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In search for drugs inhibiting multidrug resistens (Medicin resistens)

In order to develop more effective drugs reversing multidrug resistance [MDR] the molecular mechanisms whereby existing MDR-inhibitors perform their action should be learned.Phenothiazines are drugs that can modulate efflux-pumps responsible for MDR.It is unknown whether the effect of phenothiazines is a direct effect on the pumps or an indirect effect via a perturbation of the lipid bilayer.Our attempt is to investigate the interactions of different phenothiazine derivatives with the lipid bilayer of the plasma membrane, using the human erythrocyte as a cell model.The main task of our investigation is to study how phenothiazine derivatives affect the distribution of phosphatidylserine [PS] between the lipid bilayer leaflets and the glutathione transport, and to relate the effect to their molecular properties and to their capacity to inhibit MDR in cancer cells.We ask ourselves are the transporters responsible for PS flip and flop or for glutathione transport related to the multidrug efflux pump Besides this, we will also study how phenothiazine derivatives affect erythrocyte shape and whether they induce plasma membrane vesiculation.These studies will inform about the perturbing effect of the phenothiazine derivatives on the plasma membrane lipid bilayer and reveal their transmembrane distribution between the bilayer leaflets.Following these studies with human erythrocytes a similar structure-activity relationship study will be performed using multidrug-resistant cancer cell lines.

Publication(s)

16.2.1996 / 28.4.1999