Function of the Blood-Brain Barrier and Restriction of Drug Delivery to Invasive Glioma Cells: Findings in an Orthotopic Rat Xenograft Model of Glioma

Abstract

Despite aggressive treatment with radiation and chemotherapy, recurrence of glioblastoma multiforme (GBM) is inevitable. The objective of this study was to show that the blood-brain barrier (BBB), through a combination of tight junctions and active efflux transporters in the brain microvasculature, can significantly restrict delivery of molecularly targeted agents to invasive glioma cells. Transgenic mice lacking P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) were used to study efflux of erlotinib at the BBB. A U87 rat xenograft model of GBM was used to investigate the regional distribution of erlotinib to the tumor, and brain regions surrounding the tumor. The effect of concurrent administration of elacridar on regional tumor distribution of erlotinib was evaluated.We show that erlotinib transport across an intact BBB is significantly restricted due to P-gp-and Bcrp-mediated efflux transport. We then show that the BBB is sufficiently intact in areas of brain adjacent to the tumor core to significantly restrict erlotinib delivery. Inhibition of P-gp and Bcrp by the dual inhibitor elacridar dramatically increased erlotinib delivery to the tumor core, rim, and normal brain. These results provide conclusive evidence of the impact that active efflux at the BBB has on the delivery of molecularly targeted therapy to different tumor regions in glioma. These data also support the possibility that the repeated failure of clinical trials of new drugs for gliomas may be in part due to a failure to achieve effective concentrations in invasive tumor cells that reside behind an intact BBB.

Breast Cancer Resistance Protein and P-Glycoprotein Influence In Vivo Disposition of 11C-Erlotinib

“…Approximately 10% of NSCLC patients in the Western population harbor an activating mutation in their EGFR genes (e.g., the exon 19 deletion delE746-A750 or the exon 21 point mutation L858R) resulting in higher response rates to treatment with erlotinib or gefitinib, another EGFR-inhibiting TKI, as compared with patients with wild-type EGFR (1). 11 C-erlotinib has been proposed as a PET tracer to distinguish erlotinib-sensitive from erlotinibresistant NSCLC patients (2,3). In preclinical PET studies, higher uptake of 11 C-erlotinib was found in tumor xenografts with activating EGFR mutations (e.g., delE746-A750, L858R) than in tumor xenografts expressing wild-type EGFR or EGFR with secondary resistance causing mutations (exon 20 missense mutation T790 M) (2,(4)(5)(6).…”

“…In NSCLC patients, it was shown that the distribution volume of 11 C-erlotinib was significantly higher in tumors with an exon 19 deletion than in tumors with wild-type EGFR (3). Apart from visualizing the EGFR mutational status of tumors, 11 C-erlotinib PET may also be of interest to predict the distribution of erlotinib to different body tissues targeted for erlotinib treatment (e.g., lung, brain, liver).…”

“…Erlotinib is a substrate (8) and inhibitor (9) of the adenosine triphosphate-binding cassette (ABC) transporters breast cancer resistance protein (humans, ABCG2; rodents, Abcg2) and P-glycoprotein (humans, ABCB1; rodents, Abcb1a/b), resulting in a low extent of brain distribution due to ABCG2-and ABCB1-mediated efflux transport at the blood-brain barrier (BBB) (8,10,11). Apart from the BBB, ABCB1 and ABCG2 are also expressed in excretory organs, such as liver and kidney, in which they mediate excretion of drugs and their metabolites into bile and urine, respectively (12).…”

“…Apart from the BBB, ABCB1 and ABCG2 are also expressed in excretory organs, such as liver and kidney, in which they mediate excretion of drugs and their metabolites into bile and urine, respectively (12). For the future diagnostic use of 11 C-erlotinib as a PET tracer in tumor patients it is important to understand the influence of ABCB1 and ABCG2 on organ distribution and excretion of 11 C-erlotinib as patients may undergo 11 C-erlotinib PET scans both without and with concomitant treatment with therapeutic doses of erlotinib, possibly leading to partial saturation of ABCB1 and ABCG2 causing changes in tissue distribution. Moreover, ABCG2 and ABCB1 may be overexpressed in multidrug-resistant tumors and thereby influence tumor distribution of 11 C-erlotinib (13).…”

Gene Therapy for the Nervous System: Challenges and New Strategies

“…Importantly, BMVECs concentrate the expression of P-gp, a member of the ATPbinding cassette (ABC) superfamily of proteins, to the luminal surface, where P-gp acts as an efflux transporter, removing a variety of diverse chemical structures away from the brain parenchyma [163]. The function of P-gp (and the redundant function of the related multi-drug resistant proteins) has been well defined as one of the most significant challenges to delivering chemotherapeutic agents to parenchymal brain cells and tumor cells in the CNS; furthermore, the BBB has proven no less challenging for the delivery of DNA-based therapies to CNS targets [165][166][167].…”