MEMBRANE INTERACTIONS OF SOME CATAMPHIPHILIC DRUGS AND RELATION TO THEIR MULTIDRUG-RESISTANCE-REVERSING ABILITY

The multidrug-resistance (MDR)-reversing ability of the catamphiphilic drugs could be mediated through their interaction with the membrane p hospholipids. This could lead directly (through changes in membrane pe rmeability and fluidity) and/or indirectly (through inhibition of P-gl ycoprotein phosphorylation via inhibition of the phosphatidylserine-de pendent protein kinase C or changes in the conformation and functionin g of the membrane-integrated proteins via changes in the structure org anization of the surrounding membrane bilayer) to the reversal of MDR. Using differential scanning calorimetry and NMR techniques and artifi cial membranes composed of phosphatidylcholine or phosphatidylserines we found a significant correlation between the MDR-reversing activity of the drugs in doxorubicin-resistant human breast carcinoma MCF-7/DOX and murine leukaemia P388/DOX tumour cells (data taken from the liter ature) and their ability to interact with phosphatidylserines. Trans- and cis-flupentixol were found to interact most strongly with both the phospholipids, followed by trifluoperazine, chlorpromazine, triflupro mazine, flunarizine, imipramine, quinacrine and lidocaine. Differences in the interaction of trans- and cis-flupentixol with the phospholipi ds studied are suggested to be responsible for their different MDR-rev ersing ability. Verapamil showed moderate membrane activity, assuming that the membrane interactions are not the only reason for its high MD R-reversing ability. Amiodarone showed very strong interactions with p hosphatidylserines and is recommended for further MDR-reversal studies .