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Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain

Published online by Cambridge University Press:  13 May 2011

Sagar Agarwal ,
Ramola Sane ,
Rajneet Oberoi ,
John R. Ohlfest  and
William F. Elmquist
Sagar Agarwal
Affiliation:
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA
Ramola Sane
Affiliation:
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA
Rajneet Oberoi
Affiliation:
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA
John R. Ohlfest
Affiliation:
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA Department of Neurosurgery, University of Minnesota, Minneapolis, MN, USA
William F. Elmquist*
Affiliation:
Department of Pharmaceutics, University of Minnesota, Minneapolis, MN, USA Brain Barriers Research Center, University of Minnesota, Minneapolis, MN, USA
*
*Corresponding author: William F. Elmquist, Department of Pharmaceutics, University of Minnesota, 308 Harvard Street SE, Minneapolis, MN 55455, USA. E-mail: [email protected]
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Abstract

Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain–tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 13 , March 2011 , e17
Copyright
Copyright © Cambridge University Press 2011

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References

References

1Altekruse, S.F. et al. (2010) SEER Cancer Statistics Review, 1975–2007, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2007/, based on November 2009 SEER data submission, posted to the SEER web site, 2010Google Scholar
2CBTRUS (2010) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2006, Central Brain Tumor Registry of the United States, Hinsdale, IL, http://www.cbtrus.orgGoogle Scholar
3American Cancer Society (2010) Cancer Facts & Figures, American Cancer Society, AtlantaGoogle Scholar
4Stupp, R. et al. (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New England Journal of Medicine 352, 987-996CrossRefGoogle ScholarPubMed
5Wen, P.Y. and Brandes, A.A. (2009) Treatment of recurrent high-grade gliomas. Current Opinion in Neurology 22, 657-664CrossRefGoogle ScholarPubMed
6Pardridge, W.M. (2005) The blood–brain barrier: bottleneck in brain drug development. NeuroRx 2, 3-14CrossRefGoogle ScholarPubMed
7Berens, M.E. and Giese, A. (1999) “…those left behind.” Biology and oncology of invasive glioma cells. Neoplasia 1, 208-219CrossRefGoogle ScholarPubMed
8Louis, D.N. et al. (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathologica 114, 97-109CrossRefGoogle ScholarPubMed
9Ohgaki, H. and Kleihues, P. (2007) Genetic pathways to primary and secondary glioblastoma. American Journal of Pathology 170, 1445-1453CrossRefGoogle ScholarPubMed
10Maher, E.A. et al. (2006) Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. Cancer Research 66, 11502-11513CrossRefGoogle ScholarPubMed
11Liang, Y. et al. (2005) Gene expression profiling reveals molecularly and clinically distinct subtypes of glioblastoma multiforme. Proceedings of the National Academy of Sciences of the United States of America 102, 5814-5819CrossRefGoogle ScholarPubMed
12Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061-1068CrossRefGoogle Scholar
13Wen, P.Y. and Kesari, S. (2008) Malignant gliomas in adults. New England Journal of Medicine 359, 492-507CrossRefGoogle ScholarPubMed
14Kreisl, T.N. (2009) Chemotherapy for malignant gliomas. Seminars in Radiation Oncology 19, 150-154CrossRefGoogle ScholarPubMed
15McGirt, M.J. et al. (2009) Independent association of extent of resection with survival in patients with malignant brain astrocytoma. Journal of Neurosurgery 110, 156-162CrossRefGoogle ScholarPubMed
16Lacroix, M. et al. (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. Journal of Neurosurgery 95, 190-198CrossRefGoogle ScholarPubMed
17Niyazi, M. et al. (2010) Irradiation and bevacizumab in high-grade glioma retreatment settings. International Journal of Radiation Oncology, Biology, Physics Oct 27; [Epub ahead of print]Google ScholarPubMed
18Lee, C.G. et al. (2000) Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Research 60, 5565-5570Google ScholarPubMed
19Libermann, T.A. et al. (1985) Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature 313, 144-147CrossRefGoogle ScholarPubMed
20Rich, J.N. and Bigner, D.D. (2004) Development of novel targeted therapies in the treatment of malignant glioma. Nature Reviews. Drug Discovery 3, 430-446CrossRefGoogle ScholarPubMed
