© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 20, 1651-1656,
October 18, 2000
© 2000 Oxford University Press
Role of Breast Cancer Resistance Protein in the Bioavailability and Fetal Penetration of Topotecan
Affiliations of authors: J. W. Jonker, J. W. Smit, R. F. Brinkhuis, M. Maliepaard, A. H. Schinkel (Division of Experimental Therapy), J. H. M. Schellens (Divisions of Experimental Therapy and Medical Oncology), The Netherlands Cancer Institute, Amsterdam; J. H. Beijnen, Department of Pharmacy and Pharmacology, Slotervaart Hospital, Amsterdam, The Netherlands.
Correspondence to: Alfred H. Schinkel, Ph.D., Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: alfred{at}nki.nl).
 |
ABSTRACT |
|---|
 TopNotes Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Background and Methods: Breast cancer resistance protein (BCRP/MXR/ABCP) is a multidrug-resistance protein that is a member of the adenosine triphosphate-binding cassette family of drug transporters. BCRP can render tumor cells resistant to the anticancer drugs topotecan, mitoxantrone, doxorubicin, and daunorubicin. To investigate the physiologic role of BCRP, we used polarized mammalian cell lines to determine the direction of BCRP drug transport. We also used the BCRP inhibitor GF120918 to assess the role of BCRP in protecting mice against xenobiotic drugs. Bcrp1, the murine homologue of BCRP, was expressed in the polarized mammalian cell lines LLC-PK1 and MDCK-II, and the direction of Bcrp1-mediated transport of topotecan and mitoxantrone was determined. To avoid the confounding drug transport provided by P-glycoprotein (P-gp), the roles of Bcrp1 in the bioavailability of topotecan and the effect of GF120918 were studied in both wild-type and P-gp-deficient mice and their fetuses. Results: Bcrp1 mediated apically directed transport of drugs in polarized cell lines. When both topotecan and GF120918 were administered orally, the bioavailability (i.e., the extent to which a drug becomes available to a target tissue after administration) of topotecan in plasma was dramatically increased in P-gp-deficient mice (greater than sixfold) and wild-type mice (greater than ninefold), compared with the control (i.e., vehicle-treated) mice. Furthermore, treatment with GF120918 decreased plasma clearance and hepatobiliary excretion of topotecan and increased (re-)uptake by the small intestine. In pregnant GF120918-treated, P-gp-deficient mice, relative fetal penetration of topotecan was twofold higher than that in pregnant vehicle-treated mice, suggesting a function for BCRP in the maternal–fetal barrier of the placenta. Conclusions: Bcrp1 mediates apically directed drug transport, appears to reduce drug bioavailability, and protects fetuses against drugs. We propose that strategic application of BCRP inhibitors may thus lead to more effective oral chemotherapy with topotecan or other BCRP substrate drugs.
|
INTRODUCTION |
|---|
|
TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
After a period of treatment with a single cytotoxic drug, cancer cells can become resistant to multiple drugs, a phenomenon known as multidrug resistance. Several mechanisms of multidrug resistance have been identified, including the overexpression of P-glycoprotein (P-gp) and MRP1, which are members of the adenosine triphosphate-binding cassette (ABC) superfamily of transport proteins that are situated in the plasma membrane and can actively transport drugs out of the cell (1–3). Recently, breast cancer resistance protein (BCRP) (also known as mitoxantrone resistance protein [MXR] and placenta-specific ABC transporter [ABCP]), a new member of this superfamily involved in multidrug resistance, was identified in an MCF-7 breast cancer cell subline that was selected for resistance to doxorubicin. This BCRP-overexpressing cell line was markedly cross-resistant to mitoxantrone and daunorubicin (4,5). Subsequently, several other groups (6–8) have shown overexpression of BCRP or its murine homologue, Bcrp1, in cell lines selected for resistance to the anticancer agents mitoxantrone, doxorubicin, and topotecan. BCRP-mediated drug resistance could be effectively reversed by GF120918 (a P-gp inhibitor) in human (9) and murine (7) cell lines.
In this study, we investigate the direction of BCRP-mediated drug transport in various polarized cell lines and determine the role of BCRP in protecting mice against xenobiotic drugs (10), by using the efficient BCRP inhibitor GF120918.
|
MATERIALS AND METHODS |
|---|
|
TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
The mice were housed and handled according to institutional guidelines and Dutch laws. For all experiments, the animals used were male mdr1a/1b(-/-) or wild-type mice of a 99% FVB genetic background; they were 9–14 weeks of age. The mice were kept in a temperature-controlled environment with a 12-hour light–12-hour dark cycle and were given a standard diet (AM-II; Hope Farms, Woerden, The Netherlands) and acidified water ad libitum.
Reagents
Topotecan (Hycamtin®) and [14C]topotecan (56 Ci/mol) were from SmithKline Beecham Pharmaceuticals (King of Prussia, PA). GF120918 was from Glaxo Wellcome (Research Triangle Park, NC). Ketamine (Ketalar®) was from Parke-Davis (Hoofddorp, The Netherlands). Xylazine was from Sigma Chemical Co. (St. Louis, MO). Methoxyflurane (Metofane®) was from Mallinckrodt Veterinary, Inc. (Mundelein, IL). All other compounds used were reagent grade.
Drug Preparation, Administration, and Analysis
GF120918 was suspended at 5 mg/mL in a mixture of hydroxypropyl methylcellulose (10 g/L)/2% (vol/vol) Tween 80/H2O (0.5 : 1 : 98.5 [vol/vol/vol] for oral administration). Animals, lightly anesthetized with methoxyflurane, were administered GF120918 (50 mg/kg; 10 µL of drug solution/g body weight) or a corresponding amount of vehicle by gavage into the stomach. Topotecan (0.2 mg/mL) (freshly prepared in 5% [wt/vol] D-glucose; 5 µL/g body weight) was administered orally at a dose of 1.0 mg/kg body weight. For intravenous administration, topotecan or, where indicated, [14C]topotecan at 5 µL of drug solution/g body weight was injected into the tail vein of mice lightly anesthetized with methoxyflurane.
Animals were killed by cardiac puncture or axillary bleeding after being anesthetized with methoxyflurane, and their blood was collected. Heparinized plasma was mixed with three volumes of ice-cold methanol (-20 °C). Their organs were removed and subsequently homogenized in 4% (wt/vol) bovine serum albumin. Where applicable, the intestinal content was separated from the intestinal tissue before homogenization. Radioactivity in homogenates was determined as described previously (11). Because topotecan is hardly metabolized in vivo, the amounts of 14C reflect total unchanged levels of topotecan (12). The total topotecan levels (lactone plus carboxylate form) in plasma were determined by high-pressure liquid chromatography as described earlier (13). The area under the plasma concentration–time curve (AUC) was calculated (from 0 to 4 hours for oral administration and from 1 minute to 4 hours for intravenous administration) by use of the linear trapezoidal rule. Plasma bioavailability (i.e., the extent to which a drug becomes available in plasma after administration) of administered drug was determined as the ratio of the AUC after oral and intravenous administrations. For gallbladder cannulation experiments, mice were anesthetized and cannulated as described previously (14). Anesthetics, a combination of ketamine (100 mg/kg) and xylazine (6.7 mg/kg), were injected intraperitoneally into the mice at 2.33 µL/g body weight.
Ribonuclease Protection Analysis
Total RNA was isolated from mouse tissues by use of the TRIzol® reagent (Life Technologies, Inc. [GIBCO BRL], Rockville, MD), according to the manufacturer's instructions. Ribonuclease (RNase) protection assays were performed, as described previously (15), with 10 µg of total RNA per sample. A mouse probe for bcrp1 was made by cloning a 405-nucleotide (nt) polymerase chain reaction fragment (positions 1554–1959 relative to the translation start) into the pGEM-T vector (Promega Corp., Madison, WI). After the vector was linearized with restriction endonuclease EcoRI, a 280-nt antisense RNA probe was generated by transcription with SP6 RNA polymerase, yielding a protected probe fragment of 205 nt.
