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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA044729-03
Application #
3187482
Study Section
Experimental Therapeutics Subcommittee 2 (ET)
Project Start
1987-06-01
Project End
1990-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
3
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Vermont & St Agric College
Department
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
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Bhushan, A; Abramson, R; Chiu, J F et al. (1992) Expression of c-fos in human and murine multidrug-resistant cells. Mol Pharmacol 42:69-74
Tritton, T R (1991) Cell surface actions of adriamycin. Pharmacol Ther 49:293-309
Constantinides, P P; Wang, Y Y; Burke, T G et al. (1990) Transverse location of anthracyclines in lipid bilayers. Paramagnetic quenching studies. Biophys Chem 35:259-64
Posada, J; Vichi, P; Tritton, T R (1989) Protein kinase C in adriamycin action and resistance in mouse sarcoma 180 cells. Cancer Res 49:6634-9
Posada, J A; McKeegan, E M; Worthington, K F et al. (1989) Human multidrug resistant KB cells overexpress protein kinase C: involvement in drug resistance. Cancer Commun 1:285-92
Hacker, M P; Lazo, J S; Pritsos, C A et al. (1989) Immobilized adriamycin: toxic potential in vivo and in vitro. Sel Cancer Ther 5:67-72
Vichi, P; Tritton, T R (1989) Stimulation of growth in human and murine cells by adriamycin. Cancer Res 49:2679-82
Dreyer, R; Hawrot, E; Sartorelli, A C et al. (1988) Sedimentation field flow fractionation of fused unilamellar vesicles: comparison with electron microscopy and gel filtration. Anal Biochem 175:433-41

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