phosphorus-radioisotopes and Cocarcinogenesis

Formation of carcinogen-DNA adducts in rat oral epithelial cells after treatment with cigarette smoke condensate (CSC) or chewing tobacco in the presence of ethanol was investigated using the 32P-postlabeling procedure. Concomitant treatment of the cells with ethanol increased the relative adduct level over that found in cells treated with tobacco smoke condensate only. Treatment with chewing tobacco resulted in slightly higher adduct levels than in controls. Treatment of the cells with ethanol did not significantly increase the uptake of a polycyclic aromatic hydrocarbon, benzo[j]fluoranthene, however, high tar CSC alone or in combination with ethanol significantly increased the uptake of radiolabeled benzo[j]fluoranthene, suggesting that increased uptake of the carcinogens may be one of the synergistic mechanisms of alcohol in oral carcinogenesis.

Topics: Animals; Carcinogens; Cheek; Cocarcinogenesis; DNA; DNA Damage; Drug Synergism; Ethanol; Fluorenes; Isotope Labeling; Mouth Mucosa; Mouth Neoplasms; Phosphorus Radioisotopes; Plants, Toxic; Rats; Smoke; Tobacco, Smokeless

This study deals with the mechanism of the inhibitory effect exerted by the immunosuppressant ciclosporin (CsA) on phorbol-ester-induced inflammation, epidermal hyperplasia and tumor promotion in mouse skin in vivo. This effect coincides with an inhibition of the phosphorylation of a 100-kilodalton protein (p100) in epidermal cytosol in vitro, which has been identified as elongation factor 2 (EF-2) of protein biosynthesis. Phosphorylation of EF-2 is dependent on Ca2+ and calmodulin, and inhibition of EF-2 phosphorylation by CsA is due to an interaction of CsA with calmodulin. The EF-2 phosphorylation system has a metabolic half-life of 1.5 h probably due to a rather rapid turnover rate of the EF-2 kinase. Since CsA inhibits specifically 12-O-tetradecanoylphorbol-13-acetate (TAP)-stimulated but not basal protein synthesis in epidermis, it is proposed that Ca2+/calmodulin-dependent phosphorylation of EF-2 is involved in the induction of the hyperplastic response by TPA and that CsA suppresses TPA effects by inhibition of EF-2-phosphorylation and perhaps other calmodulin-dependent processes. The potential applicability of calmodulin inhibitors in the treatment of hyperproliferative skin diseases is discussed.

Topics: Animals; Calcium; Calmodulin; Cell Transformation, Neoplastic; Chromatography, DEAE-Cellulose; Cocarcinogenesis; Cycloheximide; Cyclosporins; Cytosol; Electrophoresis, Polyacrylamide Gel; Mice; Peptide Elongation Factor 2; Peptide Elongation Factors; Phosphorus Radioisotopes; Phosphorylation; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate