Beijnen J.H., Smit J.W., Meijer D.K.F., van Asperen J., Borst P., Schinkel A.H. Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr1a P-glycoprotein. Br. J. Pharmacol. 119:1996;1038-1044.
48. Sparreboom A., van Asperen J., Mayer U., Schinkel A.H., Smit J.W., Meijer D.K.F., Borst P., Nooijen W.J., Beijnen J.H., van Tellingen O. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc. Natl. Acad. Sci. USA. 94:1997;2031-2035.
49. Panwala C.M., Jones J.C., Viney J.L. A novel model of inflammatory bowel disease: mice deficient for the multiple drug resistance gene, mdr1a, spontaneously develop colitis. J. Immunol. 161:1998;5733-5744.
50. Smit J.W., Schinkel A.H., Weert B., Meijer D.K.F. Hepatobiliary and intestinal clearance of amphiphilic cationic drugs in mice in which both mdr1a and mdr1b genes have been disrupted. Br. J. Pharmacol. 124:1998;416-424.
51. Schuetz E.G., Umbenhauer D.R., Yasuda K., Brimer C., Relling M.V., Schuetz J.D., Schinkel A.H. Altered expression of hepatic cytochromes P450 in mice deficient in one or more mdr1 genes. Mol. Pharmacol. 57:2000;188-197.
52. Mayer U., Wagenaar E., Dorobek B., Beijnen J.H., Borst P., Schinkel A.H. Full blockade of intestinal P-glycoprotein and extensive inhibition of blood-brain barrier P-glycoprotein by oral treatment of mice with PSC833. J. Clin. Invest. 100:1997;2430-2436.
53. Hendrikse N.H., Schinkel A.H., de Vries E.G.E., Fluks E., van der Graaf W.T.A., Willemsen A.T.M., Vaalburg W., Franssen E.J.F. Complete in vivo reversal of P-glycoprotein pump function in the blood-brain barrier visualized with positron emission tomography. Br. J. Pharmacol. 124:1998;1413-1418.
54. Polli J.W., Jarrett J.L., Studenberg S.D., Humphreys J.E., Dennis S.W., Brouwer K.R., Wooley J.L. Role of P-glycoprotein on the CNS disposition of amprenavir (141W94), and HIV protease inhibitor. Pharmaceut. Res. 16:1999;1206-1212.
55. Wacher V.J., Wu C.-Y., Benet L.Z. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P-glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol. Carcinogen. 13:1995;129-134.
56. van Asperen J., van Tellingen O., Sparreboom A., Schinkel A.H., Borst P., Nooijen W.J., Beijnen J.H. Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833. Br. J. Cancer. 76:1997;1181-1183.
57. Meerum Terwogt J.M., Beijnen J.H., ten Bokkel Huinink W.W., Rosing H., van Tellingen O., Swart M., Schellens J.H.M. Increased systemic exposure to oral paclitaxel in cancer patients treated with cyclosporin A. Lancet. 352:1998;285.
58. Malingré M.M., Meerum Terwogt J.M., Beijnen J.H., Rosing H., Koopman F.J., van Tellingen O., Duchin K., ten Bokkel Huinink W.W., Swart M., Lieverst J., Schellens J.H.M. A phase I and pharmacokinetic study of oral paclitaxel. J. Clin. Oncol. 18:2000;2468-2475.
59. Cole S.P.C., Bhardway G., Gerlach J.H., Mackie J.E., Grant C.E., Almquist K.C., Stewart A.J., Kurz E.U., Duncan A.M.V., Deeley R.G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 258:1992;1650-1654.
60. Cole S.P.C., Sparks K.E., Fraser K., Loe D.W., Grant C.E., Wilson G.M., Deeley R.G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 54:1994;5902-5910.
61. Cole S.P.C., Sparks K.E., Fraser K., Loe D.W., Grant C.E., Wilson G.M., Deeley R.G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 54:1994;5902-5910.
62. Hooijberg J.H., Broxterman H.J., Kool M., Assaraf Y.G., Peters G.J., Noordhuis P., Scheper R.J., Borst P., Pinedo H.M., Jansen G. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res. 59:1999;2532-2535.
63. Zaman G.J.R., Flens M.J., van Leusden M.R., de Haas M., Mülder H.S., Lankelma J., Pinedo H.M., Scheper R.J., Baas F., Broxterman H.J., Borst P. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc. Natl. Acad. Sci. USA. 91:1994;8822-8826.
64. Kruh G.D., Chan A., Myers K., Gaughan K., Miki T., Aaronson S.A. Expression complementary DNA library transfer establishes mrp as a multidrug resistance gene. Cancer Res. 54:1994;1649-1652.
65. Breuninger L.M., Paul S., Gaughan K., Miki T., Chan A., Aaronson S.A., Kruh G. Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Res. 55:1995;5342-5347.
66. Leier I., Jedlitschky G., Buchholz U., Cole S.P.C., Deeley R.G., Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J. Biol. Chem. 269:1994;27807-27810.
67. Müller M., Meijer C., Zaman G.J.R., Borst P., Scheper R.J., Mulder N.H., de Vries E.G.E., Jansen P.L.M. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc. Natl. Acad. Sci. USA. 91:1994;13033-13037.
68. Evers R., Zaman G.J.R., van Deemter L., Jansen H., Calafat J., Oomen L.C.J.M., Oude Elferink R.P.J., Borst P., Schinkel A.H. Basolateral localization and export activity of the human multidrug resistance-associated protein (MRP) in polarized pig kidney cells. J. Clin. Invest. 97:1996;1211-1218.
69. Loe D.W., Almquist K.C., Cole S.P.C., Deeley R.G. ATP-dependent 17β-estradiol 17-(β-D-glucuronide) transport by multidrug resistance protein (MRP). J. Biol. Chem. 271:1996;9683-9689.
70. Schneider E., Yamazaki H., Sinha B.K., Cowan K.H. Buthionine sulfoximine-mediated sensitisation of etoposide-resistant human breast cancer MCF7 cells overexpressing the multidrug resistance-associated protein involves increased drug accumulation. Br. J. Cancer. 71:1995;738-743.
71. Zaman G.J.R., Lankelma J., van Tellingen O., Beijnen J.H., Dekker H., Paulusma C., Oude Elferink R.P.J., Baas F., Borst P. Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc. Natl. Acad. Sci. USA. 92:1995;7690-7694.
72. Rappa G., Lorico A., Flavell R.A., Sartorelli A.C. Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Res. 57:1997;5232-5237.
73. Loe D.W., Deeley R.G., Cole S.P.C. Characterization of vincristine transport by the Mr 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res. 58:1998;5130-5136.
74. Wijnholds J., Evers R., van Leusden M.R., Mol C.A.A.M., Zaman G.J.R., Mayer U., Beijnen J.H., van der Valk M., Krimpenfort P., Berns A., Borst P. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking MRP. Nature Med. 3:1997;1275-1279.
75. Lorico A., Rappa G., Finch R.A., Yang D., Flavell R.A., Sartorelli A.C. Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res. 57:1997;5238-5242.
76. 4 transporter MRP1 regulates CCL19 (MIP-3β, ELC)-dependent mobolization of dendritic cells to lymph nodes. Cell. 103:2000;757-768.
77. Wijnholds J., Scheffer G.L., van der Valk M., van der Valk P., Beijnen J.H., Scheper R.J., Borst P. Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage. J. Exp. Med. 188:1998;797-808.
78. Wijnholds J., de Lange E.C.M., Scheffer G.L., van den Berg D.-J., Mol C.A.A.M., van der Valk M., Schinkel A.H., Scheper R.J., Breimer D.D., Borst P. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J. Clin. Invest. 105:2000;279-285.
79. Johnson D.R., Finch R.A., Ling Z.P., Zeiss C.J., Sartorelli A.C. The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice. Cancer Res. 61:2001;1469-1476.
80. Lorico A., Rappa G., Flavell R.A., Sartorelli A.C. Double knockout of the MRP gene leads to increased drug sensitivity in vitro. Cancer Res. 56:1996;5351-5355.
81. Allen J.D., Brinkhuis R.F., van Deemter L., Wijnholds J., Schinkel A.H. Extensive contribution of the multidrug transporters P-glycoprotein and Mrp1 to basal drug resistance. Cancer Res. 60:2000;5761-5766.
82. Zhang D.W., Cole S.P., Deeley R.G. Identification of a nonconserved amino acid residue in multidrug resistance protein 1 important for determining substrate specificity: evidence for functional interaction between transmembrane helices 14 and 17. J. Biol. Chem. 276:2001;34966-34974.
83. 4 and chemotherapeutic agents in membrane vesicles. J. Biol. Chem. 271:1996;9675-9682.
84. Keppler D., Leier I., Jedlitschky G., König J. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance protein MRP1 and its apical isoform MRP2. Chem. Biol. Interact. 111-112:1998;153-161.
85. Holló Z., Homolya L., Hegedus T., Sarkadi B. Transport properties of the multidrug resistance protein (MRP) in human tumour cells. FEBS Lett. 383:1996;99-104.
86. Evers R., de Haas M., Sparidans R., Beijnen J., Wielinga P.R., Lankelma J., Borst P. Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br. J. Cancer. 83:2000;375-383.
87. Oude Elferink R.P.J., Meijer D.K.F., Kuipers F., Jansen P.L.M., Groen A.K., Groothuis G.M. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim. Biophys. Acta. 1241:1995;215-268.
88. Mayer R., Kartenbeck J., Büchler M., Jedlitschky G., Leier I., Keppler D. Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. J. Cell. Biol. 131:1995;137-150.
89. Paulusma C.C., Bosma P.J., Zaman G.J., Bakker C.T., Otter M., Scheffer G.L., Scheper R.J., Borst P., Oude Elferink R.P.J. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science. 271:1996;1126-1128.
90. Keppler D., König J. Hepatic secretion of conjugated drugs and endogenous substances. Semin. Liver Disease. 20:2000;265-272.
91. Koike K., Kawabe T., Tanaka T., Toh S., Uchiumi T., Wada M., Akiyama S., Ono M., Kuwano M. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res. 57:1997;5475-5479.
92. Evers R., Kool M., van Deemter L., Janssen H., Calafat J., Oomen L.C., Paulusma C.C., Oude Elferink R.P., Baas F., Schinkel A.H., Borst P P. Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. J. Clin. Invest. 101:1998;1310-1319.
93. Cui Y., König J., Buchholz U., Spring H., Leier I., Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol. Pharmacol. 55:1999;929-937.
94. Dietrich C.G., de Waart D.R., Ottenhoff R., Schoots I.G., Oude Elferink R.P.J. Increased bioavailability of the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in MRP2-deficient rats. Mol. Pharmacol. 59:2001;974-980.
95. Kala S.V., Neely M.W., Kala G., Prater C.I., Atwood D.W., Rice J.S., Lieberman M.W. The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic. J. Biol. Chem. 275:2000;33404-33408.
96. Soignet S.L., Maslak P., Wang Z.-G., Jhanwar S., Calleja E., Dardashti L.J., Corso D., DeBlasio A., Gabrilove J., Scheinberg D.A., Pandolfi P.P., Warrell R.P. Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. New Engl. J. Med. 339:1998;1341-1348.
97. Dai J., Weinberg R.S., Waxman S., Jing Y. Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood. 93:1999;268-277.
98. Dietrich C.G., de Waart D.R., Ottenhoff R., Bootsma A.H., van Gennip A.H., Oude Elferink R.P.J. 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. Carcinogenesis. 22:2001;805-811.
