Repetitive doxorubicin treatment of glioblastoma enhances the PGP expression--a special role for endothelial cells.

The glioblastoma is the highest dedifferentiated form of astrocytic brain tumors, which is refractory to chemotherapy in most cases. The lack of chemotherapeutic success is correlated with overexpression of the product P-glycoprotein (PGP) coded by the multidrug resistance 1 (MDR1) gene and a subsequent release of drugs from the tumor cells. For the chemotherapeutical treatment of glioblastomas, the endothel cell is of special importance since due to its manifold metabolic and protective tasks within the blood-brain barrier, it already has a relatively high PGP expression under physiological conditions. The aim of the present study was to analyze the uptake of the antimitotic drug Doxorubicin (DOX) and the expression of PGP in human and rat glioblastoma cell lines and in a human endothelial cell line at different time points. In the following in vivo approach DOX enriched glioblastoma cells were transplanted into rats and the developed tumor was investigated histologically. The results showed an increased uptake and an enhanced expression of PGP at certain time points in every cell line. In the tissue a DOX release was mainly observed in perivascular surroundings. It was concluded that DOX enhanced the constitutive PGP expression which led to a subsequent exclusion of DOX in tumor cells but also in the endothelial cells of the tumor vasculature. Since the vascularization is a prerequisite for tumor growth, the inhibition of the PGP expression in tumor endothelial cells might be a clinical approach to make the DOX treatment more effective.