Expression of Full-Length Mouse bcrp1 Complementary DNA in LLC-PK1 and MDCK-II Cells
The full-length mouse bcrp1 complementary DNA (cDNA) (7) was excised from pBluescript KS with SmaI and NotI and was cloned into the LZRS-MS-IRES-GFP expression vector between the SnaBI and NotI sites (16). The resulting vector was a monocistronic construct containing bcrp1 followed by sequences for an internal ribosome entry site and the enhanced green fluorescent protein. This construct was transfected to the amphotropic Phoenix producer cell line (17) by use of the calcium phosphate precipitation method. Viral supernatants from these transfected cells were used to transduce LLC-PK1 or MDCK-II cells. Transduced clones were selected first for expression of the enhanced green fluorescent protein and then for the reduced accumulation of mitoxantrone by flow cytometry. The expression of bcrp1 cDNA in selected clones was determined by northern blot analysis.
Transport Assay
Transport assays were carried out as described earlier (14), with minor modifications. M199 medium containing L-glutamine (2 mM), penicillin (100 IU/mL), streptomycin (100 µg/mL), and fetal calf serum (10%) was used throughout. Cells were seeded on microporous polycarbonate membrane filters (3.0-µm pore size, 24.5-mm diameter, TranswellTM 3414, Costar®) at a density of 2 x 106 cells/well. The cells were grown for 4 days in M199 medium with one change of medium. Ninety minutes before the start of the experiment, medium on both the apical and the basal sides of the monolayer was replaced with 2 mL of Optimem (Life Technologies Ltd., Paisley, Scotland) containing L-glutamine (2 mM), penicillin (100 IU/mL), and streptomycin (100 µg/mL) without fetal calf serum, at pH 6.5 (adjusted with HCl). The experiment was started by replacing the medium on either the apical or the basal side of the cell layer with 2 mL of Optimem (pH 6.5) containing 10 µM [14C]topotecan (7 Ci/mol) and 192 nM [3H]inulin (0.8 Ci/mmol). The cells were incubated at 37 °C in 5% CO2-95% air. After 0.5, 2, 4, 6, and 24 hours, 50 µL was taken from each compartment, and the radioactivity in each aliquot was measured. Any radioactivity crossing the monolayer and appearing in the opposite compartment was noted as the fraction of total radioactivity added at the beginning of the experiment. The tightness of the monolayer was measured by monitoring the paracellular flux of [3H]inulin to the opposite compartment. This flux was always lower than 1% of the total radioactivity per hour.
Statistical Analysis
The two-sided unpaired Student's t test was used throughout to assess the statistical significance of difference between the two sets of data. Results are presented as the means ± standard deviation. Differences were considered to be statistically significant when P<.05.
|
RESULTS |
|---|
|
TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Polarized Transport of [14C]Topotecan by Mouse Bcrp1 in Epithelial Cell Lines
To determine the direction of Bcrp1-mediated drug transport in polarized epithelia, we transduced the pig kidney cell line LLC-PK1 with a retroviral expression vector containing mouse bcrp1 cDNA. By northern blot analysis, expression of bcrp1 cDNA in two independent transductants (L-Bcrp1.1 and L-Bcrp-1.2) was 25%–50% of that found in D320 cells, a doxorubicin-selected cell line that highly overexpresses bcrp1 [(7); data not shown]. The parental and transduced cell lines were grown to confluent polarized monolayers on porous membrane filters, and vectorial transport of [14C]topotecan (10 µM) across the monolayers was determined. Background transport of topotecan by the endogenous pig P-gp (18) present in the LLC-PK1-derived lines was abolished by the addition of the P-gp inhibitor PSC 833 (10 µM). This compound hardly affects Bcrp1-mediated drug transport (data not shown). Although topotecan was translocated equally well in both apical and basolateral directions in the parental line LLC-PK1, in the bcrp1-transduced lines, it was translocated more in the apical direction and less in the basolateral direction (Fig. 1
, a and b; data for L-Bcrp1.2 [not shown] were similar to those for L-Bcrp1.1). When the Bcrp1/P-gp inhibitor GF120918 (7,9) was used, polarized topotecan transport was abolished in parental and bcrp1-transduced lines, resulting in equal levels of (passive) translocation of topotecan in both directions (Fig. 1, c and d). Similar results were obtained for [14C]topotecan and [3H]mitoxantrone when mouse bcrp1 was expressed in the polarized canine kidney cell line MDCK-II (data not shown). Thus, Bcrp1-mediated drug transport is apically directed in various polarized cells, which suggests that Bcrp1 is located apically in polarized epithelia, and can be effectively inhibited by GF120918.
|
Expression of bcrp1 Messenger RNA in Mouse Tissues
P-gp mediates apically directed drug transport in polarized cultured cells and the elimination of drugs by organs such as liver and intestine. P-gp also reduces the uptake of drugs from the intestine and prevents the accumulation of drugs in certain critical tissues and the fetus (10,19–21). To assess a possible pharmacologic role of Bcrp1, we first determined the tissue distribution of mouse bcrp1 by using RNase protection assays. Fig. 2, a, shows that mouse bcrp1 is highly expressed in kidney and expressed more moderately in liver, colon, heart, spleen, and placenta. The moderate levels of bcrp1 expression in the mouse placenta contrast with the very high levels of BCRP expression previously observed in human placenta (4,22).
|
Effect of GF120918-Mediated Inhibition of Bcrp1 on the Pharmacokinetics of Topotecan in Mice
We studied the pharmacologic role of Bcrp1 in vivo in liver, intestine, kidney, and placenta by analyzing the effects of the Bcrp1 inhibitor GF120918, which is well tolerated by both mice and humans [(23); unpublished data], on the pharmacokinetics of topotecan. Because GF120918 inhibits both P-gp and Bcrp1, we used P-gp-deficient mdr1a/1b(-/-) mice (10) to exclude any confounding effects of P-gp inhibition. Comparison of the expression of bcrp1 in several organs between wild-type and mdr1a/1b(-/-) mice established that expression of bcrp1 was not increased by the loss of P-gp (Fig. 2
, b). To study topotecan bioavailability, we administered GF120918 or vehicle orally to mdr1a/1b(-/-) mice 15 minutes before oral or intravenous administration of topotecan, and we determined the plasma concentration of topotecan as a function of time (Fig. 3, a and c). In GF120918-treated animals, the bioavailability of topotecan given orally, as measured by the AUC, was more than sixfold higher than that in vehicle-treated animals (596 ± 62 versus 96 ± 18 hours • mg/L; P<.001; Fig. 3, a). In GF120918-treated animals, the bioavailability of topotecan given intravenously increased about twofold (406 ± 25 versus 200 ± 29 hours • mg/L; P<.001; Fig. 3, c). Taking the bioavailability of intravenously administered topotecan in vehicle-treated mice as 100%, the bioavailability of topotecan administered orally was 48% ± 9% in vehicle-treated mice and 299% ± 31% in GF120918-treated mice. Thus, Bcrp1 appears to be a major determinant for the bioavailability of topotecan that is administered orally.
|
3). c) Plasma topotecan concentration versus time curves for intravenously administered topotecan in mdr1a/1b(-/-) mice treated with GF120918 or vehicle. Mdr1a/1b mice received an oral dose of GF120918 (50 mg/kg) or vehicle 15 minutes before intravenously administered topotecan (1 mg/kg). Plasma levels of topotecan were determined at 1, 5, 15, 30, 60, 120, and 240 minutes. Results are the means ± standard deviation (n Topotecan is a weak to moderate substrate for P-gp (24). Because the bioavailability of topotecan administered orally to vehicle-treated wild-type mice (41 ± 7 hours • mg/L) is twofold lower than that in vehicle-treated P-gp-deficient mdr1a/1b(-/-) mice (96 ± 18 hours • mg/L) (P<.001; compare lower curves in Fig. 3
, a and b), P-gp also appears to have a role in the bioavailability of topotecan. When wild-type mice, clinically the most relevant model, were treated with GF120918, the bioavailability of topotecan given orally increased ninefold (381 ± 41 versus 41 ± 7 hours • mg/L; P<.001). This result indicates that inhibition of both Bcrp1 and P-gp by GF120918 has a strong effect on uptake of topotecan administered orally, although the resulting availability did not quite reach the level observed in GF120918-treated mdr1a/1b(-/-) mice (596 ± 62 hours • mg/L).
