We propose to continue our study of the membrane basis for susceptibility to anticancer therapy. This application is to investigate the role of fish oil polyunsaturated fatty acids in cancer biology and therapy. There is evidence that membrane polyunsaturates of the omega-3 class, which are abundant in marine oils, can inhibit the growth of malignant neoplasms. In contradistinction, those of omega-6 class may actually promote growth. Our paradigm is the experimental insertion of fatty acids of various comparative classes into the membranes of cancer cells. We will utilize both dietary and tissue culture models. The insertion is fairly rapid and dose dependent (with plateau). The substituted membranes have no apparent major disruption of membrane structure based on preliminary evidence. The biochemical (lipid composition) and physical results (membrane order) of the substitution on plasma and intracellular membranes will be delineated. Studies on both a murine and human neoplasm are included. The effects of the substitution on the biology (self- renewal, differentiation) will be examined. Most importantly, we will investigate the potential of dietary fatty acid alteration as a therapeutic adjunct to cancer chemotherapy (Adriamycin and the membrane active drug ET-18-OCH3) and hyperthermia. Clinical contexts will be pursued, but not forced. We will also continue our investigation of the mechanisms by which membrane polyunsaturated fatty acid enrichment augments the sensitivity of leukemia cells to Adriamycin and this will include a multifaceted investigation of the role of oxygen radicals and subsequent lipid peroxidation. The studies should help understand the role of membranes in the altered biology of cancer, and the application of fatty acid alteration as adjunct to cancer therapy as part of a multimodal approach. The results could lead to application to human cancer since there are dietary methods for enriching membranes clinically.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031526-09
Application #
3169642
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1985-04-01
Project End
1993-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
9
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Kelley, E E; Buettner, G R; Burns, C P (1995) Relative alpha-tocopherol deficiency in cultured cells: free radical-mediated lipid peroxidation, lipid oxidizability, and cellular polyunsaturated fatty acid content. Arch Biochem Biophys 319:102-9
Wagner, B A; Buettner, G R; Burns, C P (1994) Free radical-mediated lipid peroxidation in cells: oxidizability is a function of cell lipid bis-allylic hydrogen content. Biochemistry 33:4449-53
Wagner, B A; Buettner, G R; Burns, C P (1993) Increased generation of lipid-derived and ascorbate free radicals by L1210 cells exposed to the ether lipid edelfosine. Cancer Res 53:711-3
Kelley, E E; Modest, E J; Burns, C P (1993) Unidirectional membrane uptake of the ether lipid antineoplastic agent edelfosine by L1210 cells. Biochem Pharmacol 45:2435-9
Buettner, G R; Kelley, E E; Burns, C P (1993) Membrane lipid free radicals produced from L1210 murine leukemia cells by photofrin photosensitization: an electron paramagnetic resonance spin trapping study. Cancer Res 53:3670-3
Wagner, B A; Buettner, G R; Burns, C P (1992) Membrane peroxidative damage enhancement by the ether lipid class of antineoplastic agents. Cancer Res 52:6045-51
Petersen, E S; Kelley, E E; Modest, E J et al. (1992) Membrane lipid modification and sensitivity of leukemic cells to the thioether lipid analogue BM 41.440. Cancer Res 52:6263-9
Burns, C P; Wagner, B A (1991) Heightened susceptibility of fish oil polyunsaturate-enriched neoplastic cells to ethane generation during lipid peroxidation. J Lipid Res 32:79-87
Burns, C P; Petersen, E S (1990) Effect of butylated hydroxytoluene on bilineage differentiation of the human HL-60 myeloblastic leukemia cell. J Cell Physiol 144:36-41
Burns, C P; Spector, A A (1990) Effects of lipids on cancer therapy. Nutr Rev 48:233-40

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