Modulation of ABC Transporters in Cancer Chemotherapy

Modulation of PGp170 (ABCB1) activity in the blood brain barrier

Although drug penetration across the blood brain barrier correlates with lipophilicity, the concentrations of some highly lipophilic drugs such as paclitaxel are extremely low in the brain after i.v. administration. It is hypothesized that such drugs are exported by the activity of P-glycoprotein 170 (Pgp), located in the luminal membrane of the endothelial cells of human brain capillaries. As an efflux pump Pgp is highly conserved in evolution and responsible for the phenomenon of classical multi drug resistance (MDR) of tumours.

We studied the effect of co-administration of the cyclosporin D derivative valspodar (SDZ PSC 833), an MDR modulator, on the paclitaxel levels in the brain of nude mice. Valspodar led to a long-lasting increase of the concentration of paclitaxel by a factor of 5-8.5 in the brain. Moreover, the treatment of nude mice bearing orthotopically growing human glioblastoma led to a decrease in tumour volume by 90 %.

Our previous study may be considered proof of concept. However, as this therapeutic approach may be compromized by increased peripheral toxicity due to increased plasma levels of the cytostatic, further investigations are currently performed to identify more selective MDR modulators (collaboration with Prof. Dr. B. König, Institute of Organic Chemistry, University of Regensburg).

Modulation of BCRP (ABCG2)

In a joined research project with the group of Prof. König we identified highly potent and selective inhibitors of the 'breast cancer resistance protein' (ABCG2 transporter), which causes atypical multidrug resistance in tumour cells and inhibits the penetration of certain cytostatic drugs across the blood brain barrier.

Recent publication

M. Kühnle, M. Egger, M. Müller, A. Mahringer, G. Bernhardt, G. Fricker, B. König, A. Buschauer, Potent and selective inhibitors of breast cancer resistance protein (ABCG2) derived from the p-glycoprotein (ABCB1) modulator tariquidar. J. Med. Chem. 52 (4), 1190–1197 (2009)

M. Hubensack, C. Müller, P. Höcherl, S. Fellner, T. Spruss, G. Bernhardt, A. Buschauer, Effect of the ABCB1 modulators elacridar and tariquidar on the distribution of paclitaxel in nude mice. J. Cancer Res. Clin. Oncol. 134 (5), 597-607 (2008)

M. Egger, X. Li, C. Müller, G. Bernhardt, A. Buschauer, B. König, Tariquidar analogues: synthesis by Cu(I)-catalysed N/O–aryl coupling and inhibitory activity against the ABCB1 transporter. Eur. J. Org. Chem. 16 (6), 2643-2649 (2007)

S. Fellner, B. Bauer, D. S. Miller, M. Schaffrik, M. Fankhänel, T. Spruß, G. Bernhardt, C. Graeff, L. Färber, H. Gschaidmeier, A. Buschauer and G. Fricker, Transport of paclitaxel (Taxol) across the blood-brain barrier in vitro and in vivo, J. Clin. Invest. 110, 1309 - 1318 (2002).