Effect of the combined treatment with mifepristone and chemotherapy on breast cancer brain metastases.

DE LA FUENTE, V; PODHAJCER OL.; RUBIN, A.; VANZULLI, S; SALVATIERRA, E.; ROJAS, P.; LANARI, C.

Washington

Congreso; AACR 108th Annual Meeting 2017; 2017

American Association for Cancer Research

The treatment of brain metastasis is limited due to the drug?s inability to cross the blood brain barrier, because of the presence of endothelial cells? multidrug resistance efflux transporters, such as the P-glycoprotein (P-gp). The antiprogestin Mifepristone (MFP) is known to inhibit the P-gp activity. We hypothesize that a combination of MFP and Pegylated doxorubicin liposomes (doxo) improves the drug efficacy on breast tumors that do not express progesterone receptors. Using the metastatic triple negative MDA-231-BrM2 breast cancer cell line, transfected with GFP and luciferase, we explored different protocols to generate tumors growing in the brain of NSG mice. Spontaneous metastases were obtained by subcutaneous injection (sc) of 2 x 106 cells, and experimental metastases by intracardiac injection (ic) of 1 x 106 cells or by intracranial injection of 2 x 105 cells. In the ic and sc models small and scattered brain metastases as well as liver, lung and kidney metastases were observed. The intracranial model enabled us to obtain measurable brain tumors in a short time. Thus we selected this method to evaluate the effect of MFP (6 mg pellets, sc) and /or doxo (4,5 mg/kg, iv) on tumors growing in the brain. Treatment was initiated 10 days after cell inoculation. The amount of tumor cells after brain excision was measured by flow cytometry (GFP) and by luminometry (luciferase activity). A decreased luminescence signal was observed in brains from mice treated with both agents as compared with the control mice (p