| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Priority Reports |
Divisions of 1 Experimental Therapy, 2 Molecular Biology, 3 Clinical Chemistry, and 4 Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands and 5 Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
Requests for reprints: Jan H.M. Schellens, Department of Medical Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-512-2569; Fax: 31-20-512-2572; E-mail: jhm{at}nki.nl.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Key Words: BCRP • imatinib mesylate • brain penetration • pantoprazole • elacridar
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Primary tumors of the central nervous system (CNS; e.g., glioblastoma multiforme) are, respectively, the third and fourth leading cause of cancer-related death among male and female young adults. Moreover, primary brain tumors are the most common solid tumor of childhood and the second leading cause of cancer death in children after leukemia. Unfortunately, the treatment of primary CNS tumors is often limited by low distribution of antitumor agents into the brain as a result of a proficient blood–brain barrier containing various efflux transporters. These include P-glycoprotein (P-gp; MDR1, ABCB1) and Breast Cancer Resistance Protein (BCRP; ABCG2), which can eliminate xenobiotics from the brain against a concentration gradient, thereby limiting CNS exposure to these compounds (5–7). A limited penetration of imatinib into the cerebrospinal fluid of humans and nonhuman primates has been reported (8–10). Preclinical in vitro and in vivo studies have shown that P-gp plays an important role in the transport of imatinib and limits the distribution of imatinib to the brain (11, 12). These studies also showed that P-gp inhibitors, like cyclosporin A and zosuquidar (LY335979), can effectively block the P-gp–mediated transport of imatinib in vitro and improve the brain penetration of imatinib in mice. Houghton et al. (13) recently showed that imatinib mesylate potently reverses BCRP-mediated resistance, but they concluded that it is not a BCRP substrate for efflux. However, as imatinib is a lipophilic drug, we hypothesized that imatinib is also a BCRP substrate. To test this hypothesis and extend the observations of Houghton et al. (13) and the recent finding of Burger et al. (14) that imatinib is a BCRP substrate in drug accumulation assays, we first investigated in Sf9-BCRP membrane vesicles whether imatinib could inhibit the BCRP-mediated transport of methotrexate (MTX; ref. 15). Secondly, we studied in Madin-Darby canine kidney strain II (MDCKII)-Bcrp1 monolayers whether imatinib is transported by Bcrp1. In addition, we studied in the MDCKII-Bcrp1 monolayers the effect of the P-gp and BCRP inhibitors elacridar and pantoprazole (15) on the transport of imatinib. Finally, we studied in Bcrp1 knockout, Mdr1a/1b knockout, and wild-type mice the role of Bcrp1, relative to P-gp, in the in vivo pharmacokinetics and brain penetration of i.v. and p.o. imatinib in the absence or presence of P-gp and BCRP inhibitors.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
Preparation of membrane vesicles and vesicular transport assays. Membrane vesicles from Sf9 cells and HEK293 cells were prepared and vesicular transport assays done as described before (15, 16) . The ATP-dependent uptake of [3H]MTX into Sf9-BCRP, and of [3H]E217ßG into Sf9-MRP1-3 and HEK293-MRP4 membrane vesicles, and of [3H]alaninyl-d4TMP into HEK293-MRP5 membrane vesicles in the absence and presence of varying concentrations of imatinib mesylate was studied following the rapid filtration method as previously described (15, 16).
Transport across Madin-Darby canine kidney strain II monolayers. The MDCKII cells were cultured in DMEM supplemented with 10% FCS and 100 units penicillin/streptomycin per milliliter. Cells were grown at 37°C with 5% CO2 under humidifying conditions. Polarized MDCKII cells stably expressing human MRP2 (ABCC2) or murine Bcrp1 (Abcg2) cDNA have been described before (15, 17) . Transepithelial transport assays were done as previously described (15).
Animals. Animals used in this study were male Bcrp1–/– (Bcrp1 knockout), Mdr1a/1b–/– (P-gp knockout), and wild-type mice of a comparable genetic background (FVB) between 9 and 14 weeks of age. Mice were housed and handled according to institutional guidelines complying with Dutch legislation as described before (15).
Drug solutions. A mixture of imatinib mesylate and [14C]imatinib (
3 µCi) was diluted with 0.9% NaCl to a final concentration of 1.6 mg/mL for i.v. administration or to a final concentration of 12.8 mg/mL for p.o. administration. A vial of pantoprazole (Pantozol, 40 mg) was diluted with 0.9% NaCl to a final concentration of 8 mg/mL. Elacridar was suspended at 10 mg/mL in a mixture of hydroxypropylmethylcellulose (10 g/L)/2% Tween 80/H2O [0.5:1:98.5 (v/v/v)] for p.o. administration.
