The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation.

The human diet contains a great variety of natural mutagens and carcinogens, as well as many natural antimutagens and anticarcinogens. Many of these mutagens and carcinogens may act through the generation of oxygen radicals. Oxygen radicals may also play a major role as endogenous initiators of degenerative processes, such as DNA damage and mutation (and promotion), that may be related to cancer, heart disease, and aging. Dietary intake of natural antioxidants could be an important aspect of the body’s defense mechanism against these agents. Many antioxidants are being identified as anticarcinogens. Characterizing and optimizing such defense systems may be an important part of a strategy of minimizing cancer and other age-related diseases.

https://science.sciencemag.org/content/sci/221/4617/1256.full.pdf

Dietary carcinogens and anticarcinogens Oxygen radicals and degenerative diseases

There is convincing evidence that cellular prooxidant states--that is, increased concentrations of active oxygen and organic peroxides and radicals--can promote initiated cells to neoplastic growth. Prooxidant states can be caused by different classes of agents, including hyperbaric oxygen, radiation, xenobiotic metabolites and Fenton-type reagents, modulators of the cytochrome P-450 electron-transport chain, peroxisome proliferators, inhibitors of the antioxidant defense, and membrane-active agents. Many of these agents are promoters or complete carcinogens. They cause chromosomal damage by indirect action, but the role of this damage in carcinogenesis remains unclear. Prooxidant states can be prevented or suppressed by the enzymes of the cellular antioxidant defense and low molecular weight scavenger molecules, and many antioxidants are antipromoters and anticarcinogens. Finally, prooxidant states may modulate the expression of a family of prooxidant genes, which are related to cell growth and differentiation, by inducing alterations in DNA structure or by epigenetic mechanisms, for example, by polyadenosine diphosphate-ribosylation of chromosomal proteins.

https://science.sciencemag.org/content/sci/227/4685/375.full.pdf

Prooxidant states and tumor promotion.

Free radicals, antioxidant enzymes, and carcinogenesis

Results from the testing of 108 coded chemicals in Chinese hamster ovary (CHO) cells for the induction of chromosome aberrations and sister chromatid exchanges (SCEs) are presented. All chemicals were tested with and without exogenous metabolic activation, using protocols designed to allow testing up to toxic doses. Cell harvest times could also be extended if chemical-induced cell cycle delay was seen. Chromosome aberrations were induced by 43 of the chemicals, and 66 induced SCEs; 37 of the chemicals were positive for both endpoints.

Chromosome aberrations and sister chromatid exchanges in chinese hamster ovary cells: Evaluations of 108 chemicals

To gain insight into the mechanism of formation of chromosomal aberrations by the tumor promoter phorbolmyristate acetate (PMA) in human lymphocytes, we investigated the effect of antioxidants and inhibitors of arachidonic acid metabolism. Among the antioxidants bovine erythrocyte CuZn superoxide dismutase, glutathione peroxidase, mannitol (a scavenger of hydroxyl radicals), butylated hydroxytoluene and butylated hydroxyanisole were anticlastogenic while catalase and dimethylfuran (a scavenger of singlet oxygen) were inactive. These results show that the induction of aberrations by PMA occurs via indirect action, i.e. the intermediacy of superoxide and hydroxyl radicals. The following inhibitors of arachidonic acid metabolism were strongly anticlastogenic: the cyclo-oxygenase inhibitors indomethacin and flufenamic acid and the lipoxygenase inhibitor BN1015. Imidazole, nordihydroguaiaretic acid BN 1048 and 5,8,11,14-eicosatetraynoic acid were moderately active. The inhibitor of phospholipase A 2 , fluocinolone acetonide, was also anticlastogenic. We conclude that the oxidative metabolism of arachidonic acid is involved in the induction of chromosomal aberrations by PMA in human lymphocytes. However, because of the limited selectivity of these drugs, it is not yet possible to identify unambiguously the step(s) in the arachidonic acid cascade responsible for PMA clastogenicity.

Suppression of tumor promoter phorbolmyristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism.

The hepatocarcinogen aflatoxin B1 (AFB1) was found to be a potent clastogen for phytohemagglutinin stimulated human lymphocytes. It also induced sister chromatid exchanges. These types of chromosomal damage were induced at very low levels of covalent AFB1 - DNA adducts suggesting that AFB1 operates in part by indirect action because of its membrane-active character. The membrane-active character of AFB1 is documented by the following results: (i) AFB1 stimulated the excretion of hydroxy- and/or hydroperoxy-arachidonic acid (AA) and free AA into the culture medium; (ii) the phospholipase A2 inhibitor p-bromophenacylbromide was anticlastogenic ; (iii) the inhibitors of the oxidative metabolism of AA indomethacin, flufenamic acid, 5,8,11,14-eicosatetraynoic acid, nordihydroguaiaretic acid and BN 1015 were anticlastogenic . These results are compatible with the induction of DNA damage by indirect action or the formation of covalent adducts via metabolic activation by cooxygenation . The observation that CuZn superoxide dismutase was anticlastogenic indicates the intermediacy of superoxide in DNA damage formation and supports the former mechanism.

Evidence for membrane-mediated chromosomal damage by aflatoxin B1 in human lymphocytes.

Bloom's syndrome (BS), an autosomal recessive hereditary disease, is clinically characterized by severe preand postnatal growth retardation, sensitivity of the facial skin to sun light, unspecific and variable immunodeficiency, and increased susceptibility to the development of cancer (German 1969). The most remarkable characteristics on the cellular level are increased rates of spontaneous chromosomal aberrations and sister chromatid exchanges (SCE) (Chaganti et al. 1974) and, therefore, BS is often referred to as a \"Chromosome Breakage Syndrome\" (German 1972). The solar skin sensitivity of BS patients is reflected in increased sensitivity of BS fibroblasts in culture to near-ultraviolet light (Zbinden and Cerutti 1981) and, on the molecular level, in excessive D N A breakage by nearultraviolet light (Hirschi et al. 1981). Previous results from our laboratory indicate that skin fibroblasts from BS patients release a low molecular weight component into the culture media which breaks chromosomes and induces SCE in phytohemagglutinin (PHA) stimulated lymphocytes from normal donors (Emerit and Cerutti 1981). Similarly, such a \"clastogenic factor\" (CF) was also detected in culture media of fibroblasts of ataxia telangiectasia patients as welI as in their plasma (Shaham et al. 1980). We report that plasma of two BS patients also contains a CF. This indicates that the formation of a CF is a bona fide characteristic of BS rather than merely a property of BS fibroblasts in tissue culture.

A. Levy

Papers

Suppression of tumor promoter phorbolmyristate acetate-induced chromosome breakage by antioxidants and inhibitors of arachidonic acid metabolism.

Evidence for membrane-mediated chromosomal damage by aflatoxin B1 in human lymphocytes.

Chromosome breakage factor in the plasma of two Bloom's syndrome patients.