21Lund-Johansen, M. et al. (1990) Effect of epidermal growth factor on glioma cell growth, migration, and invasion in vitro. Cancer Research 50, 6039-6044Google ScholarPubMed
22Nister, M. et al. (1991) Differential expression of platelet-derived growth factor receptors in human malignant glioma cell lines. Journal of Biological Chemistry 266, 16755-16763CrossRefGoogle ScholarPubMed
23Guha, A. et al. (1995) Expression of PDGF and PDGF receptors in human astrocytoma operation specimens supports the existence of an autocrine loop. International Journal of Cancer 60, 168-173CrossRefGoogle ScholarPubMed
24Maher, E.A. et al. (2001) Malignant glioma: genetics and biology of a grave matter. Genes and Development 15, 1311-1333CrossRefGoogle ScholarPubMed
25Schmidt, N.O. et al. (1999) Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. International Journal of Cancer 84, 10-183.0.CO;2-L>CrossRefGoogle ScholarPubMed
26Plate, K.H. et al. (1992) Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature 359, 845-848CrossRefGoogle ScholarPubMed
27Mukasa, A. et al. (2010) Mutant EGFR is required for maintenance of glioma growth in vivo, and its ablation leads to escape from receptor dependence. Proceedings of the National Academy of Sciences of the United States of America 107, 2616-2621CrossRefGoogle ScholarPubMed
28Heimberger, A.B. et al. (2002) Brain tumors in mice are susceptible to blockade of epidermal growth factor receptor (EGFR) with the oral, specific, EGFR-tyrosine kinase inhibitor ZD1839 (iressa). Clinical Cancer Research 8, 3496-3502Google ScholarPubMed
29Ciardiello, F. et al. (2001) Inhibition of growth factor production and angiogenesis in human cancer cells by ZD1839 (Iressa), a selective epidermal growth factor receptor tyrosine kinase inhibitor. Clinical Cancer Research 7, 1459-1465Google ScholarPubMed
30Griffero, F. et al. (2009) Different response of human glioma tumor-initiating cells to epidermal growth factor receptor kinase inhibitors. Journal of Biological Chemistry 284, 7138-7148CrossRefGoogle ScholarPubMed
31Halatsch, M.E. et al. (2004) Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. Journal of Neurosurgery 100, 523-533CrossRefGoogle ScholarPubMed
32Preusser, M. et al. (2008) Epithelial Growth Factor Receptor Inhibitors for treatment of recurrent or progressive high grade glioma: an exploratory study. Journal of Neurooncology 89, 211-218CrossRefGoogle ScholarPubMed
33Franceschi, E. et al. (2007) Gefitinib in patients with progressive high-grade gliomas: a multicentre phase II study by Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). British Journal of Cancer 96, 1047-1051CrossRefGoogle ScholarPubMed
34Rich, J.N. et al. (2004) Phase II trial of gefitinib in recurrent glioblastoma. Journal of Clinical Oncology 22, 133-142CrossRefGoogle ScholarPubMed
35Reardon, D.A. et al. (2009) Phase 2 trial of erlotinib plus sirolimus in adults with recurrent glioblastoma. Journal of Neurooncology 96, 219-230CrossRefGoogle ScholarPubMed
36Prados, M.D. et al. (2009) Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Journal of Clinical Oncology 27, 579-584CrossRefGoogle ScholarPubMed
37Raizer, J.J. et al. (2010) A phase II trial of erlotinib in patients with recurrent malignant gliomas and nonprogressive glioblastoma multiforme postradiation therapy. Neuro-oncology 12, 95-103CrossRefGoogle ScholarPubMed
38Peereboom, D.M. et al. (2009) Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. Journal of Neurooncology 98, 93-99CrossRefGoogle ScholarPubMed
39Buchdunger, E. et al. (2000) Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. Journal of Pharmacology and Experimental Therapeutics 295, 139-145Google ScholarPubMed
40Capdeville, R. et al. (2002) Glivec (STI571, imatinib), a rationally developed, targeted anticancer drug. Nature Reviews. Drug Discovery 1, 493-502CrossRefGoogle ScholarPubMed
41Ranza, E. et al. (2009) In-vitro effects of the tyrosine kinase inhibitor imatinib on glioblastoma cell proliferation. Journal of Neurooncology 96, 349-357CrossRefGoogle ScholarPubMed
42Geng, L. et al. (2006) STI571 (Gleevec) improves tumor growth delay and survival in irradiated mouse models of glioblastoma. International Journal of Radiation Oncology, Biology, Physics 64, 263-271CrossRefGoogle ScholarPubMed
43Kilic, T. et al. (2000) Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class. Cancer Research 60, 5143-5150Google ScholarPubMed
44Wen, P.Y. et al. (2006) Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99–08. Clinical Cancer Research 12, 4899-4907CrossRefGoogle ScholarPubMed
