Influence of Bevacizumab on Blood–Brain Barrier Permeability and O-(2-¹⁸F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas

Abstract

Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using -(2-F-fluoroethyl)-l-tyrosine (F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and F-FET uptake in a human xenograft model. Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment ( = 8). Time-activity curves, slope, and tumor-to-brain ratios of F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration ( = 0.055) and long-term therapy resulted in a significant decrease ( = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of F-FET uptake were observed in PET and autoradiography ( > 0.05). F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.

Combined FET PET/MRI radiomics differentiates radiation injury from recurrent brain metastasis

“…This is an interesting observation because the underlying mechanisms that determine signal intensities are thought to differ substantially. While the contrast enhancement on MRI represents disruption of the blood-brain barrier (BBB), the increased FET uptake depicted by PET is caused by an overexpression of large neutral amino acid transporters (LAT) leading to an increased accumulation of FET in brain tumors which is not influenced by the BBB permeability (Stegmayr et al, 2017a; Stegmayr et al, 2017b). The observation that the same textural parameters in MRI and FET PET have the highest discriminatory power suggest that patterns of altered amino acid transport and BBB disruption in recurrent metastasis and radionecrosis are altered in the same direction and that there is a fundamental relationship between the physiologically completely different parameters.…”

Treatment-Related Uptake of O-(2-18F-Fluoroethyl)-l-Tyrosine and l-[Methyl-3H]-Methionine After Tumor Resection in Rat Glioma Models

“…In addition to astrogliosis, other mechanisms for increased amino acid accumulation such as disruption of the bloodbrain barrier, increased perfusion, or edema must also be discussed. In different preclinical and clinical studies (31)(32)(33)(34)(35), however, no significant influence of blood-brain barrier disruption, microvessel density, perfusion, or edema on 18 F-FET uptake has been reported. Furthermore, 18 F-FET is not involved in protein synthesis, but for 3 H-MET uptake, an influence of protein incorporation cannot be excluded.…”

Current Strategies for Brain Drug Delivery

“…Bevacizumab is frequently used for malignant gliomas at a late stage of the disease. While influencing brain tumor vasculature, this treatment restores the BBB from its leakiness 84 . When Bevacizumab is used as a combined therapy, the brain uptake of other drugs in the regimen would be a concern over time.…”