We next determined how GF120918 given orally affected the levels of topotecan excreted in the small intestine. GF120918 was administered orally to mdr1a/1b(-/-) mice; 15 minutes later, [14C]topotecan was administered intravenously; then 15 and 60 minutes later, the amount of [14C]topotecan excreted into the small intestine was measured. Fifteen and 60 minutes after [14C]topotecan was administered to GF120918-treated animals, the percentage of total [14C]topotecan in the small intestinal lumen was about twofold and threefold lower, respectively, and the plasma levels were about 1.5-fold and 2.5-fold higher compared with vehicle-treated animals (Table 1). These observations could reflect diminished excretion of topotecan into the small intestine and/or increased (re-)uptake from the small intestine, both caused by GF120918. To analyze this effect further, we separately determined the hepatobiliary, direct intestinal, and renal excretion of [14C]topotecan. For the measurement of hepatobiliary excretion, anesthetized mdr1a/1b(-/-) mice with a cannulated gallbladder were given GF120918 or vehicle orally 15 minutes before they were given [14C]topotecan intravenously, and the amount of topotecan excreted was determined over the next hour. Hepatobiliary excretion of unchanged topotecan was substantially decreased in GF120918-treated animals for the first 10 minutes after topotecan administration (5.5% ± 2.6%) compared with that of vehicle-treated animals (14.7 % ± 2.4%) (P = .011); however, after about 20 minutes, the excretion rate in both gradually became similar (Fig. 3, d). This observation and the fact that biliary topotecan excretion was not completely blocked by GF120918 suggest that hepatic Bcrp1 was not completely blocked by GF120918 or that there are additional transporters for topotecan in the bile canalicular membrane. In contrast to the hepatobiliary excretion of topotecan, the effect of GF120918 treatment on direct intestinal (7.5% ± 2.5% with GF120918 and 11.6% ± 1.1% with vehicle) or renal (12.6% ± 7.9% with GF120918 and 18.0% ± 10.4% with vehicle) excretion of total radioactivity was not statistically significant. These data suggest that the GF120918-induced high bioavailability of topotecan administered orally results primarily from a combination of its increased intestinal (re-)uptake and decreased hepatobiliary excretion.
|
Pharmacologic Role of Bcrp1 in Placenta
P-gp has been shown to be functionally active in the pharmacologically important blood–brain, blood–testis, and maternal–fetal barriers (10,20). The high expression of BCRP messenger RNA (mRNA) in human placenta and (to a lesser extent) in mouse placenta suggested to us that BCRP might also play a role in protecting fetuses against xenobiotics. So that we could test this hypothesis, pregnant mdr1a/1b(-/-) dams at gestation day 15.5 were administered GF120918 or vehicle orally 2 hours before intravenous administration of [14C]topotecan; 30 minutes after receiving [14C]topotecan, fetuses and maternal plasma were collected. We found that levels of [14C]topotecan were about 3.2-fold higher in fetuses of GF120918-treated dams, whereas at the same time maternal plasma levels were only about 1.6-fold increased (Table 1). These results indicate that mouse Bcrp1 plays an important role in protecting the fetus from topotecan. Because BCRP mRNA expression is much higher in human placenta, the role of BCRP in humans could be even more pronounced. In contrast, for the blood–brain and blood–testis barriers, we found no indication that Bcrp1 has a role in limiting drug penetration, as determined by the distribution of intravenously administered [14C]topotecan or [3H]mitoxantrone in tissues of GF120918-treated and vehicle-treated mdr1a/1b (-/-) mice (data not shown).
|
DISCUSSION |
|---|
|
TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Our data show that Bcrp1 mediates apically directed transport of its drug substrates and support the view that Bcrp1 is important in preventing intestinal (re-)uptake and in mediating hepatobiliary excretion of transported drugs. In these ways, Bcrp1 restricts the bioavailability of orally administered drugs. Moreover, it also protects fetuses through its presence in the maternal–fetal barrier. Our data strongly suggest that Bcrp1 is present and functional in the apical membrane of the intestinal epithelium, in the bile canalicular membrane, and in the membrane of placental trophoblasts that is in contact with the maternal circulation.
The highest levels of bcrp1 mRNA were found in the kidney, suggesting that Bcrp1 might play an important pharmacologic role in the renal excretion of substrate drugs. Our experiments measuring this renal excretion gave highly variable results between individual mice and were essentially not influenced by GF120918 (12.6% ± 7.9% with GF120918 and 18.0% ± 10.4% with vehicle). Studies in patients also have found high variability in renal elimination of topotecan (mean = 40%; range = 26%–80%) (25). A possible explanation for the high variability in renal excretion is that human and murine kidneys could have several transport mechanisms for topotecan that vary extensively among individuals.
Oral administration of drugs is highly preferred for its convenience and potential use on an outpatient basis. However, the therapeutic use of orally administered drugs is frequently limited by the poor and (consequently) highly variable drug bioavailability, factors that are largely determined by the extent to which the drugs are absorbed from the gut, metabolized, and excreted. The narrow therapeutic index of most anticancer drugs implies that this variability will frequently result in excessive toxicity or, conversely, in inadequate efficacy. For instance, for topotecan administered orally, the bioavailability in humans is moderate, with a high inter-patient variation (30% ± 7.7%) (26), and current chemotherapeutic schedules for topotecan are, therefore, mainly based on intravenous administration (27). Our findings suggest that, by combining topotecan administered orally with an effective BCRP (and P-gp) inhibitor, such as GF120918, the bioavailability of topotecan and thus its clinical usefulness might be dramatically improved. We should note that, based on these data, no conclusions can be made about whether the therapeutic index of topotecan (i.e., toxicity of topotecan for a tumor as opposed to its overall toxicity to the organism) is improved by GF120918. However, the ability to inhibit placental Bcrp1 with orally administered GF120918 suggests that a BCRP component of multidrug resistance in clinical tumors could also be blocked with GF120918 administered orally because the systemic exposure to GF120918 is apparently high enough.
Although we cannot exclude the possibility that other, as yet unidentified, GF120918-sensitive topotecan transporters are also contributing to the in vivo pharmacologic effects that we observed, the potential clinical application of GF120918 to improve the bioavailability of topotecan administered orally to patients should be pursued. In fact, we have started clinical trials to test whether it is feasible to increase the bioavailability of topotecan administered orally to patients by blocking BCRP with GF120918. If this procedure is successful in patients as well, it may prove to be applicable to other drugs transported by BCRP.
|
NOTES |
|---|
Supported by grants NKI 97-1434 and NKI 97-1433 (to A. H. Schinkel) and NKI 99-2060 (to J. H. M. Schellens and A. H. Schinkel) from the Dutch Cancer Society.
