Aminoisoquinolines Penetrate the Blood-Tumor Barrier and May Inhibit Metastasis of Lung Cancer to the Brain.

Two out of five patients with non-small cell lung cancer (NSCLC) develop brain metastases with 3-8 month overall survival time. One of the greatest challenges for developing chemotherapeutics for brain metastases of NSCLC is the blood-brain barrier (BBB). The BBB is composed of endothelial cells with distinct tight junctions, pericytes, a unique basement membrane and astrocyte endfeet. This unique vasculature structure opposes the movement of deleterious molecules, toxins, and drugs from the bloodstream into the central nervous system. We have previously characterized a shift from the impermeable BBB to a heterogeneously permeable blood-tumor barrier (BTB) during the formation of brain metastases of non-small cell lung cancer. These changes in permeability and composition may make brain tumors more accessible to therapeutics delivered through the bloodstream. One potential therapeutic is aminoisoquinolines. In vitrodata has demonstrated the efficacy of aminoisoquinolines in growth inhibition of lung cancers. They do so through inhibition of AuroraB and p70S6K kinases, two kinases critical to proliferation of lung cancer cells. Herein, we investigate the ability of aminoisoquinolines to inhibit metastasis of NSCLC to the brain through the BTB. We hypothesize that treatment of mice harboring brain-seeking NSCLC cells with aminoisoquinolines will prevent formation of brain metastases. Nineteen athymic nude mice were injected with brain-seeking NSCLC tumor cells, adenocarcinoma subtype (A549), via ultrasound-guided intracardiac injection. The mice were then treated with one of two aminoisoquinolines or a vehicle control. After 10 days of treatment, brains were procured from the animals and evaluated microscopically for presence or absence of brain metastases. We identified an average of 4.25 (n=4) metastases in animals treated with the aminoisoquinoline HSN 789, with an average diameter of 15.66 micrometers. Animals treated with the aminoisoquinoline HSN 804 had an average of 18.5 metastases (n=2), with an average diameter of 23.00 micrometers. Animals treated with the vehicle control failed to form brain metastases; we are investigating cell viability in this experimental group. A complete evaluation of cell viability in all treatment groups will reveal the in vivo therapeutic efficacy of aminoisoquinolines for treatment of brain metastases of NSCLC. Preliminary data suggest that treatment with aminoisoquinolines may be sufficient to inhibit growth of brain metastases from NSCLC.