The role of membranes in the mechanism of action of the antineoplastic agent adriamycin. Spin-labeling studies with chronically hypoxic and drug-resistant tumor cells.

Electron spin resonance spectroscopy has been employed to analyze the changes in membrane order parameter in Sarcoma 180 cells under conditions in which an alteration in cellular susceptibility to the chemotherapeutic agent adriamycin is demonstrable. Changes in relative membrane fluidity using the paramagnetic probe 5-doxyl stearic acid were found to be associated with two phenomena which result in an altered cellular response to adriamycin: (a) the presence of an oxygen-deficient environment and (b) the expression of drug resistance. Under hypoxic conditions, in which the susceptibility to the cytotoxic action of adriamycin is increased, a decrease in bulk membrane order parameter was observed. Upon reoxygenation, the membrane fluidity and enhanced susceptibility to adriamycin reverted to control conditions with the same time course. In the case of drug-resistant cells, a progressive decrease in membrane fluidity was also observed which correlated with the degree of resistance to adriamycin. These data suggest that the physical alterations in the membrane reported by the spin label may be functionally linked to biological alterations in sensitivity to adriamycin.