Abstract 2080: Demonstration of casual relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer
Authors: Mohammad Afroz Shareef , Adkins Chris E. , Dolan Emma L. , Terrell-Hall Tori B. , Lockman Paul R. 
Published: July 2016

Background: 10-16% of women with advanced breast cancer will develop symptomatic brain metastases, the survival rate of which is less than 2 years. When metastasis develop within the brain, the BBB anatomy changes due to increased angiogenesis with increase in permeability of BBB in the tumor region (&gt; 1mm diameter). We have also demonstrated in our previous study that, once the metastases are established in the brain (&gt;1 mm in diameter) chemotherapy fails to induce cytotoxicity in most of them. The efficacy of a chemotherapeutic agent in the metastatic brain tumors significantly correlates to its uptake in the micro metastases (&lt; 0.5 mm in diameter). Therefore, it is important to characterize the permeability changes in micrometastases using permeability markers 14C-AIB (104 Da) and Texas Red dextran (3kDa) in five novel brain seeking cell lines (4T1, MDA-MB-231BR HER2+, MDA-MB-231BR, JIMT-1Br and Sum190) which preferentially develop brain metastases of breast cancer.

Methods: Female nude mice were intracardially injected with different human brain seeking breast cancer cell and allowed it to metastasize. Metastases were allowed to develop until neurologic symptoms appeared and animals were injected with IV bolus dose of permeability markers 14C-AIB (104 Da) and Texas Red dextran (3kDa) 10 minutes prior to euthanasia. After euthanasia rain sample were harvested, sectioned and analyzed by autoradiography and fluorescent microscopy.

Results: Passive permeability changes in 4T1 metastatic lesions was 3.171 + 1.52 (SD) for 14C-AIB, and 2.529 + 0.84 (SD) for the passive diffusion marker 3kDa Texas Red Dextran(TRD). MDA-MB-231BR HER2 metastatic lesions has 14C-AIB permeability 4.936 + 3.6 (SD) and for TRD 1.301 + 0.49 (SD). For MDA-MB-231Br cell line permeability changes with 14C-AIB was found to be 3.001 ± 0.1514 (SD) and the BTB permeability to TRD ranged was found to be 1.159 ± 0.3137 (SD). In JIMT-1Br, 14C-AIB permeability was found to be 2.212 + 0.72 (SD) and TRD was 1.502 + 0.344 (SD). Sum190 micrometastases showed maximum 14C-AIB permeability in the range of 1 to 28.64 fold (Mean was 10.11 ± 5.68; SD) and TRD was found to be in the range of 1 to 2.10 (Mean was 1.287 ± 0.293; SD).

Conclusions: We have demonstrated that there are differences in passive permeability between each cell line and there are differences in overall survival and the size of lesions at the time neurological symptoms develop. The increased permeability of the vasculature of CNS micrometastases is critically important for both diagnosis and treatment.

Citation Format: Afroz Shareef Mohammad, Chris E. Adkins, Emma L. Dolan, Tori B. Terrell-Hall, Paul R. Lockman. Demonstration of casual relationship between blood-tumor barrier permeability changes and chemotherapeutic uptake and effect in brain micrometastases of breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2080.