45Raymond, E. et al. (2008) Phase II study of imatinib in patients with recurrent gliomas of various histologies: a European Organisation for Research and Treatment of Cancer Brain Tumor Group Study. Journal of Clinical Oncology 26, 4659-4665CrossRefGoogle ScholarPubMed
46Premkumar, D.R. et al. (2010) Dasatinib synergizes with JSI-124 to inhibit growth and migration and induce apoptosis of malignant human glioma cells. Journal of Carcinogenesis 9, 7Google ScholarPubMed
47Batchelor, T.T. et al. (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11, 83-95CrossRefGoogle ScholarPubMed
48Batchelor, T.T. et al. (2010) Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Journal of Clinical Oncology 28, 2817-2823CrossRefGoogle ScholarPubMed
49Kreisl, T.N. et al. (2009) A pilot study of everolimus and gefitinib in the treatment of recurrent glioblastoma (GBM). Journal of Neurooncology 92, 99-105CrossRefGoogle ScholarPubMed
50Reardon, D.A. et al. (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. Journal of Clinical Oncology 23, 9359-9368CrossRefGoogle ScholarPubMed
51Desjardins, A. et al. (2007) Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. Journal of Neurooncology 83, 53-60CrossRefGoogle ScholarPubMed
52Lamar, R.E. et al. (2009) Phase II trial of radiation therapy/temozolomide followed by temozolomide/sorafenib in the first-line treatment of glioblastoma multiforme (GBM). ASCO Meeting Abstracts 27, 2018Google Scholar
53Grisanti, S. et al. (2010) Phase II study of sunitinib and irinotecan in patients with recurrent high-grade glioma (HGG). ASCO Meeting Abstracts 28, e12537Google Scholar
54Galanis, E. et al. (2005) Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. Journal of Clinical Oncology 23, 5294-5304CrossRefGoogle ScholarPubMed
55Sathornsumetee, S. et al. (2007) Phase I trial of imatinib mesylate, hydroxyurea and vatalanib for patients with recurrent glioblastoma multiforme (GBM). 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 25, 2027CrossRefGoogle Scholar
56Kamoun, W.S. et al. (2009) Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice. Journal of Clinical Oncology 27, 2542-2552CrossRefGoogle ScholarPubMed
57Wilhelm, S.M. et al. (2008) Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Molecular Cancer Therapeutics 7, 3129-3140CrossRefGoogle ScholarPubMed
58O'Farrell, A.M. et al. (2003) SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 101, 3597-3605CrossRefGoogle ScholarPubMed
59de Bouard, S. et al. (2007) Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro-oncology 9, 412-423CrossRefGoogle ScholarPubMed
60Siegelin, M.D. et al. (2010) Sorafenib exerts anti-glioma activity in vitro and in vivo. Neurosci Lett 478, 165-170CrossRefGoogle ScholarPubMed
61Rich, J.N. et al. (2005) ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors. Clinical Cancer Research 11, 8145-8157CrossRefGoogle ScholarPubMed
62Yiin, J.J. et al. (2010) ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain. Molecular Cancer Therapeutics 9, 929-941CrossRefGoogle ScholarPubMed
63Hu, X. et al. (2005) mTOR promotes survival and astrocytic characteristics induced by Pten/AKT signaling in glioblastoma. Neoplasia 7, 356-368CrossRefGoogle ScholarPubMed
64Lee, J. et al. (2006) Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines. Cancer Cell 9, 391-403CrossRefGoogle ScholarPubMed
65Hawkins, B.T. and Davis, T.P. (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacological Reviews 57, 173-185CrossRefGoogle ScholarPubMed
66Pardridge, W.M. (1999) Blood–brain barrier biology and methodology. Journal of Neurovirology 5, 556-569CrossRefGoogle ScholarPubMed
67Pardridge, W.M. (1998) CNS drug design based on principles of blood–brain barrier transport. Journal of Neurochemistry 70, 1781-1792CrossRefGoogle ScholarPubMed
68Ajay, , Bemis, G.W. and Murcko, M.A. (1999) Designing libraries with CNS activity. Journal of Medicinal Chemistry 42, 4942-4951CrossRefGoogle ScholarPubMed
69Vilar, S., Chakrabarti, M. and Costanzi, S. (2010) Prediction of passive blood–brain partitioning: straightforward and effective classification models based on in silico derived physicochemical descriptors. Journal of Molecular Graphics and Modelling 28, 899-903CrossRefGoogle ScholarPubMed
70Mahar Doan, K.M. et al. (2002) Passive permeability and P-glycoprotein-mediated efflux differentiate central nervous system (CNS) and non-CNS marketed drugs. Journal of Pharmacology and Experimental Therapeutics 303, 1029-1037CrossRefGoogle ScholarPubMed
71Golden, P.L. and Pollack, G.M. (2003) Blood–brain barrier efflux transport. Journal of Pharmaceutical Sciences 92, 1739-1753CrossRefGoogle ScholarPubMed
