Reactive oxygen species (superoxide, hydrogen peroxide, and hydroxyl and peroxy radicals) are genotoxic and have been implicated in the activation of procarcinogens. The copper chelate Cu(II) (3,5-diisopropylsalicylate)2[Cu(Dips)2] is capable of detoxifying these oxygen species and can inhibit the mutagenicity and tumorigenicity of the procarcinogen DMBA. The major objectives of this proposal are: (1) to survey the effects of Cu(Dips)2 and its analogues on the mutagenicity and cytotoxicity of a variety of promutagens and direct acting mutagens; (2) determine whether Cu(Dips)2 effects are due to its oxygen scavenging properties; (3) survey the effects of a series of Cu(Dips)2 analogues that are either more or less lipophilic than the parent compound; (4) characterize the contributions of enzymes of the arachidonic acid pathway (prostaglandin endoperoxide synthetase (PES) and lipoxygenases) to promutagen metabolism in the skin, and determine whether Cu(Dips)2 inhibits these enzymes; (5) include tumor experiments to determine whether Cu(Dips)2 and its analogues can inhibit the initiation phase of two-stage chemical carcinogenesis in murine skin. Structural analogues of Cu(Dips)2 that are either more or less lipophilic than the parent compound, or lack the oxygen scavenging properties of Cu(Dips)2 will be tested with a variety of mutagens in both an Ames S. typhimurium revertant assay, and a keratinocyte cell-mediated mutation assay. The novel possibility that lipoxygenases and PES contribute to the metabolism of xenobiotics in murine skin, and that Cu(Dips)2 affects these enzymes, will be examined by determining the effects of the singular and combinational use of lipoxygenase or PES inhibitors with Cu(Dips)2 in the keratinocyte cell-mediated mutation assay, and the effects of these agents on the metabolism of hydrocarbons and the synthesis of prostaglandins and hydroperoxy fatty acids in cultured keratinocytes, and their abilities to act as anti-initiators in a murine skin two-stage carcinogenesis protocol. Effects of Cu(Dips)2 on the cyclooxygenase and peroxidase activities of PES will also be analyzed in ram seminal vesicles, a tissue that has no P-450-dependent monooxygenase activities. Copper chelates are currently in use, or are being considered for use in clinical medicine. The studies of this proposal will evaluate the chemo-preventive values of copper chelates as anti-initiators, and characterize the contributions of enzymes of the arachidonic acid pathway to xenobiotic metabolism in skin.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA040823-03
Application #
3181118
Study Section
(SSS)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1987-09-01
Budget End
1988-08-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
Organized Research Units
DUNS #
001910777
City
Houston
State
TX
Country
United States
Zip Code
77030
Quan, T; Reiners Jr, J J; Bell, A O et al. (1994) Cytotoxicity and genotoxicity of (+/-)-benzo[a]pyrene-trans-7,8-dihydrodiol in CYP1A1-expressing human fibroblasts quantitatively correlate with CYP1A1 expression level. Carcinogenesis 15:1827-32
Scholler, A; Hong, N J; Bischer, P et al. (1994) Short and long term effects of cytoskeleton-disrupting drugs on cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells: suppression by the microtubule inhibitor nocodazole. Mol Pharmacol 45:944-54
Reiners Jr, J J; Scholler, A; Bischer, P et al. (1993) Suppression of cytochrome P450 Cyp1a-1 induction in murine hepatoma 1c1c7 cells by 12-O-tetradecanoylphorbol-13-acetate and inhibitors of protein kinase C. Arch Biochem Biophys 301:449-54
Reiners Jr, J J; Cantu, A R; Scholler, A (1992) Phorbol ester-mediated suppression of cytochrome P450 Cyp1a-1 induction in murine skin: involvement of protein kinase C. Biochem Biophys Res Commun 186:970-6
Reiners Jr, J J; Cantu, A R; Thai, G et al. (1992) Differential expression of basal and hydrocarbon-induced cytochrome P-450 monooxygenase and quinone reductase activities in subpopulations of murine epidermal cells differing in their stages of differentiation. Drug Metab Dispos 20:360-6
Reiners Jr, J J; Pavone, A; Cantu, A R et al. (1992) Differential expression of cytochrome P-450 in proliferating and quiescent cultures of murine lung epithelial cells. Biochem Biophys Res Commun 183:193-8
Reiners Jr, J J; Kodari, E; Cappel, R E et al. (1991) Assessment of the antioxidant/prooxidant status of murine skin following topical treatment with 12-O-tetradecanoylphorbol-13-acetate and throughout the ontogeny of skin cancer. Part II: Quantitation of glutathione and glutathione disulfide. Carcinogenesis 12:2345-52
Reiners Jr, J J; Thai, G; Rupp, T et al. (1991) Assessment of the antioxidant/prooxidant status of murine skin following topical treatment with 12-O-tetradecanoylphorbol-13-acetate and throughout the ontogeny of skin cancer. Part I: Quantitation of superoxide dismutase, catalase, glutathione peroxidase Carcinogenesis 12:2337-43
Reiners Jr, J J; Rupp, T; Conti, C J (1991) Modulation of xanthine dehydrogenase and oxidase activities during the hormonal induction of vaginal epithelial differentiation in ovariectomized mice. Differentiation 47:69-75
MacLeod, M C; Mann, K L; Thai, G et al. (1991) Inhibition by 2,6-dithiopurine and thiopurinol of binding of a benzo(a)pyrene diol epoxide to DNA in mouse epidermis and of the initiation phase of two-stage tumorigenesis. Cancer Res 51:4859-64

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