Drug administration and analysis. All mice received [14C]imatinib mesylate either by i.v. administration in the tail vein at a dose of 12.5 mg/kg or by p.o. administration at a dose of 100 mg/kg. The study comprised nine different study groups:
Blood samples (30 µL) were taken from the tail vein at 5, 15, 30, 60, 90, and 120 minutes after i.v. administration of imatinib, or at 10, 20, 40, 60, 120, 180, and 240 minutes after p.o. administration of imatinib. After the last sampling time point, animals were anesthetized with methoxyflurane, their remaining blood collected by cardiac puncture, and organs were removed after sacrifice by cervical dislocation. Coagulation of blood was prevented by use of heparinized capillaries for blood sampling. The plasma fraction of the blood samples was collected after centrifugation at 3,000 x g for 5 minutes. The organs were homogenized in 4% (w/v) bovine serum albumin. Radioactivity in the plasma samples and the tissue homogenates was determined by liquid scintillation counting (Tri-Carb 2100 CA Liquid Scintillation analyzer, Canberra Packard, Groningen, the Netherlands).
Pharmacokinetic and statistical analyses. Pharmacokinetic parameters after administration of imatinib were calculated by noncompartmental methods using the software package MW (version 3.02, MediWare, Groningen, the Netherlands).
The area under the plasma concentration–time curve (AUC) was calculated from 0 to 120 minutes (i.v. imatinib) or from 0 to 240 minutes (p.o. imatinib) using the linear-logarithmic trapezoidal method. The clearance was calculated by the formula Cl = dose / AUC (15).
The two-sided unpaired Student's t test was used to assess the statistical significance of difference between two sets of data. Results are presented as means ± SD. Differences were considered to be statistically significant when P < 0.05.
Calculation of brain penetration of imatinib. We determined the brain concentration of imatinib by measuring the radioactivity in whole brain homogenates, which were collected 2 hours after administration of i.v. imatinib or 4 hours after administration of p.o. imatinib. Because imatinib has a low CNS distribution (8–10), we subtracted the concentration of imatinib in the brain vascular space (i.e., 1.4% of the plasma concentration at t = 2 hours for i.v. imatinib or at t = 4 hours for p.o. imatinib) from the brain concentration found in whole brain homogenates (11). We then calculated the brain penetration of i.v. imatinib by determining the imatinib brain concentration at t = 2 hours relative to the plasma AUC (0-2 hours), as the AUC better reflects the overall imatinib exposure to the brain than the plasma concentration at 2 hours after administration. The brain penetration of p.o. imatinib was calculated in the same manner using the AUC (0-4 hours).
|
Results and Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
0.2 µmol/L), confirming that imatinib potently inhibits BCRP-mediated transport, as shown by Houghton et al. (13). Imatinib (up to 10 µmol/L concentrations) did not affect the MRP-mediated transport of E217ßG, neither in Sf9 membrane vesicles, containing MRP1, 2, or 3, nor in HEK293 membrane vesicles, containing MRP4 (data not shown). The MRP5-mediated transport of alaninyl-d4TMP (16) was not affected either in membrane vesicles from HEK293 cells, stably overexpressing MRP5 (data not shown).
|
20% net active transport per h), which was saturable at concentrations above 10 µmol/L (Fig. 2A). Imatinib was not transported by MRP2 (data not shown). As shown by Dai et al. (11), the net active transport of 1.9 µmol/L imatinib by P-gp in MDCKII cells was 6% per hour; thus, Bcrp1 seems to transport imatinib at least as efficiently as P-gp.
|
Role of Bcrp1 in the clearance of imatinib in mice. In cancer patients, imatinib is administered p.o., but to exclude any variation at the absorption level, we initially administered [14C]imatinib mesylate (12.5 mg/kg) i.v. to Bcrp1–/– (Bcrp1 knockout), Mdr1a/1b–/– (P-gp knockout), and wild-type mice. We determined the clearance after measurement of imatinib plasma concentrations by total radioactivity over a 120-minute time period. As shown in Fig. 3A, the clearance of i.v. imatinib was 1.6-fold decreased in Bcrp1 knockout mice compared with control mice (P < 0.01). In P-gp knockout mice, the clearance of i.v. imatinib was 1.25-fold decreased compared with control mice (P < 0.01). These results show that Bcrp1 plays an important, and maybe even a more prominent role than P-gp, in the clearance of i.v. imatinib in mice.