72Kusuhara, H. and Sugiyama, Y. (2005) Active efflux across the blood–brain barrier: role of the solute carrier family. NeuroRx 2, 73-85CrossRefGoogle ScholarPubMed
73Sun, H. et al. (2003) Drug efflux transporters in the CNS. Advanced Drug Delivery Reviews 55, 83-105CrossRefGoogle ScholarPubMed
74Nicolazzo, J.A. and Katneni, K. (2009) Drug transport across the blood–brain barrier and the impact of breast cancer resistance protein (ABCG2). Current Topics in Medicinal Chemistry 9, 130-147CrossRefGoogle ScholarPubMed
75Borst, P. et al. (2000) A family of drug transporters: the multidrug resistance-associated proteins. Journal of the National Cancer Institute 92, 1295-1302CrossRefGoogle ScholarPubMed
76Schinkel, A.H. and Jonker, J.W. (2003) Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Advanced Drug Delivery Reviews 55, 3-29CrossRefGoogle ScholarPubMed
77Schinkel, A.H. (1999) P-glycoprotein, a gatekeeper in the blood–brain barrier. Advanced Drug Delivery Reviews 36, 179-194CrossRefGoogle ScholarPubMed
78Loscher, W. and Potschka, H. (2005) Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases. Progress in Neurobiology 76, 22-76CrossRefGoogle ScholarPubMed
79Juliano, R.L. and Ling, V. (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica et Biophysica Acta 455, 152-162CrossRefGoogle ScholarPubMed
80Ueda, K. et al. (1986) The mdr1 gene, responsible for multidrug-resistance, codes for P-glycoprotein. Biochemical and Biophysical Research Communications 141, 956-962CrossRefGoogle ScholarPubMed
81Cordon-Cardo, C. et al. (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood–brain barrier sites. Proceedings of the National Academy of Sciences of the United States of America 86, 695-698CrossRefGoogle ScholarPubMed
82Thiebaut, F. et al. (1989) Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. Journal of Histochemistry and Cytochemistry 37, 159-164CrossRefGoogle ScholarPubMed
83Barrand, M.A., Robertson, K.J. and von Weikersthal, S.F. (1995) Comparisons of P-glycoprotein expression in isolated rat brain microvessels and in primary cultures of endothelial cells derived from microvasculature of rat brain, epididymal fat pad and from aorta. FEBS Letters 374, 179-183CrossRefGoogle ScholarPubMed
84Hegmann, E.J., Bauer, H.C. and Kerbel, R.S. (1992) Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells. Cancer Research 52, 6969-6975Google ScholarPubMed
85Tsuji, A. et al. (1992) P-glycoprotein as the drug efflux pump in primary cultured bovine brain capillary endothelial cells. Life Sciences 51, 1427-1437CrossRefGoogle ScholarPubMed
86Beaulieu, E. et al. (1997) P-glycoprotein is strongly expressed in the luminal membranes of the endothelium of blood vessels in the brain. Biochemical Journal 326 (Pt 2), 539-544CrossRefGoogle ScholarPubMed
87Schinkel, A.H. et al. (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77, 491-502CrossRefGoogle ScholarPubMed
88Schinkel, A.H. et al. (1997) Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proceedings of the National Academy of Sciences of the United States of America 94, 4028-4033CrossRefGoogle ScholarPubMed
89Jonker, J.W. et al. (2005) Contribution of the ABC transporters Bcrp1 and Mdr1a/1b to the side population phenotype in mammary gland and bone marrow of mice. Stem Cells 23, 1059-1065CrossRefGoogle Scholar
90Fine, R.L. et al. (2006) Randomized study of paclitaxel and tamoxifen deposition into human brain tumors: implications for the treatment of metastatic brain tumors. Clinical Cancer Research 12, 5770-5776CrossRefGoogle ScholarPubMed
91Pitz, M.W. et al. (2011) Tissue concentration of systemically administered antineoplastic agents in human brain tumors. Journal of Neurooncology Mar 12; [Epub ahead of print]CrossRefGoogle ScholarPubMed
92Fattori, S. et al. (2007) Human brain tumors: multidrug-resistance P-glycoprotein expression in tumor cells and intratumoral capillary endothelial cells. Virchows Archiv 451, 81-87CrossRefGoogle ScholarPubMed
93Allikmets, R. et al. (1998) A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Research 58, 5337-5339Google ScholarPubMed
94Ashmore, S.M., Thomas, D.G. and Darling, J.L. (1999) Does P-glycoprotein play a role in clinical resistance of malignant astrocytoma? Anticancer Drugs 10, 861-872CrossRefGoogle ScholarPubMed
95Doyle, L.A. and Ross, D.D. (2003) Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22, 7340-7358CrossRefGoogle ScholarPubMed
96Zhou, S. et al. (2001) 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 Medicine 7, 1028-1034CrossRefGoogle Scholar
