Abstract
BackgroundP-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood–brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood–brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors.Materials and methodsWe performed positron emission tomography imaging with the radiolabeled ABCB1 inhibitor [11C]tariquidar, a prototypical ABCB1/ABCG2 substrate, in seven patients with non-contrast -enhancing brain tumors (WHO grades I–III). In addition, ABCB1 and ABCG2 levels were determined in surgically resected tumor tissue of four patients using quantitative targeted absolute proteomics.ResultsBrain distribution of [11C]tariquidar was found to be very low across the whole brain and not significantly different between tumor and tumor-free brain tissue. Only one patient showed a small area of enhanced [11C]tariquidar uptake within the brain tumor. ABCG2/ABCB1 ratios in surgically resected tumor tissue (1.4 ± 0.2) were comparable to previously reported ABCG2/ABCB1 ratios in isolated human micro-vessels (1.3), which suggested that no overexpression of ABCB1 or ABCG2 occurred in the investigated tumors.ConclusionsOur data suggest that the investigated brain tumors had an intact BBTB, which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates. Therefore, effective drugs for antitumor treatment should have high passive permeability and lack ABCB1/ABCG2 substrate affinity.Trial registrationEuropean Union Drug Regulating Authorities Clinical Trials Database (EUDRACT), 2011-004189-13. Registered on 23 February 2012, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2011-004189-13.
Highlights
Malignant brain tumors are considered as the most debilitating tumor types, mostly due to a bad quality of life, poor prognosis and limited therapeutic success [1]
Our data suggest that the investigated brain tumors had an intact blood–brain tumor barrier (BBTB), which is impermeable to anticancer drugs, which are dual ABCB1/ABCG2 substrates
The main finding of our study was that brain delivery of [11C]tariquidar was comparably low in tumor and tumor-free brain tissue, which suggested that ABCB1/ABCG2 transport activity was sufficiently intact in tumor tissue to restrict brain entry of anticancer drugs which are dual ABCB1/ABCG2 substrates
Summary
Malignant brain tumors are considered as the most debilitating tumor types, mostly due to a bad quality of life, poor prognosis and limited therapeutic success [1]. In 2010, in the USA alone, more than 130,000 patients with primary malignant brain tumors were identified [1]. Depending on the tumor type and localization, treatment recommendations comprise surgical removal, adjuvant radiotherapy and/or chemotherapy (e.g., temozolomide) [1, 3]. Chemotherapy has failed to improve survival leading to a lethal course of the disease within 12–18 months in particular in high-grade brain tumors. P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) are two efflux transporters expressed at the blood–brain barrier which effectively restrict the brain distribution of the majority of currently known anticancer drugs. High-grade brain tumors often possess a disrupted blood–brain tumor barrier (BBTB) leading to enhanced accumulation of magnetic resonance imaging contrast agents, and possibly anticancer drugs, as compared to normal brain. In contrast to high-grade brain tumors, considerably less information is available with respect to BBTB integrity in lower grade brain tumors
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