Comparison of the membrane-related effects of cytarabine and other agents on model membranes.
The membrane-associated effects of a series of chemotherapeutic and other drugs were examined via differential scanning calorimetry and by their modulation of the action of porcine phospholipase A2 (PLA2) on bilayer substrates. The drugs examined included: cytarabine, amino-glycoside antibiotics, adriamycin, dibucaine, butacaine, and VP-16. The bilayers employed were phase-separated ternary lipid mixtures containing dimyristoylphosphatidylcholine: palmitoyllysolecithin: and either hexadecanoic acid (fatty acid ternary mixture) or hexadecanol (alcohol ternary mixture). Effects of the more hydrophilic drugs (cytarabine and aminoglycoside antibiotics) on the calorimetric profiles of the negatively charged (fatty acid-containing) and the neutral (hexadecanol-containing) ternary lipid mixtures indicate that the interaction of these drugs with biomembranes is likely to be dominated by electrostatic interactions. All of the drugs investigated, including the more hydrophobic adriamycin, dibucaine, butacaine, and VP-16, affected the phase equilibrium in the membrane and exhibited apparent noncompetitive inhibition of the action of PLA2 on bilayers composed of ternary lipid substrates. In addition, cytarabine inhibited fusion of fatty acid-containing ternary mixtures.


CONCLUSIONS
These drug:membrane interactions leading to a shift in the phase equilibria were apparently regiospecific. Hydrophilic drug:membrane interactions included an important electrostatic component. The effects of all of the drugs employed in this study on the action of PLA2 on a bilayer substrate (fatty acid-containing ternary lipid mixture) are hypothesized to be a result of the drug-mediated shift in phase equilibria away from the optimally active phase distribution. As a result, PLA2 binds with normal affinity to the membrane, but its membrane substrate is not catalytically turned over. It is evident that these drugs can directly affect cellular homeostasis in a manner that can show a dependence on the nature of the membrane surface.
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002462:Cell Membrane / Q000187:drug effects*; D003124:Colorimetry; D003561:Cytarabine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D008051:Lipid Bilayers; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D054467:Phospholipases A2
D000900:Anti-Bacterial Agents; D008051:Lipid Bilayers; D003561:Cytarabine; D004317:Doxorubicin; D010741:Phospholipases A; D054467:Phospholipases A2