97Haimeur, A. et al. (2004) The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation. Current Drug Metabolism 5, 21-53CrossRefGoogle ScholarPubMed
98Huai-Yun, H. et al. (1998) Expression of multidrug resistance-associated protein (MRP) in brain microvessel endothelial cells. Biochemical and Biophysical Research Communications 243, 816-820CrossRefGoogle ScholarPubMed
99Demeule, M. et al. (2001) Expression of multidrug-resistance P-glycoprotein (MDR1) in human brain tumors. International Journal of Cancer 93, 62-66CrossRefGoogle ScholarPubMed
100Nabors, M.W. et al. (1991) Multidrug resistance gene (MDR1) expression in human brain tumors. Journal of Neurosurgery 75, 941-946CrossRefGoogle ScholarPubMed
101Mohri, M., Nitta, H. and Yamashita, J. (2000) Expression of multidrug resistance-associated protein (MRP) in human gliomas. Journal of Neurooncology 49, 105-115CrossRefGoogle ScholarPubMed
102Zhang, Y. et al. (2004) Plasma membrane localization of multidrug resistance-associated protein homologs in brain capillary endothelial cells. Journal of Pharmacology and Experimental Therapeutics 311, 449-455CrossRefGoogle ScholarPubMed
103Calatozzolo, C. et al. (2005) Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. Journal of Neurooncology 74, 113-121CrossRefGoogle ScholarPubMed
104Bleau, A.M. et al. (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226-235CrossRefGoogle ScholarPubMed
105Mirski, S.E., Gerlach, J.H. and Cole, S.P. (1987) Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Research 47, 2594-2598Google Scholar
106Cole, S.P. et al. (1992) Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650-1654CrossRefGoogle Scholar
107Nies, A.T. et al. (2004) Expression and immunolocalization of the multidrug resistance proteins, MRP1-MRP6 (ABCC1–ABCC6), in human brain. Neuroscience 129, 349-360CrossRefGoogle ScholarPubMed
108Dombrowski, S.M. et al. (2001) Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42, 1501-1506CrossRefGoogle ScholarPubMed
109Miller, D.S. et al. (2000) Xenobiotic transport across isolated brain microvessels studied by confocal microscopy. Molecular Pharmacology 58, 1357-1367CrossRefGoogle ScholarPubMed
110Potschka, H., Fedrowitz, M. and Loscher, W. (2003) Multidrug resistance protein MRP2 contributes to blood–brain barrier function and restricts antiepileptic drug activity. Journal of Pharmacology and Experimental Therapeutics 306, 124-131CrossRefGoogle ScholarPubMed
111Potschka, H. and Loscher, W. (2001) Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain. Neuroreport 12, 2387-2389CrossRefGoogle ScholarPubMed
112Potschka, H., Fedrowitz, M. and Loscher, W. (2001) P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 12, 3557-3560CrossRefGoogle ScholarPubMed
113Loscher, W. and Potschka, H. (2002) Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. Journal of Pharmacology and Experimental Therapeutics 301, 7-14CrossRefGoogle ScholarPubMed
114Sun, H. et al. (2001) Transport of fluorescein in MDCKII-MRP1 transfected cells and mrp1-knockout mice. Biochemical and Biophysical Research Communications 284, 863-869CrossRefGoogle ScholarPubMed
115Leggas, M. et al. (2004) Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Molecular and Cellular Biology 24, 7612-7621CrossRefGoogle ScholarPubMed
116Doyle, L.A. et al. (1998) A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America 95, 15665-15670CrossRefGoogle ScholarPubMed
117Miyake, K. et al. (1999) Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Research 59, 8-13Google ScholarPubMed
118Robey, R.W. et al. (2007) ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Reviews 26, 39-57CrossRefGoogle ScholarPubMed
119Cooray, H.C. et al. (2002) Localisation of breast cancer resistance protein in microvessel endothelium of human brain. Neuroreport 13, 2059-2063CrossRefGoogle ScholarPubMed
120Hori, S. et al. (2004) Functional expression of rat ABCG2 on the luminal side of brain capillaries and its enhancement by astrocyte-derived soluble factor(s). Journal of Neurochemistry 90, 526-536CrossRefGoogle ScholarPubMed
121Cisternino, S. et al. (2004) Expression, up-regulation, and transport activity of the multidrug-resistance protein Abcg2 at the mouse blood–brain barrier. Cancer Research 64, 3296-3301CrossRefGoogle ScholarPubMed
122Eisenblatter, T. and Galla, H.J. (2002) A new multidrug resistance protein at the blood–brain barrier. Biochemical and Biophysical Research Communications 293, 1273-1278CrossRefGoogle ScholarPubMed