99. Mottino A.D., Hoffman T., Jennes L., Vore M. Expression and localization of multidrug resistant protein mrp2 in rat small intestine. J. Pharm. Exp. Ther. 293:2000;717-723.
100. van Aubel R.A., Hartog A., Bindels R.J., van Os C.H., Russel F.G. Expression and immunolocalization of multidrug resistance protein 2 in rabbit small intestine. Eur. J. Pharmacol. 400:2000;195-198.
101. Schaub T.P., Kartenbeck J., König J., Vogel O., Witzgall R., Kriz W., Keppler D. Expression of the conjugate export pump encoded by the mrp2 gene in the apical membrane of kidney proximal tubules. J. Am. Soc. Nephrol. 8:1997;1213-1221.
102. Schaub T.P., Kartenbeck J., König J., Spring H., Dorsam J., Staehler G., Storkel S., Thon W.F., Keppler D. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J. Am. Soc. Nephrol. 10:1999;1159-1169.
103. Taipalensuu J., Törnblom H., Lindberg G., Einarsson C., Sjöqvist F., Melhus H., Garberg P., Sjöström B., Lundgren B., Artursson P. Correlation of gene expression of ten drug efflux proteins of the human ATP-binding cassette transporter family in normal human jejunum and in human intestinal epithelial Caco-2 cell monolayers. J. Pharmacol. Exp. Ther. 299:2001;164-170.
104. Masuda M., I'izuka Y., Yamazaki M., Nishigaki R., Kato Y., Ni'inuma K., Suzuki H., Sugiyama Y. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res. 57:1997;3506-3510.
105. Miller D.S., Nobmann S.N., Gutmann H., Toeroek M., Drewe J., Fricker G. Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Mol. Pharmacol. 58:2000;1357-1367.
106. St.-Pierre M.V., Serrano M.A., Macias R.I., Dubs U., Hoechli M., Lauper U., Meier P.J., Marin J.J. Expression of members of the multidrug resistance protein family in human term placenta. Am. J. Physiol. 279:2000;R1495-R1503.
107. Büchler M., König J., Brom M., Kartenbeck J., Spring H., Horie T., Keppler D. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J. Biol. Chem. 271:1996;15091-15098.
108. van Aubel R.A.M.H., van Kuijck M.A., Koenderink J.B., Deen P.M.T., van Os C.H., Russel F.G.M. Adenosine triphosphate-dependent transport of anionic conjugates by the rabbit multidrug resistance-associated protein Mrp2 expressed in insect cells. Mol. Pharmacol. 53:1998;1062-1067.
109. Bakos E., Evers R., Sinkó E., Váradi A., Borst P., Sarkadi B. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol. Pharmacol. 57:2000;760-768.
110. Chen Z.-S., Kawabe T., Ono M., Aoki S., Sumizawa T., Furukawa T., Uchiumi T., Wada M., Kuwano M., Akiyama S.-I. Effect of multidrug resistance-reversing agents on transporting activity of human canalicular multispecific organic anion transporter. Mol. Pharmacol. 56:1999;1219-1228.
111. Cantz T., Nies A.T., Brom M., Hofmann A.F., Keppler D. MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells. Am. J. Physiol. 278:2000;G522-G531.
112. Shapiro A.B., Ling V. Positively cooperative sites for drug transport by P-glycoprotein with distinct drug specificities. Eur. J. Biochem. 250:1997;130-137.
113. Kondratov R.V., Komarov P.G., Becker Y., Ewenson A., Gudkov A.V. Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein. Proc. Natl. Acad. Sci. USA. 98:2001;14078-14083.
114. 1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity. J. Biol. Chem. 276:2001;38108-38114.
115. Leslie E.M., Ito K., Upadhyaya P., Hecht S.S., Deeley R.G., Cole S.P.C. Transport of the β-O-glucuronide of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1). J. Biol. Chem. 276:2001;27846-27854.
116. Shapiro A.B., Fox K., Lam P., Ling V. Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. Eur. J. Biochem. 259:1999;841-850.