|
Effect of Bcrp1 on the brain penetration of intravenous imatinib in mice. As shown in Fig. 4A, the brain penetration of i.v. imatinib in Bcrp1 knockout mice was 2.5-fold increased compared with control mice, whereas in P-gp knockout mice this was 3.6-fold increased. These results show that Bcrp1 in the blood-brain barrier limits the brain penetration of imatinib, but to a lower extent than P-gp does.
|
70% to 80% (18), the role for Bcrp1 in the brain penetration of imatinib is likely more important than suggested by the 1.2-fold increase in control mice compared with P-gp knockout mice. Thus, co-administration of elacridar effectively increases the brain penetration of imatinib, by inhibition of both P-gp and Bcrp1 at the blood-brain barrier. The brain penetration of i.v. imatinib in wild-type mice pretreated with pantoprazole was 1.8-fold increased compared with control mice (Fig. 4A). In P-gp knockout mice pretreated with pantoprazole, the imatinib brain penetration was 4.7-fold increased compared with control wild-type mice and 1.3-fold compared with control P-gp knockout mice. Thus, when P-gp is absent, additional inhibition of Bcrp1 by pantoprazole further increases the brain penetration of imatinib. In Bcrp1 knockout mice pretreated with pantoprazole, the brain penetration of imatinib increased 2.3-fold compared with control mice and was not significantly different from control Bcrp1 knockout mice. These results suggest that co-administration of pantoprazole increases the brain penetration of imatinib in mice by inhibition of Bcrp1 and not by P-gp inhibition.
Effect of pantoprazole on the brain penetration of p.o. imatinib in mice. Both pantoprazole and imatinib are usually given as p.o. formulation to patients. Therefore, we also administered p.o. [14C]imatinib mesylate (100 mg/kg) to wild-type mice, which were treated with p.o. pantoprazole or with p.o. NaCl 0.9% only as control. As shown in Fig. 4B, the brain penetration of p.o. imatinib in mice treated with p.o. pantoprazole was 5.2-fold increased compared with control mice. These results suggest that co-administration of p.o. pantoprazole and p.o. imatinib is more effective than co-administration of i.v. pantoprazole and i.v. imatinib to increase the brain penetration of imatinib. However, we cannot exclude that other mechanisms, such as Cyp3a-mediated metabolism, also play a role. Ketoconazole, a potent CYP3A4 inhibitor, was shown to significantly decrease the apparent clearance of p.o. imatinib with a mean reduction of 29% and decrease the AUC (0-24 hours) of the metabolite CGP74588by 13% in patients (19). As pantoprazole only weakly inhibits human CYP3A4 (20), interference at the CYP3A4 level is most likely less important than for ketoconazole. To further elucidate whether Cyp3a metabolism of imatinib is inhibited in mice when pantoprazole is co-administered, additional studies in which parental imatinib and metabolites are quantitated need to be conducted.
In conclusion, our results show that besides P-gp, Bcrp1 also plays an important role in the pharmacokinetics and brain penetration of imatinib. The brain penetration of imatinib can be improved by the co-administration of P-gp and/or BCRP inhibitors, such as elacridar and pantoprazole. Furthermore, our results suggest that inhibition of both Bcrp1 and P-gp is more effective than inhibition of P-gp alone to increase the brain penetration of imatinib. Moreover, inhibition of Bcrp1 by co-administration of p.o. pantoprazole and p.o. imatinib is even more effective than co-administration of i.v. pantoprazole and i.v. imatinib to increase the brain penetration of imatinib. In view of reported CNS relapses in imatinib-treated patients with acute leukemias, and promising activity of imatinib against glioblastoma, our concept of improved delivery of imatinib to the brain by co-administration of P-gp and BCRP inhibitors warrants further preclinical and clinical investigations (21, 22).
|
Acknowledgments |
|---|
We thank Piet Borst (Division of Molecular Biology, the Netherlands Cancer Institute, Amsterdam, the Netherlands) for critically reading the manuscript, Liesbeth de Lange (Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden, the Netherlands) for scientific input, Monique van Eijndhoven (Division of Experimental Therapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands) for technical assistance, and Els Wagenaar (Division of Experimental Therapy, the Netherlands Cancer Institute, Amsterdam, the Netherlands) for providing us with mice.