123Lee, Y.J. et al. (2005) Investigation of efflux transport of dehydroepiandrosterone sulfate and mitoxantrone at the mouse blood–brain barrier: a minor role of breast cancer resistance protein. Journal of Pharmacology and Experimental Therapeutics 312, 44-52CrossRefGoogle ScholarPubMed
124Zhao, R. et al. (2009) Breast cancer resistance protein interacts with various compounds in vitro, but plays a minor role in substrate efflux at the blood–brain barrier. Drug Metabolism and Disposition 37, 1251-1258CrossRefGoogle Scholar
125Enokizono, J. et al. (2008) Quantitative investigation of the role of breast cancer resistance protein (Bcrp/Abcg2) in limiting brain and testis penetration of xenobiotic compounds. Drug Metabolism and Disposition 36, 995-1002CrossRefGoogle ScholarPubMed
126Breedveld, P. et al. (2005) 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 Research 65, 2577-2582CrossRefGoogle ScholarPubMed
127Agarwal, S. et al. (2010) Role of breast cancer resistance protein (ABCG2/BCRP) in the distribution of Sorafenib to the brain. Journal of Pharmacology and Experimental Therapeutics 336, 223-233CrossRefGoogle Scholar
128de Vries, N.A. et al. (2007) P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan. Clinical Cancer Research 13, 6440-6449CrossRefGoogle ScholarPubMed
129Polli, J.W. et al. (2009) 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)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016). Drug Metabolism and Disposition 37, 439-442CrossRefGoogle Scholar
130Chen, Y. et al. (2009) P-glycoprotein and breast cancer resistance protein influence brain distribution of dasatinib. Journal of Pharmacology and Experimental Therapeutics 330, 956-963CrossRefGoogle ScholarPubMed
131Lagas, J.S. et al. (2009) Brain accumulation of dasatinib is restricted by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) and can be enhanced by elacridar treatment. Clinical Cancer Research 15, 2344-2351CrossRefGoogle ScholarPubMed
132Agarwal, S. et al. (2010) Distribution of gefitinib to the brain is limited by P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2)-mediated active efflux. Journal of Pharmacology and Experimental Therapeutics 334, 147-155CrossRefGoogle Scholar
133Kodaira, H. et al. (2010) Kinetic analysis of the cooperation of P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp/Abcg2) in limiting the brain and testis penetration of erlotinib, flavopiridol, and mitoxantrone. Journal of Pharmacology and Experimental Therapeutics 333, 788-796CrossRefGoogle ScholarPubMed
134Lagas, J.S. et al. (2010) Breast cancer resistance protein and P-glycoprotein limit sorafenib brain accumulation. Molecular Cancer Therapeutics 9, 319-326CrossRefGoogle ScholarPubMed
135Tanaka, Y. et al. (2005) Tissue distribution and hormonal regulation of the breast cancer resistance protein (Bcrp/Abcg2) in rats and mice. Biochemical and Biophysical Research Communications 326, 181-187CrossRefGoogle ScholarPubMed
136Hofer, S. and Frei, K. (2007) Gefitinib concentrations in human glioblastoma tissue. Journal of Neurooncology 82, 175-176CrossRefGoogle ScholarPubMed
137Jain, R.K. et al. (2007) Angiogenesis in brain tumours. Nature Reviews. Neuroscience 8, 610-622CrossRefGoogle ScholarPubMed
138Gilbertson, R.J. and Rich, J.N. (2007) Making a tumour's bed: glioblastoma stem cells and the vascular niche. Nature Reviews. Cancer 7, 733-736CrossRefGoogle ScholarPubMed
139Silbergeld, D.L. and Chicoine, M.R. (1997) Isolation and characterization of human malignant glioma cells from histologically normal brain. Journal of Neurosurgery 86, 525-531CrossRefGoogle ScholarPubMed
140Spiegl-Kreinecker, S. et al. (2002) Expression and functional activity of the ABC-transporter proteins P-glycoprotein and multidrug-resistance protein 1 in human brain tumor cells and astrocytes. Journal of Neurooncology 57, 27-36CrossRefGoogle ScholarPubMed
141Decleves, X. et al. (2002) Molecular and functional MDR1-Pgp and MRPs expression in human glioblastoma multiforme cell lines. International Journal of Cancer 98, 173-180CrossRefGoogle ScholarPubMed
142Dean, M., Fojo, T. and Bates, S. (2005) Tumour stem cells and drug resistance. Nature Reviews. Cancer 5, 275-284CrossRefGoogle ScholarPubMed
143Bronger, H. et al. (2005) ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Research 65, 11419-11428CrossRefGoogle ScholarPubMed
144Bahr, O. et al. (2003) P-glycoprotein and multidrug resistance-associated protein mediate specific patterns of multidrug resistance in malignant glioma cell lines, but not in primary glioma cells. Brain Pathology 13, 482-494CrossRefGoogle ScholarPubMed