117. Kiuchi Y., Suzuki H., Hirohashi T., Tyson C.A., Sugiyama Y. cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3). FEBS Lett. 433:1998;149-152.
118. Kool M., van der Linden M., de Haas M., Scheffer G.L., de Vree J.M., Smith A.J., Jansen G., Peters G.J., Ponne N., Scheper R.J., Oude Elferink R.P.J., Baas F., Borst P. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc. Natl. Acad. Sci. USA. 96:1999;6914-6919.
119. König J., Rost D., Cui Y., Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology. 29:1999;1156-1163.
120. Hirohashi T., Suzuki H., Sugiyama Y. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J. Biol. Chem. 274:1999;15181-15185.
121. Hirohashi T., Suzuki H., Takikawa H., Sugiyama Y. ATP-dependent transport of bile salts by multidrug resistance-associated protein 3 (Mrp3). J. Biol. Chem. 275:2000;2905-2910.
122. Zeng H., Bain L.J., Belinsky M.G., Kruh G.D. Expression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents. Cancer Res. 59:1999;5964-5967.
123. Zeng H., Liu G G., Rea P.A., Kruh G.D. Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Res. 60:2000;4779-4784.
124. 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. 276:2001;46400-46407.
125. Kool M., de Haas M., Scheffer G.L., Scheper R.J., van Eijk M.J.T., Juijn J.A., Baas F., Borst P. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologs of the multidrug resistance-associated resistance protein (MRP1), in human cancer cell lines. Cancer Res. 57:1997;3537-3547.
126. Scheffer G.L., Kool M., de Haas M., de Vree J.M.L., Pijnenborg A.C.L.M., Bosman D.K., Oude Elferink R.P.J., van der Valk P., Borst P., Scheper R.J. Tissue distribution and induction of human MRP3. Lab. Investigation. 82:2002;193-201.
127. Rost D., König J., Weiss G., Klar E., Stremmel W., Keppler D. Expression and localization of the multidrug resistance proteins mrp2 and mrp3 in human gallbladder epithelia. Gastroenterology. 121:2001;1203-1208.
128. Hirohashi T., Suzuki H., Ito K., Ogawa K., Kume K., Shimizu T., Sugiyama Y. Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol. Pharmacol. 53:1998;1068-1075.
129. Lee K., Belinsky M.G., Bell D.W., Testa J.R., Kruh G.D. Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res. 58:1998;2741-2747.
130. Schuetz J.D., Connely M.C., Sun D., Paibir S.G., Flynn P.M., Srinivas R.V., Kumar A., Fridland A. MRP4: a previously unidentified factor in resistance to nucleotide-based antiviral drugs. Nat. Med. 5:1999;1048-1051.
131. Lee K., Klein-Szanto A.J.P., Kruh G.D. Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. J. Natl. Cancer Inst. 92:2000;1934-1940.
132. Chen Z.-S., Lee K., Kruh G.D. Transport of cyclic nucleotides and estradiol 17-β-D-glucuronide by multidrug resistance protein 4. J. Biol. Chem. 276:2001;33747-33754.
133. van Aubel R.A.M.H., Smeets P.H.E., Peters J.G.P., Bindels R.J.M., Russel F.G.M. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubule: the putative efflux pump for urinary cAMP and cGMP. J. Am. Soc. Nephrol. 13:2002;595-603.
134. McAleer M.A., Breen M.A., White N.L., Matthews N. pABC11 (also known as MOAT-C and MRP5) a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J. Biol. Chem. 274:1999;23541-23548.
135. Wijnholds J., Mol C.A.A.M., van Deemter L., de Haas M., Scheffer G.L., Baas F., Beijnen J.H., Scheper R.J., Hatse S., de Clercq E., Balzarini J., Borst P. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc. Natl. Acad. Sci. USA. 97:2000;7476-7481.
136. Jedlitschky G., Burchell B., Keppler D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J. Biol. Chem. 275:2000;30069-30074.
