Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies – targeting transporter regulation and direct transporter inhibition – have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a “cooperative team of gatekeepers” at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field.

Glioblastoma multiforme, due to 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 faced by cancer researchers is to effectively deliver drugs to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts 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, which transport drugs out of the brain back into the blood. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumor 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 tumor. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend upon 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–tumor-cell barrier, a barrier due to expression of efflux transporters in tumor cells, that together can significantly influence drug response. It then discusses the special challenge of glioma as a disease of the whole brain, which lends particular emphasis to the need to effectively deliver drugs across the BBB to reach both the central tumor and the invasive glioma cells.

Gefitinib is an orally active inhibitor of the epidermal growth factor receptor approved for use in patients with locally advanced or metastatic non-small cell lung cancer. It has also been evaluated in several clinical trials for treatment of brain tumors such as high-grade glioma. In this study, we investigated the influence of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) on distribution of gefitinib to the central nervous system. In vitro studies conducted in MadinDarby canine kidney II cells indicate that both P-gp and BCRP effectively transport gefitinib, limiting its intracellular accumulation. In vivo studies demonstrated that transport of gefitinib across the blood-brain barrier (BBB) is significantly limited. Steady-state brain-to-plasma (B/P) concentration ratios were 70-fold higher in the Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice (ratio of approximately 7) compared with wild-type mice (ratio of approximately 0.1). The B/P ratio after oral administration increased significantly when gefitinib was coadministered with the dual P-gp and BCRP inhibitor elacridar. We investigated the integrity of tight junctions in the Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice and found no difference in the brain inulin and sucrose space between the wild-type and Mdr1a/b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice. This suggested that the dramatic enhancement in the brain distribution of gefitinib is not due to a leakier BBB in these mice. These results show that brain distribution of gefitinib is restricted due to active efflux by P-gp and BCRP. This finding is of clinical significance for therapy in brain tumors such as glioma, where concurrent administration of a dual inhibitor such as elacridar can increase delivery and thus enhance efficacy of gefitinib.Malignant gliomas account for approximately 70% of all new cases of malignant primary brain tumors diagnosed in the United States every year. Glioblastoma multiforme (GBM) is the most common type of glioma, accounting for approximately 60 to 70% of malignant gliomas (Wen and Kesari, 2008; CBTRUS, 2008) and claiming 12,000 lives every year (Davis et al., 2001). Epidermal growth factor receptor (EGFR) and its variant EGFRvIII play a critical role in the development of an aggressive phenotype of GBM; EGFR amplification, mutation, and overexpression are associated with poor prognosis and resistance to therapy (Brandes et al., 2008). Several therapeutic strategies targeting EGFR in GBM have been proposed, including the use of monoclonal antibodies against EGFR or EGFRvIII, vaccine therapies, bispecific antibodies, toxin-linked conjugates, and small molecule tyrosine kinase inhibitors (Omuro et al., 2007).

The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of Pglycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-␣-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12␣-octahydropyrazino1Ј,2Ј: 1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concentration ratios less than 0.12 in wild-type mice, which increased approximately 8-fold in Mdr1a/ b(Ϫ/Ϫ) Bcrp1(Ϫ/Ϫ) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(Ϫ/Ϫ) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concentration. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.Chronic myelogenous leukemia (CML) accounts for 15 to 20% of all cases of adult leukemia in western populations (Quintá s-Cardama et al., 2007). Imatinib (Gleevec; STI 571) is a first-generation tyrosine kinase inhibitor (TKI) that was approved for use in the treatment of CML and gastrointestinal stromal tumor (Druker, 2003). Imatinib inhibits the BCR-ABL, c-kit, platelet-derived growth factor, and the Ablrelated gene tyrosine kinases . CNS involvement is a common complication seen in CML, and most patients with CML and Ph ϩ acute lymphoblastic leukemia (Ph ϩ ALL) develop extramedullary involvement during the course of their disease. CNS failure has been reported in approximately 20% of imatinib-treated patients with CML or Ph ϩ ALL (Leis et al., 2004). CNS relapses were observed in patients despite a complete hematological response (Leis et Article, publication date, and c...