145Kuan, C.T. et al. (2010) MRP3: a molecular target for human glioblastoma multiforme immunotherapy. BMC Cancer 10, 468CrossRefGoogle ScholarPubMed
146Dai, H. et al. (2003) Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux. Journal of Pharmacology and Experimental Therapeutics 304, 1085-1092CrossRefGoogle Scholar
147Bihorel, S. et al. (2007) Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec) across the mouse blood–brain barrier. Journal of Neurochemistry 102, 1749-1757CrossRefGoogle ScholarPubMed
148Leis, J.F. et al. (2004) Central nervous system failure in patients with chronic myelogenous leukemia lymphoid blast crisis and Philadelphia chromosome positive acute lymphoblastic leukemia treated with imatinib (STI-571). Leukemia and Lymphoma 45, 695-698CrossRefGoogle ScholarPubMed
149Polli, J.W. et al. (2008) The role of efflux and uptake transporters in [N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethy l]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, lapatinib) disposition and drug interactions. Drug Metabolism and Disposition 36, 695-701CrossRefGoogle Scholar
150Yang, J.J. et al. (2010) P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor. Drug Metabolism Letters 4, 201-212CrossRefGoogle ScholarPubMed
151de Vries, N.A. et al. (2010) Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP. Investigational New Drugs Oct 21; [Epub ahead of print]Google Scholar
152de Lange, E.C. and Danhof, M. (2002) Considerations in the use of cerebrospinal fluid pharmacokinetics to predict brain target concentrations in the clinical setting: implications of the barriers between blood and brain. Clinical Pharmacokinetics 41, 691-703CrossRefGoogle ScholarPubMed
153Hofer, S., Frei, K. and Rutz, H.P. (2006) Gefitinib accumulation in glioblastoma tissue. Cancer Biology and Therapy 5, 483-484CrossRefGoogle ScholarPubMed
154McKillop, D. et al. (2005) Tumor penetration of gefitinib (Iressa), an epidermal growth factor receptor tyrosine kinase inhibitor. Molecular Cancer Therapeutics 4, 641-649CrossRefGoogle ScholarPubMed
155Stewart, D.J. et al. (1982) Human central nervous system distribution of cis-diamminedichloroplatinum and use as a radiosensitizer in malignant brain tumors. Cancer Research 42, 2474-2479Google ScholarPubMed
156Stewart, D.J. et al. (1983) Concentration of vinblastine in human intracerebral tumor and other tissues. Journal of Neurooncology 1, 139-144CrossRefGoogle ScholarPubMed
157Stewart, D.J. et al. (1984) Penetration of VP-16 (etoposide) into human intracerebral and extracerebral tumors. Journal of Neurooncology 2, 133-139Google ScholarPubMed
158Blakeley, J.O. et al. (2009) Effect of blood brain barrier permeability in recurrent high grade gliomas on the intratumoral pharmacokinetics of methotrexate: a microdialysis study. Journal of Neurooncology 91, 51-58CrossRefGoogle ScholarPubMed
159Bell, E. Jr. and Karnosh, L.J. (1949) Cerebral hemispherectomy; report of a case 10 years after operation. Journal of Neurosurgery 6, 285-293CrossRefGoogle ScholarPubMed
160Matsukado, Y., Maccarty, C.S. and Kernohan, J.W. (1961) The growth of glioblastoma multiforme (astrocytomas, grades 3 and 4) in neurosurgical practice. Journal of Neurosurgery 18, 636-644CrossRefGoogle ScholarPubMed
161Scherer, H.-J. (1938) Structural development in gliomas. American Journal of Cancer 34, 334-351Google Scholar
162Hesselink, J.R. and Press, G.A. (1988) MR contrast enhancement of intracranial lesions with Gd-DTPA. Radiologic Clinics of North America 26, 873-887CrossRefGoogle ScholarPubMed
163Lockman, P.R. et al. (2010) Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clinical Cancer Research 16, 5664-5678CrossRefGoogle ScholarPubMed
164Rosso, L. et al. (2009) A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients. Cancer Research 69, 120-127CrossRefGoogle ScholarPubMed
165Molina, J.R. et al. (2010) Invasive glioblastoma cells acquire stemness and increased Akt activation. Neoplasia 12, 453-463CrossRefGoogle ScholarPubMed
166Singh, S.K. et al. (2004) Identification of human brain tumour initiating cells. Nature 432, 396-401CrossRefGoogle ScholarPubMed
167Liu, G. et al. (2006) Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Molecular Cancer 5, 67CrossRefGoogle ScholarPubMed
168Bao, S. et al. (2006) Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760CrossRefGoogle ScholarPubMed
169Bleau, A.M., Huse, J.T. and Holland, E.C. (2009) The ABCG2 resistance network of glioblastoma. Cell Cycle 8, 2936-2944CrossRefGoogle ScholarPubMed