137. Doyle L.A., Yang W., Abruzzo L.V., Krogmann T., Gao Y., Rishi A.K., Ross D.D. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc. Natl. Acad. Sci. USA. 95:1998;15665-15670.
138. Chen Y.-N., Mickley L.A., Schwartz A.M., Acton E.M., Hwang J., Fojo T. Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J. Biol. Chem. 265:1990;10073-10080.
139. Lee J.S., Scala S., Matsumoto Y., Dickstein B., Robey R., Zhan Z., Altenberg G., Bates S.E. Reduced drug accumulation and multidrug resistance in human breast cancer cells without associated P-glycoprotein or MRP overexpression. J. Cell. Biochem. 65:1997;513-526.
140. Miyake K., Mickley L., Litman T., Zhan Z., Robey R., Cristensen B.,
141. 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. 58:1998;5337-5339.
142. Berge K.E., Tian H., Graf G.A., Yu L., Grishin N.V., Schultz J., Kwiterovich P., Shan B., Barnes R., Hobbs H.H. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 290:2000;1771-1775.
143. Lee M.-H., Lu K., Hazard S., Yu H., Shulenin S., Hidaka H., Kojima H., Allikmets R., Sakuma N., Pegoraro R., Srivastava A.K., Salen G., Dean M., Patel S.B. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nature Genet. 27:2001;79-83.
144. Allen J.D., Brinkhuis R.F., Wijnholds J., Schinkel A.H. The mouse Bcrp/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 59:1999;4237-4241.
145. Knutsen T., Rao V.K., Ried T., Mickley L., Schneider E., Miyake K., Ghadimi B.M., Padilla-Nash H., Pack S., Greenberger L., Cowan K., Dean M., Fojo T., Bates S. Amplification of 4q21-q22 and the MXR gene in independently derived mitoxantrone-resistant cell lines. Genes Cromosom. Cancer. 27:2000;110-116.
146. Ewart G.D., Howells A.J. ABC transporters involved in transport of eye pigment precursors in Drosophila melanogaster. Ambudkar S., Gottesman M.M. Methods in Enzymology. Vol. 292:1998;213-224 Academic Press, San Diego.
147. Scheffer G.L., Maliepaard M., Pijnenborg A.C.L.M., van Gastelen M.A., de Jong M.C., Schroeijers A.B., van der Kolk D.M., Allen J.D., Ross D.D., van der Valk P., Dalton W.S., Schellens J.H.M., Scheper R.J. Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone- and topotecan-resistant cell lines. Cancer Res. 60:2000;2589-2593.
148. Rocchi E., Khodjakov A., Volk E.L., Yang C.-H., Litman T., Bates S.E., Schneider E. The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem. Biophys. Res. Comm. 271:2000;42-46.
149. Jonker J.W., Smit J.W., Brinkhuis R.F., Maliepaard M., Beijnen J.H., Schellens J.H.M., Schinkel A.H. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J. Natl. Cancer Inst. 92:2000;1651-1656.
150. Litman T., Brangi M., Hudson E., Fetsch P., Abati A., Ross D.D., Miyake K., Resau J.H., Bates S.E. The multidrug-resistant phenotype associated with overexpression of the new ABC half-transporter, MXR (ABCG2). J. Cell Sci. 113:2000;2011-2021.
151. Ross D.D., Yang W., Abruzzo L.V., Dalton W.S., Schneider E., Lage H., Dietel M., Greenberger L., Cole S.P.C., Doyle L.A. Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J. Natl. Cancer Inst. 91:1999;429-433.
152. Maliepaard M., van Gastelen M.A., de Jong L.A., Pluim D., van Waardenburg R.C.A.M., Ruevekamp-Helmers M.C., Floot B.J.G., Schellens J.H.M. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res. 59:1999;4559-4563.
