The Anticancer Drug Chlorambucil Interacts with the Human Erythrocyte Membrane and Model Phospholipid Bilayers

1999 ◽  
Vol 54 (12) ◽  
pp. 1089-1095 ◽  
Author(s):  
Mario Suwalsky ◽  
Pedro Hernández ◽  
Fernando Villena ◽  
Carlos P. Sotomayor

The plasma membrane has gained increasing attention as a possible target of antitumor drugs. It has been reported that they act as growth factor antagonists, growth factor receptor blockers, interfere with mitogenic signal transduction or exert direct cytotoxic effects. Chlorambucil (4-[p-(bis[2-chloroethyl]amino)phenyl]butyric acid) is an alkylating agent widely used in the treatment of chronic lymphocytic leukaemia. Contradictory reports have been published concerning its interaction with cell membranes. Whereas a decrease in the fluidity of Ehrlich ascite tumor cells has been adduced, no evidences were found that chlorambucil changes membrane lipid fluidity and alkylating agents had effects in these systems even at highly toxic concentrations. Our results showed that chlorambucil at a dose equivalent to its therapeutical concentration in the plasma (3.6 μm) caused the human erythrocyte membrane to develop cup-shaped forms (stomatocytes). Accordingly to the bilayer couple hypothesis, this means that the drug is inserted into the inner monolayer of the erythrocyte membrane, a conclusion supported by X-ray diffraction performed on multilayers of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE), representative of phospholipid classes located in the outer and inner monolayers of the erythrocyte membrane, respectively. It is concluded that the cytotoxic effect of chlorambucil might be due to alteration of the structure and therefore of the physiological properties of cell membranes such as fluidity, permeability, receptor and channel functions.

2004 ◽  
Vol 59 (5-6) ◽  
pp. 427-431 ◽  
Author(s):  
Mario Suwalsky ◽  
Sigrid Mennickent ◽  
Beryl Norris ◽  
Fernando Villena ◽  
Francisco Cuevas ◽  
...  

Phenytoin (diphenylhydantoin) is an antiepileptic agent effective against all types of partial and tonic-clonic seizures. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro. This effect is mediated by a slowing of the rate of recovery of voltage activated Na+ channels from inactivation. For this reasons it was thought of interest to study the binding affinities of phenytoin with cell membranes and their perturbing effects upon membrane structures. The effects of phenytoin on the human erythrocyte membrane and molecular models have been investigated in the present work. This report presents the following evidence that phenytoin interacts with cell membranes: a) X-ray diffraction and fluorescence spectroscopy of phospholipid bilayers showed that phenytoin perturbed a class of lipids found in the outer moiety of cell membranes; b) in isolated unsealed human erythrocyte membranes (IUM) the drug induced a disordering effect on the polar head groups and acyl chains of the erythrocyte membrane lipid bilayer; c) in scanning electron microscopy (SEM) studies on human erythrocytes the formation of echinocytes was observed, due to the insertion of phenytoin in the outer monolayer of the red cell membrane. This is the first time that an effect of phenytoin on the red cell shape is described. However, the effects of the drug were observed at concentrations higher than those currently found in plasma when phenytoin is therapeutically administered.


1974 ◽  
Vol 249 (4) ◽  
pp. 1022-1025
Author(s):  
Klaus Stellner ◽  
Sen-Itiroh Hakomori

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