170Nakai, E. et al. (2009) Enhanced MDR1 expression and chemoresistance of cancer stem cells derived from glioblastoma. Cancer Investigation 27, 901-908CrossRefGoogle ScholarPubMed
171Chu, L. et al. (2007) [Expression and significance of ABCG2 in human malignant glioma]. Ai Zheng 26, 1090-1094Google ScholarPubMed
172Shervington, A. and Lu, C. (2008) Expression of multidrug resistance genes in normal and cancer stem cells. Cancer Investigation 26, 535-542CrossRefGoogle ScholarPubMed
173Westphal, M. et al. (2003) A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro-oncology 5, 79-88CrossRefGoogle ScholarPubMed
174Attenello, F.J. et al. (2008) Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: a 10-year institutional experience. Annals of Surgical Oncology 15, 2887-2893CrossRefGoogle ScholarPubMed
175Bock, H.C. et al. (2010) First-line treatment of malignant glioma with carmustine implants followed by concomitant radiochemotherapy: a multicenter experience. Neurosurgical Review 33, 441-449CrossRefGoogle ScholarPubMed
176Bidros, D.S., Liu, J.K. and Vogelbaum, M.A. (2009) Future of convection-enhanced delivery in the treatment of brain tumors. Future Oncology 6, 117-125CrossRefGoogle Scholar
177Kunwar, S. et al. (2010) Phase III randomized trial of CED of IL13-PE38QQR vs gliadel wafers for recurrent glioblastoma. Neuro-oncology 12, 871-881CrossRefGoogle ScholarPubMed
178Lidar, Z. et al. (2004) Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study. Journal of Neurosurgery 100, 472-479CrossRefGoogle ScholarPubMed
179Kroll, R.A. and Neuwelt, E.A. (1998) Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 42, 1083-1099; discussion 1099–1100CrossRefGoogle ScholarPubMed
180Nomura, T., Inamura, T. and Black, K.L. (1994) Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors. Brain Research 659, 62-66CrossRefGoogle ScholarPubMed
181Hall, W.A. et al. (2006) Osmotic blood–brain barrier disruption chemotherapy for diffuse pontine gliomas. Journal of Neurooncology 77, 279-284CrossRefGoogle ScholarPubMed
182Boockvar, J.A. et al. (2010) Safety and maximum tolerated dose of superselective intraarterial cerebral infusion of bevacizumab after osmotic blood–brain barrier disruption for recurrent malignant glioma. Journal of Neurosurgery 114, 624-632CrossRefGoogle ScholarPubMed
183Lhomme, C. et al. (2008) Phase III study of valspodar (PSC 833) combined with paclitaxel and carboplatin compared with paclitaxel and carboplatin alone in patients with stage IV or suboptimally debulked stage III epithelial ovarian cancer or primary peritoneal cancer. Journal of Clinical Oncology 26, 2674-2682CrossRefGoogle ScholarPubMed
184Carlson, R.W. et al. (2006) A pilot phase II trial of valspodar modulation of multidrug resistance to paclitaxel in the treatment of metastatic carcinoma of the breast (E1195): a trial of the Eastern Cooperative Oncology Group. Cancer Investigation 24, 677-681CrossRefGoogle ScholarPubMed
185Ruff, P. et al. (2009) A randomized, placebo-controlled, double-blind phase 2 study of docetaxel compared to docetaxel plus zosuquidar (LY335979) in women with metastatic or locally recurrent breast cancer who have received one prior chemotherapy regimen. Cancer Chemotherapy and Pharmacology 64, 763-768CrossRefGoogle ScholarPubMed
186Cripe, L.D. et al. (2010) Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia: a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood 116, 4077-4085CrossRefGoogle Scholar
187Kruijtzer, C.M. et al. (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. Journal of Clinical Oncology 20, 2943-2950CrossRefGoogle ScholarPubMed
188Planting, A.S. et al. (2005) A phase I and pharmacologic study of the MDR converter GF120918 in combination with doxorubicin in patients with advanced solid tumors. Cancer Chemotherapy and Pharmacology 55, 91-99CrossRefGoogle ScholarPubMed
189Sikic, B.I. (1997) Pharmacologic approaches to reversing multidrug resistance. Seminars in Hematology 34, 40-47Google ScholarPubMed

Further reading, resources and contacts

Van Meir, E.G. et al. (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA: A Cancer Journal for Clinicians 60, 166-193Google ScholarPubMed
Berens, M.E. and Giese, A. (1999) “…those left behind.” Biology and oncology of invasive glioma cells. Neoplasia 1, 208-19CrossRefGoogle ScholarPubMed
Lagas, J.S., Vlaming, M.L. and Schinkel, A.H. (2009) Pharmacokinetic assessment of multiple ATP-binding cassette transporters: the power of combination knockout mice. Molecular Interventions 9, 136-45CrossRefGoogle ScholarPubMed