A differential interaction of daunomycin, adriamycin and their derivatives with human erythrocytes and phospholipid bilayers.
Drug-membrane association of daunomycin, adriamycin and three of its derivatives, adriamycin-14-octanoate (AD-14-OCTA), adriamycin-14-acetate (AD-14-ACE) and N-trifluoroacetyladriamycin-14-valerate (AD32), was studied using phospholipid bilayers and human erythrocytes. The various drugs exhibited a differential affinity to membrane-lipid domains. Lipid-incorporated drugs exhibit a marked change in the shape of the emission spectrum which was utilized for the evaluation of the apparent dielectric constant, epsilon, of the environment surrounding the anthracycline moiety, as well as for the determination ofthe partitioning constant. By measuring the fluorescence polarization and the fluorescence lifetime of the incorporated drugs, rotational relaxation times of 4--8 ns were derived. These parameters provide a supportive evidence of the association of the fluorophore of the drugs with membrane-lipid domains. The anthracycline derivatives interact to a different degree with dipalmitoyl phosphatidylcholine and phosphatidylserine as reflected by changes in their thermotropic properties assessed by differential scanning calorimetry. Daunomycin was the most effective in decreasing the temperature of the phase transition and brought about a comparable reduction in the enthalpy of melting as AD32 and AD-14-OCTA. Adariamycin was the least potent of the series. AD-14-ACE and AD32 protected erythrocytes against hypotonic lysis, adriamycin and daunomycin had no significant effect on the susceptibility to hypotonic lysis, whereas AD-14-OCTA proved to be hemolytic even at low concentration (approx. 10(-7M).
D002152:Calorimetry, Differential Scanning; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000097:blood; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000097:blood; D004910:Erythrocyte Membrane / Q000378:metabolism* / Q000648:ultrastructure; D004912:Erythrocytes / Q000378:metabolism*; D006801:Humans; D008081:Liposomes; D008855:Microscopy, Electron, Scanning; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
D008081:Liposomes; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D004317:Doxorubicin; D003630:Daunorubicin