Received 7/ 7/04. Revised 1/26/05. Accepted 1/26/05.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
|---|
This article has been cited by other articles:
|
|
 |
|
  J. F. Deeken, R. W. Robey, S. Shukla, K. Steadman, A. R. Chakraborty, B. Poonkuzhali, E. G. Schuetz, S. Holbeck, S. V. Ambudkar, and S. E. Bates Identification of Compounds that Correlate with ABCG2 Transporter Function in the National Cancer Institute Anticancer Drug Screen Mol. Pharmacol., November 1, 2009; 76(5): 946 - 956. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Massard, J. Zonierek, M. Gross-Goupil, K. Fizazi, C. Szczylik, and B. Escudier Incidence of brain metastases in renal cell carcinoma treated with sorafenib Ann. Onc., October 22, 2009; (2009) mdp411v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Hu, Z. Chen, R. Franke, S. Orwick, M. Zhao, M. A. Rudek, A. Sparreboom, and S. D. Baker Interaction of the Multikinase Inhibitors Sorafenib and Sunitinib with Solute Carriers and ATP-Binding Cassette Transporters Clin. Cancer Res., October 1, 2009; 15(19): 6062 - 6069. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Chen, S. Agarwal, N. M. Shaik, C. Chen, Z. Yang, and W. F. Elmquist P-glycoprotein and Breast Cancer Resistance Protein Influence Brain Distribution of Dasatinib J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 956 - 963. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
L. Zhou, K. Schmidt, F. R. Nelson, V. Zelesky, M. D. Troutman, and B. Feng The Effect of Breast Cancer Resistance Protein and P-Glycoprotein on the Brain Penetration of Flavopiridol, Imatinib Mesylate (Gleevec), Prazosin, and 2-Methoxy-3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)propanoic Acid (PF-407288) in Mice Drug Metab. Dispos., May 1, 2009; 37(5): 946 - 955. [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]
|
|
|
|
|
|
J. S. Lagas, R. A.B. van Waterschoot, V. A.C.J. van Tilburg, M. J. Hillebrand, N. Lankheet, H. Rosing, J. H. Beijnen, and A. H. Schinkel Brain Accumulation of Dasatinib Is Restricted by P-Glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2) and Can Be Enhanced by Elacridar Treatment Clin. Cancer Res., April 1, 2009; 15(7): 2344 - 2351. [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]
|
|
|
|
|
|
S. Shukla, R. W. Robey, S. E. Bates, and S. V. Ambudkar Sunitinib (Sutent, SU11248), a Small-Molecule Receptor Tyrosine Kinase Inhibitor, Blocks Function of the ATP-Binding Cassette (ABC) Transporters P-Glycoprotein (ABCB1) and ABCG2 Drug Metab. Dispos., February 1, 2009; 37(2): 359 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Polli, K. L. Olson, J. P. Chism, L. St. John-Williams, R. L. Yeager, S. M. Woodard, V. Otto, S. Castellino, and V. E. Demby An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016) Drug Metab. Dispos., February 1, 2009; 37(2): 439 - 442. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. S. Narang, C. Fraga, N. Kumar, J. Shen, S. Throm, C. F. Stewart, and C. M. Waters Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier Am J Physiol Cell Physiol, August 1, 2008; 295(2): C440 - C450. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Hiwase, V. Saunders, D. Hewett, A. Frede, S. Zrim, P. Dang, L. Eadie, L. B. To, J. Melo, S. Kumar, et al. Dasatinib Cellular Uptake and Efflux in Chronic Myeloid Leukemia Cells: Therapeutic Implications Clin. Cancer Res., June 15, 2008; 14(12): 3881 - 3888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, A. Ose, A. H. Schinkel, and Y. Sugiyama Quantitative Investigation of the Role of Breast Cancer Resistance Protein (Bcrp/Abcg2) in Limiting Brain and Testis Penetration of Xenobiotic Compounds Drug Metab. Dispos., June 1, 2008; 36(6): 995 - 1002. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Garner, E. Solon, C.-M. Lai, J. Lin, G. Luo, K. Jones, J. Duan, C. P. Decicco, T. Maduskuie, S. E. Mercer, et al. Role of P-Glycoprotein and the Intestine in the Excretion of DPC 333 [(2R)-2-{(3R)-3-Amino-3-[4-(2-methylquinolin-4-ylmethoxy)phenyl]-2-oxopyrrolidin-1-yl}-N-hydroxy-4-methylpentanamide] in Rodents Drug Metab. Dispos., June 1, 2008; 36(6): 1102 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Liu, C. Chen, and B. J. Smith Progress in Brain Penetration Evaluation in Drug Discovery and Development J. Pharmacol. Exp. Ther., May 1, 2008; 325(2): 349 - 356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. W. Robey, A. Lazarowski, and S. E. Bates P-Glycoprotein--a Clinical Target in Drug-Refractory Epilepsy? Mol. Pharmacol., May 1, 2008; 73(5): 1343 - 1346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. W. Polli, J. E. Humphreys, K. A. Harmon, S. Castellino, M. J. O'Mara, K. L. Olson, L. St. John-Williams, K. M. Koch, and C. J. Serabjit-Singh The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions Drug Metab. Dispos., April 1, 2008; 36(4): 695 - 701. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ose, H. Kusuhara, K. Yamatsugu, M. Kanai, M. Shibasaki, T. Fujita, A. Yamamoto, and Y. Sugiyama P-glycoprotein Restricts the Penetration of Oseltamivir Across the Blood-Brain Barrier Drug Metab. Dispos., February 1, 2008; 36(2): 427 - 434. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. P. van Erp, H. Gelderblom, M. O. Karlsson, J. Li, M. Zhao, J. Ouwerkerk, J. W. Nortier, H.-J. Guchelaar, S. D. Baker, and A. Sparreboom Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib Clin. Cancer Res., December 15, 2007; 13(24): 7394 - 7400. [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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
J. Enokizono, H. Kusuhara, and Y. Sugiyama Effect of Breast Cancer Resistance Protein (Bcrp/Abcg2) on the Disposition of Phytoestrogens Mol. Pharmacol., October 1, 2007; 72(4): 967 - 975. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Marchetti, R. Mazzanti, J. H. Beijnen, and J. H. M. Schellens Concise Review: Clinical Relevance of Drug Drug and Herb Drug Interactions Mediated by the ABC Transporter ABCB1 (MDR1, P-glycoprotein) Oncologist, August 1, 2007; 12(8): 927 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. V. Boddy, J. Sludden, M. J. Griffin, C. Garner, J. Kendrick, P. Mistry, C. Dutreix, D. R. Newell, and S. G. O'Brien Pharmacokinetic Investigation of Imatinib Using Accelerator Mass Spectrometry in Patients with Chronic Myeloid Leukemia Clin. Cancer Res., July 15, 2007; 13(14): 4164 - 4169. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. L. Muldoon, C. Soussain, K. Jahnke, C. Johanson, T. Siegal, Q. R. Smith, W. A. Hall, K. Hynynen, P. D. Senter, D. M. Peereboom, et al. Chemotherapy Delivery Issues in Central Nervous System Malignancy: A Reality Check J. Clin. Oncol., June 1, 2007; 25(16): 2295 - 2305. [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]
|
|
|
|
|
|
J. F. Deeken and W. Loscher The Blood-Brain Barrier and Cancer: Transporters, Treatment, and Trojan Horses Clin. Cancer Res., March 15, 2007; 13(6): 1663 - 1674. [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]
|
|
|
|
 |
|
 A. Yokota, S. Kimura, S. Masuda, E. Ashihara, J. Kuroda, K. Sato, Y. Kamitsuji, E. Kawata, Y. Deguchi, Y. Urasaki, et al. INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity Blood, January 1, 2007; 109(1): 306 - 314. [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]
|
|
|
|
|
|
T. Nakanishi, K. Shiozawa, B. A. Hassel, and D. D. Ross Complex interaction of BCRP/ABCG2 and imatinib in BCR-ABL-expressing cells: BCRP-mediated resistance to imatinib is attenuated by imatinib-induced reduction of BCRP expression Blood, July 15, 2006; 108(2): 678 - 684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. White, V. A. Saunders, P. Dang, J. Engler, A. C. W. Zannettino, A. C. Cambareri, S. R. Quinn, P. W. Manley, and T. P. Hughes OCT-1-mediated influx is a key determinant of the intracellular uptake of imatinib but not nilotinib (AMN107): reduced OCT-1 activity is the cause of low in vitro sensitivity to imatinib Blood, July 15, 2006; 108(2): 697 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Reardon, J. N. Rich, H. S. Friedman, and D. D. Bigner Recent Advances in the Treatment of Malignant Astrocytoma J. Clin. Oncol., March 10, 2006; 24(8): 1253 - 1265. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Reardon, M. J. Egorin, J. A. Quinn, J. N. Rich Sr, I. Gururangan, J. J. Vredenburgh, A. Desjardins, S. Sathornsumetee, J. M. Provenzale, J. E. Herndon II, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme J. Clin. Oncol., December 20, 2005; 23(36): 9359 - 9368. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Theou, S. Gil, A. Devocelle, C. Julie, A. Lavergne-Slove, A. Beauchet, P. Callard, R. Farinotti, A. Le Cesne, A. Lemoine, et al. Multidrug Resistance Proteins in Gastrointestinal Stromal Tumors: Site-Dependent Expression and Initial Response to Imatinib Clin. Cancer Res., November 1, 2005; 11(21): 7593 - 7598. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