153. Kawabata S., Oka M., Shiozawa K., Tsukamoto K., Nakatomi K., Soda H., Fukuda M., Ikegami Y., Sugahara K., Yamada Y., Kamihira S., Doyle L.A., Ross D.D., Kohno S. Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells. Biochem. Biophys. Res. Comm. 280:2001;1216-1223.
154. Robey R.W., Medina-Perez W.Y., Nishiyama K., Lahusen T., Miyake K., Litman T., Senderowicz A.M., Ross D.D., Bates S.E. Overexpression of the ATP-binding cassette half-transporter, ABCG2 (MXR/BCRP/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin. Cancer Res. 7:2001;145-152.
155. Komatani H., Kotani H., Hara Y., Nakagawa R., Matsumoto M., Arakawa H., Nishimura S. Identification of breast cancer resistance 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. 61:2001;2827-2832.
156. Hazlehurst L.A., Foley N.E., Gleason-Guzman M.C., Hacker M.P., Cress A.E., Greenberger L.M., de Jong M.C., Dalton W.S. Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res. 59:1999;1021-1028.
157. 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. 60:2000;47-50.
158. Robey R.W., Honjo Y., van de Laar A., Miyake K., Regis J.T., Litman T., Bates S.E. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochim. Biophys. Acta. 1512:2001;171-182.
159. Brangi M., Litman T., Ciotti M., Nishiyama K., Kohlhagen G., Takimoto C., Robey R., Pommier Y., Fojo T., 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. Cancer Res. 59:1999;5938-5946.
160. Rabindran S.K., He H., Singh M., Brown E., Collins K.I., Annable T., Greenberger L.M. Reversal of a novel multidrug resistance mechanism in human colon carcinoma cells by fumitremorgin C. Cancer Res. 58:1998;5850-5858.
161. Slapak C.A., Mizunuma M., Kufe D.W. Expression of the multidrug resistance associated protein and P-glycoprotein in doxorubicin-selected human myeloid leukemia cells. Blood. 84:1994;3113-3121.
162. Choi K.H., Chen C.J., Kriegler M., Roninson I.B. An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell. 53:1988;519-529.
163. Volk E.L., Rohde K., Rhee M., McGuire J.J., Doyle L.A., Ross D.D., Schneider E. Methotrexate cross-resistance in a mitoxantrone-selected multidrug-resistant MCF7 breast cancer cell line is attributable to enhanced energy-dependent drug efflux. Cancer Res. 60:2000;3514-3521.
164. He H., Rabindran S.G., Greenberger L.M., Carter G.T. Fumitremorgin C analogs that reverse mitoxantrone resistance in human colon carcinoma cells. Med. Chem. Res. 9:1999;424-437.
165. van Loevezijn A., Allen J.D., Schinkel A.H., Koomen G.-J. Inhibition of BCRP-mediated drug efflux by fumitremorgin-type indolyl diketopiperazines. Biorgan. Med. Chem. Lett. 11:2001;29-32.
166. Erlichman C., Boerner S.A., Hallgren C.G., Spieker R., Wang X.Y., James C.D., Scheffer G.L., Maliepaard M., Ross D.D., Bible K.C., Kaufmann S.H. 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. 61:2001;739-748.
167. Zhou S., Schuetz J.D., Bunting K.D., Colapietro A.-M., Sampath J., Morris J.J., Lagutina I., Grosveld G.C., Osawa M., Nakauchi H., Sorrentino B.P. 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. 7:2001;1028-1034.
168. Scharenberg C.W., Harkey M.A., Torok-Storb B. The ABCG2 transporter is an efficient Hoechst 33342 efflux pump and is preferentially expressed by immature hematopoietic progenitors. Blood. 99:2002;507-512.
169. Kruijtzer C.M.F., Beijnen J.H., Rosing H., Ten Bokkel Huinink W.W., Schot M., Jewell R.C., Paul E.M., Schellens J.H.M. Increased oral bioavailability of topotecan in combination with the Breast Cancer Resistance Protein and P-glycoprotein inhibitor GF120918. J. Clin. Oncol. 20:2002;2943-2950.