Heterogeneous Blood-Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer
By P. Lockman, R. K. Mittapalli, Kunal S. Taskar, Vinay Rudraraju, B. Gril, K. A. Bohn, C. Adkins, A. Roberts, H. Thorsheim, Julie A. Gaasch and 4 more. Clinical Cancer Research, 2010
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Purpose: Brain metastases of breast cancer appear to be increasing in incidence, confer significant morbidity, and threaten to compromise gains made in systemic chemotherapy. The blood–tumor barrier (BTB) is compromised in many brain metastases; however, the extent to which this influences chemotherapeutic delivery and efficacy is unknown. Herein, we answer this question by measuring BTB passive integrity, chemotherapeutic drug uptake, and anticancer efficacy in vivo in two breast cancer models that metastasize preferentially to brain. Experimental Design:Experimental brain metastasis drug uptake and BTB permeability were simultaneously measured using novel fluorescent and phosphorescent imaging techniques in immune-compromised mice. Drug-induced apoptosis and vascular characteristics were assessed using immunofluorescent microscopy. Results: Analysis of over 2,000 brain metastases from two models (human 231-BR-Her2 and murine 4T1-BR5) showed partial BTB permeability compromise in greater than 89% of lesions, varying in magnitude within and between metastases. Brain metastasis uptake of 14C-paclitaxel and 14C-doxorubicin was generally greater than normal brain but less than 15% of that of other tissues or peripheral metastases, and only reached cytotoxic concentrations in a small subset (∼10%) of the most permeable metastases. Neither drug significantly decreased the experimental brain metastatic ability of 231-BR-Her2 tumor cells. BTB permeability was associated with vascular remodeling and correlated with overexpression of the pericyte protein desmin. Conclusions: This work shows that the BTB remains a significant impediment to standard chemotherapeutic delivery and efficacy in experimental brain metastases of breast cancer. New brain permeable drugs will be needed. Evidence is presented for vascular remodeling in BTB permeability alterations. Clin Cancer Res; 16(23); 5664–78. ©2010 AACR.
Subfields: Neurology, Pulmonary and Respiratory Medicine, Radiology, Nuclear Medicine and Imaging
View Paper: https://www.semanticscholar.org/paper/493d5c39f2d5853a7df88190cd7f29658aafba54
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Citations in the corpus
- The microenvironmental landscape of brain tumors (2017, background): “It is also becoming apparent that BBB integrity is heterogeneously affected within brain tumors (Lockman et al., 2010; Morikawa et al., 2015).”
- A blood–brain barrier overview on structure, function, impairment, and biomarkers of integrity (2020, background): “[189] showed that the BBB remains partially intact in experimental brain metastases and thus impair drug delivery, requiring a need for brain permeable molecular therapeutics.”