Relationship of Phthalanilide-Lipid Complexes to Uptake and Retention of 2-Chloro-4′,4″-di(2-imidazolin-2-yl)terephthalanilide (NSC 60339) by Sensitive and Resistant P388 Leukemia Cells

P388 lymphocytic leukemia cells that are either sensitive or resistant to 2-chloro-4′,4″-di(2-imidazolin-2-yl)terephthalanilide, NSC 60339, take up an equivalent amount of drug 0.5 hr after a single dose of the drug is given to host mice. The drug is found primarily in the mitochondrial and nuclear fractions of the cells after disruption of the cells and differential centrifugation. Within 24 hr the concentration of drug in resistant cells decreases significantly, but the concentration in sensitive cells does not. Most of the decrease in drug is from the nuclear fraction. Washing 0.5-hr treated cells with sucrose rather than with saline extracts 58% of drug as lipid complexes from resistant cells but extracts only 12% of drug as drug-lipid complexes from sensitive cells. The distribution in biphasic solvents of drug-lipid complexes is different for the 2 cell lines. The difference in partition coefficients for the drug-lipid complexes and the difference in mobilization of drug-lipid complexes by the 2 cell lines are discussed in relation to known effects that fatty acids have on the interfacial behavior of the phospholipids and in terms of a mechanism by which cells may become resistant to phthalanilide chemotherapy.