We thank J. D. Allen, P. Borst, and O. van Tellingen for their suggestions with regard to the manuscript; Glaxo Wellcome (Research Triangle Park, NC) for providing GF120918; SmithKline Beecham Pharmaceuticals (King of Prussia, PA) for providing [14C]topotecan; and E. Nooteboom and A. S. Pfauth for their excellent technical assistance.
|
REFERENCES |
|---|
|
TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;445:152–62.
2 Gros P, Croop J, Housman D. Mammalian multidrug resistance gene: complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell 1986;47:371–80.[CrossRef][Web of Science][Medline]
3
Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992;258:1650–4.
4
Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 1998;95:15665–70.
5
Ross DD, Yang W, Abruzzo LV, Dalton WS, Schneider E, Lage H, et al. Atypical multidrug resistance: breast cancer resistance protein messenger RNA expression in mitoxantrone-selected cell lines. J Natl Cancer Inst 1999;91:429–33.
6
Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res 1999;59:8–13.
7
Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH. The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res 1999;59:4237–41.
8
Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, et al. Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999;59:4559–63.
9 de Bruin M, Miyake K, Litman T, Robey R, Bates SE. Reversal of resistance by GF120918 in cell lines expressing the ABC half-transporter, MXR. Cancer Lett 1999;146:117–26.[CrossRef][Web of Science][Medline]cancerlit;20120409
10 Schinkel AH. The physiological function of drug-transporting P-glycoproteins. Semin Cancer Biol 1997;8:161–70.[CrossRef][Web of Science][Medline]
11 Mayer U, Wagenaar E, Beijnen JH, Smit JW, Meijer DK, van Asperen J, et al. 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 1996;119:1038–44.[Web of Science][Medline]
12 Herben VM, ten Bokkel Huinink WW, Dubbelman AC, Mandjes IA, Groot Y, van Gortel-van Zomeren DM, et al. Phase I and pharmacologic study of sequential intravenous topotecan and oral etoposide. Br J Cancer 1997;76:1500–8.[Web of Science][Medline]cancerlit;98062121
13 Rosing H, van Zomeren DM, Doyle E, ten Bokkel WW, Schellens JH, Bult A, et al. Quantification of topotecan and its metabolite N-desmethyltopotecan in human plasma, urine and faeces by high-performance liquid chromatographic methods. J Chromatogr B Biomed Sci Appl 1999;727:191–203.[CrossRef][Medline]cancerlit;99287183
14 Jonker JW, Wagenaar E, van Deemter L, Gottschlich R, Bender HM, Dasenbrock J, et al. Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug. Br J Pharmacol 1999;127:43–50.[CrossRef][Web of Science][Medline]
15 Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, 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 1994;77:491–502.[CrossRef][Web of Science][Medline]
16 Michiels F, van der Kammen RA, Janssen L, Nolan G, Collard JG. Expression of Rho GTPases using retroviral vectors. Methods Enzymol 2000;325:295–302.[Web of Science][Medline]
17 Kinsella TM, Nolan GP. Episomal vectors rapidly and stably produce high-titer recombinant retrovirus. Hum Gene Ther 1996;7:1405–13.[Web of Science][Medline]cancerlit;97001207
18 Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Invest 1995;96:1698–705.
19
Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 1997;94:2031–5.
20 Meerum Terwogt JM, Beijnen JH, ten Bokkel Huinink WW, Rosing H, Schellens JH. Co-administration of cyclosporin enables oral therapy with paclitaxel [letter] [published erratum appears in Lancet 1998;352:824]. Lancet 1998;352:285.[CrossRef]cancerlit;98352721
21 Smit JW, Huisman MT, van Tellingen O, Wiltshire HR, Schinkel AH. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. J Clin Invest 1999;104:1441–7.[Web of Science][Medline]
22
Allikmets R, Schriml LM, 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 1998;58:5337–9.
23
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 1993;53:4595–602.
24
Chen AY, Yu C, Potmesil M, Wall ME, Wani MC, Liu LF. Camptothecin overcomes MDR1-mediated resistance in human KB carcinoma cells. Cancer Res 1991;51:6039–44.
25 Herben VM, ten Bokkel Huinink WW, Beijnen JH. Clinical pharmacokinetics of topotecan. Clin Pharmacokinet 1996;31:85–102.[Web of Science][Medline]cancerlit;97006638
26 Schellens JH, Creemers GJ, Beijnen JH, Rosing H, de Boer-Dennert M, McDonald M, et al. Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase I inhibitor. Br J Cancer 1996;73:1268–71.[Web of Science][Medline]cancerlit;96222459
27 van Warmerdam LJ, Verweij J, Schellens JH, Rosing H, Davies BE, de Boer-Dennert M, et al. Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 1995;35:237–45.[CrossRef][Web of Science][Medline]cancerlit;95103682
Manuscript received March 7, 2000; revised July 31, 2000; accepted August 7, 2000.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  E Kis, T Nagy, M Jani, E Molnar, J Janossy, O Ujhellyi, K Nemet, K Heredi-Szabo, and P Krajcsi Leflunomide and its metabolite A771726 are high affinity substrates of BCRP: implications for drug resistance Ann Rheum Dis, July 1, 2009; 68(7): 1201 - 1207. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Lagas, M. L.H. Vlaming, and A. H. Schinkel Pharmacokinetic Assessment of Multiple ATP-binding Cassette Transporters: The Power of Combination Knockout Mice Mol. Interv., June 1, 2009; 9(3): 136 - 145. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Zhao, T. J. Raub, G. A. Sawada, S. C. Kasper, J. A. Bacon, A. S. Bridges, and G. M. Pollack Breast Cancer Resistance Protein Interacts with Various Compounds in Vitro, but Plays a Minor Role in Substrate Efflux at the Blood-Brain Barrier Drug Metab. Dispos., June 1, 2009; 37(6): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Marquez, N. E. Caceres, M.-P. Mingeot-Leclercq, P. M. Tulkens, and F. Van Bambeke Identification of the Efflux Transporter of the Fluoroquinolone Antibiotic Ciprofloxacin in Murine Macrophages: Studies with Ciprofloxacin-Resistant Cells Antimicrob. Agents Chemother., June 1, 2009; 53(6): 2410 - 2416. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Oostendorp, E. van de Steeg, C. M. M. van der Kruijssen, J. H. Beijnen, K. E. Kenworthy, A. H. Schinkel, and J. H. M. Schellens Organic Anion-Transporting Polypeptide 1B1 Mediates Transport of Gimatecan and BNP1350 and Can Be Inhibited by Several Classic ATP-Binding Cassette (ABC) B1 and/or ABCG2 Inhibitors Drug Metab. Dispos., April 1, 2009; 37(4): 917 - 923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Giri, S. Agarwal, N. Shaik, G. Pan, Y. Chen, and W. F. Elmquist Substrate-Dependent Breast Cancer Resistance Protein (Bcrp1/Abcg2)-Mediated Interactions: Consideration of Multiple Binding Sites in in Vitro Assay Design Drug Metab. Dispos., March 1, 2009; 37(3): 560 - 570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Molina, S. H. Kaufmann, J. M. Reid, S. D. Rubin, M. Galvez-Peralta, R. Friedman, K. S. Flatten, K. M. Koch, T. M. Gilmer, R. J. Mullin, et al. Evaluation of Lapatinib and Topotecan Combination Therapy: Tissue Culture, Murine Xenograft, and Phase I Clinical Trial Data Clin. Cancer Res., December 1, 2008; 14(23): 7900 - 7908. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Petrovic, J.-H. Wang, and M. Piquette-Miller Effect of Endotoxin on the Expression of Placental Drug Transporters and Glyburide Disposition in Pregnant Rats Drug Metab. Dispos., September 1, 2008; 36(9): 1944 - 1950. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. de Wolf, R. Jansen, H. Yamaguchi, M. de Haas, K. van de Wetering, J. Wijnholds, J. Beijnen, and P. Borst Contribution of the drug transporter ABCG2 (breast cancer resistance protein) to resistance against anticancer nucleosides Mol. Cancer Ther., September 1, 2008; 7(9): 3092 - 3102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Giri, N. Shaik, G. Pan, T. Terasaki, C. Mukai, S. Kitagaki, N. Miyakoshi, and W. F. Elmquist Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) on Pharmacokinetics and Central Nervous System Penetration of Abacavir and Zidovudine in the Mouse Drug Metab. Dispos., August 1, 2008; 36(8): 1476 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. S. Lagas, R. W. Sparidans, R. A. B. van Waterschoot, E. Wagenaar, J. H. Beijnen, and A. H. Schinkel P-Glycoprotein Limits Oral Availability, Brain Penetration, and Toxicity of an Anionic Drug, the Antibiotic Salinomycin Antimicrob. Agents Chemother., March 1, 2008; 52(3): 1034 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, E.-W. Lee, L. Zhou, P. C. K. Leung, D. D. Ross, J. D. Unadkat, and Q. Mao Progesterone Receptor (PR) Isoforms PRA and PRB Differentially Regulate Expression of the Breast Cancer Resistance Protein in Human Placental Choriocarcinoma BeWo Cells Mol. Pharmacol., March 1, 2008; 73(3): 845 - 854. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhou, S. B. Naraharisetti, H. Wang, J. D. Unadkat, M. F. Hebert, and Q. Mao The Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Fetal Distribution of Glyburide in the Pregnant Mouse: An Obstetric-Fetal Pharmacology Research Unit Network and University of Washington Specialized Center of Research Study Mol. Pharmacol., March 1, 2008; 73(3): 949 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Zhang, H. Wang, J. D. Unadkat, and Q. Mao Breast Cancer Resistance Protein 1 Limits Fetal Distribution of Nitrofurantoin in the Pregnant Mouse Drug Metab. Dispos., December 1, 2007; 35(12): 2154 - 2158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Henrich, R. W. Robey, H. R. Bokesch, S. E. Bates, S. Shukla, S. V. Ambudkar, M. Dean, and J. B. McMahon New inhibitors of ABCG2 identified by high-throughput screening Mol. Cancer Ther., December 1, 2007; 6(12): 3271 - 3278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-P. Wu, S. Shukla, A. M. Calcagno, M. D. Hall, M. M. Gottesman, and S. V. Ambudkar Evidence for dual mode of action of a thiosemicarbazone, NSC73306: a potent substrate of the multidrug resistance linked ABCG2 transporter Mol. Cancer Ther., December 1, 2007; 6(12): 3287 - 3296. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Marchetti, R. L. Oostendorp, D. Pluim, M. van Eijndhoven, O. van Tellingen, A. H. Schinkel, R. Versace, J. H. Beijnen, R. Mazzanti, and J. H. Schellens In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2 Mol. Cancer Ther., December 1, 2007; 6(12): 3307 - 3313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Evseenko, P. Murthi, J. W. Paxton, G. Reid, B. S. Emerald, K. M. Mohankumar, P. E. Lobie, S. P. Brennecke, B. Kalionis, and J. A. Keelan The ABC transporter BCRP/ABCG2 is a placental survival factor, and its expression is reduced in idiopathic human fetal growth restriction FASEB J, November 1, 2007; 21(13): 3592 - 3605. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. de Vries, J. Zhao, E. Kroon, T. Buckle, J. H. Beijnen, and O. van Tellingen P-Glycoprotein and Breast Cancer Resistance Protein: Two Dominant Transporters Working Together in Limiting the Brain Penetration of Topotecan Clin. Cancer Res., November 1, 2007; 13(21): 6440 - 6449. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pan, N. Giri, and W. F. Elmquist Abcg2/Bcrp1 Mediates the Polarized Transport of Antiretroviral Nucleosides Abacavir and Zidovudine Drug Metab. Dispos., July 1, 2007; 35(7): 1165 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Yamagata, H. Kusuhara, M. Morishita, K. Takayama, H. Benameur, and Y. Sugiyama Improvement of the Oral Drug Absorption of Topotecan through the Inhibition of Intestinal Xenobiotic Efflux Transporter, Breast Cancer Resistance Protein, by Excipients Drug Metab. Dispos., July 1, 2007; 35(7): 1142 - 1148. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Okumura, M. Katoh, T. Sawada, M. Nakajima, Y. Soeno, H. Yabuuchi, T. Ikeda, C. Tateno, K. Yoshizato, and T. Yokoi Humanization of Excretory Pathway in Chimeric Mice with Humanized Liver Toxicol. Sci., June 1, 2007; 97(2): 533 - 538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Pal, D. Mehn, E. Molnar, S. Gedey, P. Meszaros, T. Nagy, H. Glavinas, T. Janaky, O. von Richter, G. Bathori, et al. Cholesterol Potentiates ABCG2 Activity in a Heterologous Expression System: Improved in Vitro Model to Study Function of Human ABCG2 J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1085 - 1094. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. E.L.M. Kuppens, E. O. Witteveen, R. C. Jewell, S. A. Radema, E. M. Paul, S. G. Mangum, J. H. Beijnen, E. E. Voest, and J. H.M. Schellens A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients Clin. Cancer Res., June 1, 2007; 13(11): 3276 - 3285. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Jonker, S. Musters, M. L. H. Vlaming, T. Plosch, K. E. R. Gooijert, M. J. Hillebrand, H. Rosing, J. H. Beijnen, H. J. Verkade, and A. H. Schinkel Breast cancer resistance protein (Bcrp1/Abcg2) is expressed in the harderian gland and mediates transport of conjugated protoporphyrin IX Am J Physiol Cell Physiol, June 1, 2007; 292(6): C2204 - C2212. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Linton Structure and Function of ABC Transporters Physiology, April 1, 2007; 22(2): 122 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Q. Xia, N. Liu, G. T. Miwa, and L.-S. Gan Interactions of Cyclosporin A with Breast Cancer Resistance Protein Drug Metab. Dispos., April 1, 2007; 35(4): 576 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Evseenko, J. W. Paxton, and J. A. Keelan Independent Regulation of Apical and Basolateral Drug Transporter Expression and Function in Placental Trophoblasts by Cytokines, Steroids, and Growth Factors Drug Metab. Dispos., April 1, 2007; 35(4): 595 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. S. Lee, H.-E. Jeong, J.-M. Yi, H.-J. Jung, J.-E. Jang, E.-Y. Kim, S.-J. Lee, and J.-G. Shin Identification and Functional Assessment of BCRP Polymorphisms in a Korean Population Drug Metab. Dispos., April 1, 2007; 35(4): 623 - 632. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang and M. E. Morris Effects of the Flavonoid Chrysin on Nitrofurantoin Pharmacokinetics in Rats: Potential Involvement of ABCG2 Drug Metab. Dispos., February 1, 2007; 35(2): 268 - 274. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, X. Wu, K. Hudkins, A. Mikheev, H. Zhang, A. Gupta, J. D. Unadkat, and Q. Mao Expression of the breast cancer resistance protein (Bcrp1/Abcg2) in tissues from pregnant mice: effects of pregnancy and correlations with nuclear receptors. Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1295 - E1304. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Turner, J. L. Gump, C. Zhang, J. M. Cook, D. Marchion, L. Hazlehurst, P. Munster, M. J. Schell, W. S. Dalton, and D. M. Sullivan ABCG2 expression, function, and promoter methylation in human multiple myeloma Blood, December 1, 2006; 108(12): 3881 - 3889. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. K. W. To, Z. Zhan, and S. E. Bates Aberrant Promoter Methylation of the ABCG2 Gene in Renal Carcinoma Mol. Cell. Biol., November 15, 2006; 26(22): 8572 - 8585. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Staud, Z. Vackova, K. Pospechova, P. Pavek, M. Ceckova, A. Libra, L. Cygalova, P. Nachtigal, and Z. Fendrich Expression and Transport Activity of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Dually Perfused Rat Placenta and HRP-1 Cell Line J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 53 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Sarkadi, L. Homolya, G. Szakacs, and A. Varadi Human Multidrug Resistance ABCB and ABCG Transporters: Participation in a Chemoimmunity Defense System. Physiol Rev, October 1, 2006; 86(4): 1179 - 1236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Seamon, C. A. Rugg, S. Emanuel, A. M. Calcagno, S. V. Ambudkar, S. A. Middleton, J. Butler, V. Borowski, and L. M. Greenberger Role of the ABCG2 drug transporter in the resistance and oral bioavailability of a potent cyclin-dependent kinase/Aurora kinase inhibitor. Mol. Cancer Ther., October 1, 2006; 5(10): 2459 - 2467. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Szatmari, G. Vamosi, P. Brazda, B. L. Balint, S. Benko, L. Szeles, V. Jeney, C. Ozvegy-Laczka, A. Szanto, E. Barta, et al. Peroxisome Proliferator-activated Receptor {gamma}-regulated ABCG2 Expression Confers Cytoprotection to Human Dendritic Cells J. Biol. Chem., August 18, 2006; 281(33): 23812 - 23823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Choudhuri and C. D. Klaassen Structure, Function, Expression, Genomic Organization, and Single Nucleotide Polymorphisms of Human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) Efflux Transporters International Journal of Toxicology, July 1, 2006; 25(4): 231 - 259. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Saito, H. Hirano, H. Nakagawa, T. Fukami, K. Oosumi, K. Murakami, H. Kimura, T. Kouchi, M. Konomi, E. Tao, et al. A New Strategy of High-Speed Screening and Quantitative Structure-Activity Relationship Analysis to Evaluate Human ATP-Binding Cassette Transporter ABCG2-Drug Interactions J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1114 - 1124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Huang, Y. Wang, and S. Grimm ATP-DEPENDENT TRANSPORT OF ROSUVASTATIN IN MEMBRANE VESICLES EXPRESSING BREAST CANCER RESISTANCE PROTEIN Drug Metab. Dispos., May 1, 2006; 34(5): 738 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Leggas, J. C. Panetta, Y. Zhuang, J. D. Schuetz, B. Johnston, F. Bai, B. Sorrentino, S. Zhou, P. J. Houghton, and C. F. Stewart Gefitinib Modulates the Function of Multiple ATP-Binding Cassette Transporters In vivo. Cancer Res., May 1, 2006; 66(9): 4802 - 4807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Wang, L. Zhou, A. Gupta, R. R. Vethanayagam, Y. Zhang, J. D. Unadkat, and Q. Mao Regulation of BCRP/ABCG2 expression by progesterone and 17beta-estradiol in human placental BeWo cells Am J Physiol Endocrinol Metab, May 1, 2006; 290(5): E798 - E807. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Evseenko, J. W. Paxton, and J. A. Keelan ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1357 - R1365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. M. zu Schwabedissen, M. Grube, A. Dreisbach, G. Jedlitschky, K. Meissner, K. Linnemann, C. Fusch, C. A. Ritter, U. Volker, and H. K. Kroemer EPIDERMAL GROWTH FACTOR-MEDIATED ACTIVATION OF THE MAP KINASE CASCADE RESULTS IN ALTERED EXPRESSION AND FUNCTION OF ABCG2 (BCRP) Drug Metab. Dispos., April 1, 2006; 34(4): 524 - 533. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-i. Nezasa, X. Tian, M. J. Zamek-Gliszczynski, N. J. Patel, T. J. Raub, and K. L. R. Brouwer ALTERED HEPATOBILIARY DISPOSITION OF 5 (AND 6)-CARBOXY-2',7'-DICHLOROFLUORESCEIN IN Abcg2 (Bcrp1) AND Abcc2 (Mrp2) KNOCKOUT MICE Drug Metab. Dispos., April 1, 2006; 34(4): 718 - 723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Merino, A. I. Alvarez, M. M. Pulido, A. J. Molina, A. H. Schinkel, and J. G. Prieto BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) TRANSPORTS FLUOROQUINOLONE ANTIBIOTICS AND AFFECTS THEIR ORAL AVAILABILITY, PHARMACOKINETICS, AND MILK SECRETION Drug Metab. Dispos., April 1, 2006; 34(4): 690 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. Henrich, H. R. Bokesch, M. Dean, S. E. Bates, R. W. Robey, E. I. Goncharova, J. A. Wilson, and J. B. McMahon A High-Throughput Cell-Based Assay for Inhibitors of ABCG2 Activity J Biomol Screen, March 1, 2006; 11(2): 176 - 183. [Abstract] [PDF]
|
|
|
|
 |
|
 A. E.v. Herwaarden, E. Wagenaar, B. Karnekamp, G. Merino, J. W. Jonker, and A. H. Schinkel Breast cancer resistance protein (Bcrp1/Abcg2) reduces systemic exposure of the dietary carcinogens aflatoxin B1, IQ and Trp-P-1 but also mediates their secretion into breast milk Carcinogenesis, January 1, 2006; 27(1): 123 - 130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Rudek, M. Zhao, N. F. Smith, R. W. Robey, P. He, G. Hallur, S. Khan, M. Hidalgo, A. Jimeno, A. D. Colevas, et al. In vitro and In vivo Clinical Pharmacology of Dimethyl Benzoylphenylurea, a Novel Oral Tubulin-Interactive Agent Clin. Cancer Res., December 1, 2005; 11(23): 8503 - 8511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Dilda, A. S. Don, K. M. Tanabe, V. J. Higgins, J. D. Allen, I. W. Dawes, and P. J. Hogg Mechanism of Selectivity of an Angiogenesis Inhibitor From Screening a Genome-Wide Set of Saccharomyces cerevisiae Deletion Strains J Natl Cancer Inst, October 19, 2005; 97(20): 1539 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. A. Mathias, J. Hitti, and J. D. Unadkat P-glycoprotein and breast cancer resistance protein expression in human placentae of various gestational ages Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2005; 289(4): R963 - R969. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Kalabis, A. Kostaki, M. H. Andrews, S. Petropoulos, W. Gibb, and S. G. Matthews Multidrug Resistance Phosphoglycoprotein (ABCB1) in the Mouse Placenta: Fetal Protection Biol Reprod, October 1, 2005; 73(4): 591 - 597. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hirano, K. Maeda, S. Matsushima, Y. Nozaki, H. Kusuhara, and Y. Sugiyama Involvement of BCRP (ABCG2) in the Biliary Excretion of Pitavastatin Mol. Pharmacol., September 1, 2005; 68(3): 800 - 807. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mirchandani, H. Hochster, A. Hamilton, L. Liebes, H. Yee, J. P. Curtin, S. Lee, J. Sorich, C. Dellenbaugh, and F. M. Muggia Phase I Study of Combined Pegylated Liposomal Doxorubicin with Protracted Daily Topotecan for Ovarian Cancer Clin. Cancer Res., August 15, 2005; 11(16): 5912 - 5919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-f. Zhou, X. Yang, Q. Wang, R. A. Coburn, and M. E. Morris EFFECTS OF DIHYDROPYRIDINES AND PYRIDINES ON MULTIDRUG RESISTANCE MEDIATED BY BREAST CANCER RESISTANCE PROTEIN: IN VITRO AND IN VIVO STUDIES Drug Metab. Dispos., August 1, 2005; 33(8): 1220 - 1228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Meyer zu Schwabedissen, G. Jedlitschky, M. Gratz, S. Haenisch, K. Linnemann, C. Fusch, I. Cascorbi, and H. K. Kroemer VARIABLE EXPRESSION OF MRP2 (ABCC2) IN HUMAN PLACENTA: INFLUENCE OF GESTATIONAL AGE AND CELLULAR DIFFERENTIATION Drug Metab. Dispos., July 1, 2005; 33(7): 896 - 904. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. R. Vethanayagam, H. Wang, A. Gupta, Y. Zhang, F. Lewis, J. D. Unadkat, and Q. Mao FUNCTIONAL ANALYSIS OF THE HUMAN VARIANTS OF BREAST CANCER RESISTANCE PROTEIN: I206L, N590Y, AND D620N Drug Metab. Dispos., June 1, 2005; 33(6): 697 - 705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. A. Sesink, I. C. W. Arts, V. C. J. de Boer, P. Breedveld, J. H. M. Schellens, P. C. H. Hollman, and F. G. M. Russel Breast Cancer Resistance Protein (Bcrp1/Abcg2) Limits Net Intestinal Uptake of Quercetin in Rats by Facilitating Apical Efflux of Glucuronides Mol. Pharmacol., June 1, 2005; 67(6): 1999 - 2006. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Merino, J. W. Jonker, E. Wagenaar, M. M. Pulido, A. J. Molina, A. I. Alvarez, and A. H. Schinkel TRANSPORT OF ANTHELMINTIC BENZIMIDAZOLE DRUGS BY BREAST CANCER RESISTANCE PROTEIN (BCRP/ABCG2) Drug Metab. Dispos., May 1, 2005; 33(5): 614 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Q. Xia, N. Liu, D. Yang, G. Miwa, and L.-S. Gan EXPRESSION, LOCALIZATION, AND FUNCTIONAL CHARACTERISTICS OF BREAST CANCER RESISTANCE PROTEIN IN CACO-2 CELLS Drug Metab. Dispos., May 1, 2005; 33(5): 637 - 643. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Merino, J. W. Jonker, E. Wagenaar, A. E. van Herwaarden, and A. H. Schinkel The Breast Cancer Resistance Protein (BCRP/ABCG2) Affects Pharmacokinetics, Hepatobiliary Excretion, and Milk Secretion of the Antibiotic Nitrofurantoin Mol. Pharmacol., May 1, 2005; 67(5): 1758 - 1764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Merino, A. E. van Herwaarden, E. Wagenaar, J. W. Jonker, and A. H. Schinkel Sex-Dependent Expression and Activity of the ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (BCRP/ABCG2) in Liver Mol. Pharmacol., May 1, 2005; 67(5): 1765 - 1771. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kolwankar, D. D. Glover, J. A. Ware, and T. S. Tracy EXPRESSION AND FUNCTION OF ABCB1 AND ABCG2 IN HUMAN PLACENTAL TISSUE Drug Metab. Dispos., April 1, 2005; 33(4): 524 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Breedveld, D. Pluim, G. Cipriani, P. Wielinga, O. van Tellingen, A. H. Schinkel, and J. H.M. Schellens The Effect of Bcrp1 (Abcg2) on the In vivo Pharmacokinetics and Brain Penetration of Imatinib Mesylate (Gleevec): Implications for the Use of Breast Cancer Resistance Protein and P-Glycoprotein Inhibitors to Enable the Brain Penetration of Imatinib in Patients Cancer Res., April 1, 2005; 65(7): 2577 - 2582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhou, Y. Zong, P. A. Ney, G. Nair, C. F. Stewart, and B. P. Sorrentino Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels Blood, March 15, 2005; 105(6): 2571 - 2576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, X. Wang, K. Sagawa, and M. E. Morris FLAVONOIDS CHRYSIN AND BENZOFLAVONE, POTENT BREAST CANCER RESISTANCE PROTEIN INHIBITORS, HAVE NO SIGNIFICANT EFFECT ON TOPOTECAN PHARMACOKINETICS IN RATS OR MDR1A/1B (-/-) MICE Drug Metab. Dispos., March 1, 2005; 33(3): 341 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Adachi, H. Suzuki, A. H. Schinkel, and Y. Sugiyama Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen Mol. Pharmacol., March 1, 2005; 67(3): 923 - 928. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. F. K. Ejendal and C. A. Hrycyna Differential Sensitivities of the Human ATP-Binding Cassette Transporters ABCG2 and P-Glycoprotein to Cyclosporin A Mol. Pharmacol., March 1, 2005; 67(3): 902 - 911. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kobayashi, I. Ieiri, T. Hirota, H. Takane, S. Maegawa, J. Kigawa, H. Suzuki, E. Nanba, M. Oshimura, N. Terakawa, et al. FUNCTIONAL ASSESSMENT OF ABCG2 (BCRP) GENE POLYMORPHISMS TO PROTEIN EXPRESSION IN HUMAN PLACENTA Drug Metab. Dispos., January 1, 2005; 33(1): 94 - 101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-J. Lee, H. Kusuhara, J. W. Jonker, A. H. Schinkel, and Y. Sugiyama Investigation of Efflux Transport of Dehydroepiandrosterone Sulfate and Mitoxantrone at the Mouse Blood-Brain Barrier: A Minor Role of Breast Cancer Resistance Protein J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 44 - 52. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Pavek, G. Merino, E. Wagenaar, E. Bolscher, M. Novotna, J. W. Jonker, and A. H. Schinkel Human Breast Cancer Resistance Protein: Interactions with Steroid Drugs, Hormones, the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine, and Transport of Cimetidine J. Pharmacol. Exp. Ther., January 1, 2005; 312(1): 144 - 152. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. F. Stewart, M. Leggas, J. D. Schuetz, J. C. Panetta, P. J. Cheshire, J. Peterson, N. Daw, J. J. Jenkins III, R. Gilbertson, G. S. Germain, et al. Gefitinib Enhances the Antitumor Activity and Oral Bioavailability of Irinotecan in Mice Cancer Res., October 15, 2004; 64(20): 7491 - 7499. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Mizuno, M. Suzuki, H. Kusuhara, H. Suzuki, K. Takeuchi, T. Niwa, J. W. Jonker, and Y. Sugiyama 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., September 1, 2004; 32(9): 898 - 901. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. de Jong, S. Marsh, R. H. J. Mathijssen, C. King, J. Verweij, A. Sparreboom, and H. L. McLeod ABCG2 Pharmacogenetics: Ethnic Differences in Allele Frequency and Assessment of Influence on Irinotecan Disposition Clin. Cancer Res., September 1, 2004; 10(17): 5889 - 5894. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Breedveld, N. Zelcer, D. Pluim, O. Sonmezer, M. M. Tibben, J. H. Beijnen, A. H. Schinkel, O. van Tellingen, P. Borst, and J. H. M. Schellens Mechanism of the Pharmacokinetic Interaction between Methotrexate and Benzimidazoles: Potential Role for Breast Cancer Resistance Protein in Clinical Drug-Drug Interactions Cancer Res., August 15, 2004; 64(16): 5804 - 5811. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Ward and L. M. Azzarano Preclinical Pharmacokinetic Properties of the P-Glycoprotein Inhibitor GF120918A (HCl salt of GF120918, 9,10-Dihydro-5-methoxy-9-oxo-N-[4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]phenyl]-4-acridine-carboxamide) in the Mouse, Rat, Dog, and Monkey J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 703 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Bates, W. Y. Medina-Perez, G. Kohlhagen, S. Antony, T. Nadjem, R. W. Robey, and Y. Pommier ABCG2 Mediates Differential Resistance to SN-38 (7-Ethyl-10-hydroxycamptothecin) and Homocamptothecins J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 836 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Polli, T. M. Baughman, J. E. Humphreys, K. H. Jordan, A. L. Mote, L. O. Webster, R. J. Barnaby, G. Vitulli, L. Bertolotti, K. D. Read, et al. THE SYSTEMIC EXPOSURE OF AN N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST IS LIMITED IN MICE BY THE P-GLYCOPROTEIN AND BREAST CANCER RESISTANCE PROTEIN EFFLUX TRANSPORTERS Drug Metab. Dispos., July 1, 2004; 32(7): 722 - 726. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gupta, Y. Zhang, J. D. Unadkat, and Q. Mao HIV Protease Inhibitors Are Inhibitors but Not Substrates of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 334 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ozvegy-Laczka, T. Heged""s, G. Varady, O. Ujhelly, J. D. Schuetz, A. Varadi, G. Keri, L. Orfi, K. Nemet, and B. Sarkadi High-Affinity Interaction of Tyrosine Kinase Inhibitors with the ABCG2 Multidrug Transporter Mol. Pharmacol., June 1, 2004; 65(6): 1485 - 1495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhang, X. Yang, and M. E. Morris Flavonoids Are Inhibitors of Breast Cancer Resistance Protein (ABCG2)-Mediated Transport Mol. Pharmacol., May 1, 2004; 65(5): 1208 - 1216. [Abstract] [Full Text]
|
|
|
|
|
|
S. U. C. Sankatsing, J. H. Beijnen, A. H. Schinkel, J. M. A. Lange, and J. M. Prins P Glycoprotein in Human Immunodeficiency Virus Type 1 Infection and Therapy Antimicrob. Agents Chemother., April 1, 2004; 48(4): 1073 - 1081. [Full Text] [PDF]
|
|
|
|
|
|
P. L. R. Ee, S. Kamalakaran, D. Tonetti, X. He, D. D. Ross, and W. T. Beck Identification of a Novel Estrogen Response Element in the Breast Cancer Resistance Protein (ABCG2) Gene Cancer Res., February 15, 2004; 64(4): 1247 - 1251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. S. Pang MODELING OF INTESTINAL DRUG ABSORPTION: ROLES OF TRANSPORTERS AND METABOLIC ENZYMES (FOR THE GILLETTE REVIEW SERIES) Drug Metab. Dispos., December 1, 2003; 31(12): 1507 - 1519. [Full Text] [PDF]
|
|
|
|
 |
|
 C G Dietrich, A Geier, and R P J Oude Elferink ABC of oral bioavailability: transporters as gatekeepers in the gut Gut, December 1, 2003; 52(12): 1788 - 1795. [Full Text] [PDF]
|
|
|
|
|
|
T. Nakanishi, L. A. Doyle, B. Hassel, Y. Wei, K. S. Bauer, S. Wu, D. W. Pumplin, H.-B. Fang, and D. D. Ross Functional Characterization of Human Breast Cancer Resistance Protein (BCRP, ABCG2) Expressed in the Oocytes of Xenopus laevis Mol. Pharmacol., December 1, 2003; 64(6): 1452 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. van Herwaarden, J. W. Jonker, E. Wagenaar, R. F. Brinkhuis, J. H. M. Schellens, J. H. Beijnen, and A. H. Schinkel The Breast Cancer Resistance Protein (Bcrp1/Abcg2) Restricts Exposure to the Dietary Carcinogen 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine Cancer Res., October 1, 2003; 63(19): 6447 - 6452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Imai, S. Asada, S. Tsukahara, E. Ishikawa, T. Tsuruo, and Y. Sugimoto Breast Cancer Resistance Protein Exports Sulfated Estrogens but Not Free Estrogens Mol. Pharmacol., September 1, 2003; 64(3): 610 - 618. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama Impact of Drug Transporter Studies on Drug Discovery and Development Pharmacol. Rev., September 1, 2003; 55(3): 425 - 461. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z.-S. Chen, R. W. Robey, M. G. Belinsky, I. Shchaveleva, X.-Q. Ren, Y. Sugimoto, D. D. Ross, S. E. Bates, and G. D. Kruh Transport of Methotrexate, Methotrexate Polyglutamates, and 17{beta}-Estradiol 17-({beta}-D-glucuronide) by ABCG2: Effects of Acquired Mutations at R482 on Methotrexate Transport Cancer Res., July 15, 2003; 63(14): 4048 - 4054. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shimano, M. Satake, A. Okaya, J. Kitanaka, N. Kitanaka, M. Takemura, M. Sakagami, N. Terada, and T. Tsujimura Hepatic Oval Cells Have the Side Population Phenotype Defined by Expression of ATP-Binding Cassette Transporter ABCG2/BCRP1 Am. J. Pathol., July 1, 2003; 163(1): 3 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Suzuki, H. Suzuki, Y. Sugimoto, and Y. Sugiyama ABCG2 Transports Sulfated Conjugates of Steroids and Xenobiotics J. Biol. Chem., June 13, 2003; 278(25): 22644 - 22649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R O. Elferink Cholestasis Gut, May 1, 2003; 52(90002): ii42 - 48. [Abstract] [Full Text]
|
|
|
|
|
|
J. D. Allen, S. C. van Dort, M. Buitelaar, O. van Tellingen, and A. H. Schinkel Mouse Breast Cancer Resistance Protein (Bcrp1/Abcg2) Mediates Etoposide Resistance and Transport, but Etoposide Oral Availability Is Limited Primarily by P-glycoprotein Cancer Res., March 15, 2003; 63(6): 1339 - 1344. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. H. Stephens, J. Tanianis-Hughes, N. B. Higgs, M. Humphrey, and G. Warhurst Region-Dependent Modulation of Intestinal Permeability by Drug Efflux Transporters: In Vitro Studies in mdr1a(-/-) Mouse Intestine J. Pharmacol. Exp. Ther., December 1, 2002; 303(3): 1095 - 1101. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.M.F. Kruijtzer, J.H. Beijnen, and J.H.M. Schellens Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview Oncologist, December 1, 2002; 7(6): 516 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Jonker, M. Buitelaar, E. Wagenaar, M. A. van der Valk, G. L. Scheffer, R. J. Scheper, T. Plosch, F. Kuipers, R. P. J. O. Elferink, H. Rosing, et al. The breast cancer resistance protein protects against a major chlorophyll-derived dietary phototoxin and protoporphyria PNAS, November 26, 2002; 99(24): 15649 - 15654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zhou, J. J. Morris, Y. Barnes, L. Lan, J. D. Schuetz, and B. P. Sorrentino Bcrp1 gene expression is required for normal numbers of side population stem cells in mice, and confers relative protection to mitoxantrone in hematopoietic cells in vivo PNAS, September 17, 2002; 99(19): 12339 - 12344. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Hudes Boosting Bioavailability of Topotecan: What Do We Gain? J. Clin. Oncol., July 1, 2002; 20(13): 2918 - 2919. [Full Text] [PDF]
|
|
|
|
|
|
C. M.F. Kruijtzer, J. H. Beijnen, H. Rosing, W. W. ten Bokkel Huinink, M. Schot, R. C. Jewell, E. M. Paul, and J. H.M. Schellens Increased Oral Bioavailability of Topotecan in Combination With the Breast Cancer Resistance Protein and P-Glycoprotein Inhibitor GF120918 J. Clin. Oncol., July 1, 2002; 20(13): 2943 - 2950. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||