The objective of this research is to explore the role of cellular membranes as targets for cancer chemotherapy. Of special concern is the antineoplastic agent adriamycin and related anthracycline cogeners. Even though nuclear DNA has been considered as the target for adriamycin action, evidence from numberous laboratories has suggested that cell surface properties are also modulated by the drug and thus may represent an additional site of drug action. Results from this laboratory have confirmed this idea and, in fact, adriamycin can be actively cytotoxic under conditions where it does not enter the cell and bind to DNA, but only accesses the cell surface. Experiments are proposed to synthesize and characterize a variety of immunobilized anthracycline types. These materials will then be used in experimental protocols designed to ascertain the mechanism of cell-surface-induced cytotoxicity and to separate the intracellular from the extracellular effects of these antineoplastic agents. A second major objective is to explore the role of membrane fluidity in mediating the cytotoxic actions of the anthracyclines. Available evidence indicates that modulation of fluidity is one of the earlier events in the initiation of the cytotoxic cascade. Consequently, fluorescence spectroscopy will be employed to determine how anthracyclines alter membrane fluidity by monitoring both rotational and translational motion in tumor cell plasma membranes. In addition, experiments will be conducted to learn how the structure of a particular anthracycline congener is functionally coupled to its ability both to be cytotoxic and to alter membrane fluidity.
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