title: Characterization of passive permeability at the blood-tumor barrier in five preclinical models of brain metastases of breast cancer.
abstract: The blood-brain barrier (BBB) is compromised in brain metastases, allowing for enhanced drug permeation into brain. The extent and heterogeneity of BBB permeability in metastatic lesions is important when considering the administration of chemotherapeutics. Since permeability characteristics have been described in limited experimental models of brain metastases, we sought to define these changes in five brain-tropic breast cancer cell lines: MDA-MB-231BR (triple negative), MDA-MB-231BR-HER2, JIMT-1-BR3, 4T1-BR5 (murine), and SUM190 (inflammatory HER2 expressing). Permeability was assessed using quantitative autoradiography and fluorescence microscopy by co-administration of the tracers (14)C-aminoisobutyric acid (AIB) and Texas red conjugated dextran prior to euthanasia. Each experimental brain metastases model produced variably increased permeability to both tracers; additionally, the magnitude of heterogeneity was different among each model with the highest ranges observed in the SUM190 (up to 45-fold increase in AIB) and MDA-MB-231BR-HER2 (up to 33-fold in AIB) models while the lowest range was observed in the JIMT-1-BR3 (up to 5.5-fold in AIB) model. There was no strong correlation observed between lesion size and permeability in any of these preclinical models of brain metastases. Interestingly, the experimental models resulting in smaller mean metastases size resulted in shorter median survival while models producing larger lesions had longer median survival. These findings strengthen the evidence of heterogeneity in brain metastases of breast cancer by utilizing five unique experimental models and simultaneously emphasize the challenges of chemotherapeutic approaches to treat brain metastases.
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
authors.forename: Chris E
authors.initials: CE
authors.lastname: Adkins
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
authors.forename: Afroz S
authors.initials: AS
authors.lastname: Mohammad
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.|Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA.
authors.forename: Tori B
authors.initials: TB
authors.lastname: Terrell-Hall
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Dolan
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Shah
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Sechrest
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Griffith
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, 1 Medical Center Drive, Morgantown, WV, 26506-9050, USA. prlockman@hsc.wvu.edu.|Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, 79106, USA. prlockman@hsc.wvu.edu.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Lockman
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000473:pathology*; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051379:Mice; D010539:Permeability; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human
keywords: Blood–brain barrier; Blood–tumor barrier; Brain metastasis; Breast cancer; Permeability