Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer.
OBJECTIVE
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.


METHODS
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.
Lockman
Paul R
PR
Department of Pharmaceutical Sciences, Cancer Biology Center, Texas Tech University Health Sciences Center, Amarillo, Texas 79106, USA. paul.lockman@ttuhsc.edu
Mittapalli
Rajendar K
RK
Taskar
Kunal S
KS
Rudraraju
Vinay
V
Gril
Brunilde
B
Bohn
Kaci A
KA
Adkins
Chris E
CE
Roberts
Amanda
A
Thorsheim
Helen R
HR
Gaasch
Julie A
JA
Huang
Suyun
S
Palmieri
Diane
D
Steeg
Patricia S
PS
Smith
Quentin R
QR
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000627:therapeutic use; D010539:Permeability; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004317:Doxorubicin; D017239:Paclitaxel