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Volume 110, Issue 1
Displaying 1-3 of 3 articles from this issue
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Takeki TSUTSUI1997 Volume 110 Issue 1 Pages 1-9
Published: 1997
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSEstrogens are clearly carcinogenic in humans and rodents, but the mechanisms by which these hormones induce cancer are only partially understood. Stimulation of cell proliferation and gene expression by binding to the estrogen receptor is one important mechanism in hormonal carcinogenesis; however, estrogenicity is not sufficient to explain the carcinogenic activity of all estrogens because some estrogens are not carcinogenic. Estrogens are nonmutagenic in many assays, but exhibit specific types of genotoxic activity under certain conditions. We have studied extensively the mechanisms by which estrogens induce neoplastic transformation in a model in vitro system. Diethylstilbestrol (DES) and 17β-estradiol (E2) and their metabolites induce morphological and neoplastic transformation of Syrian hamster embryo (SHE) cells that express no measurable levels of estrogen receptor. The estrogens induce DNA adduct formation that is detected by 32P-postlabeling. DNA adduct formation is detected in cells treated with DES, but not in cells treated with either α-or β-dienestrol. Similarly, morphological transformation of SHE calls is induced by treatment with DES, but not by treatment with α-or β-dienestrol. Exposure of SHE cells to E2 and its metabolites 2-hydroxyestradiol and 4-hydroxyestradiol leads to covalent DNA adduct formation, corresponding to the induction of cell transformation. Induction of morphological transformation of SHE cells by estrogens correlates well with the ability of estrogens to induce DNA adduct formation. DNA damage caused by DNA adduct formation may be important in hormonal carcinogenesis. It is clear that hormones affect carcinogenesis by epigenetic mechanisms such as stimulation of cell proliferation of estrogen-dependent target cells and reprogramming of cellular differentiation and gene expression. In addition, significant evidence exists that certain estrogens can also cause genetic alterations by mechanisms not involving the classic estrogen receptor. These findings indicate that hormonal carcinogenesis is most likely a result of the interplay of both genetic and epigenetic factors.View full abstractDownload PDF (7080K) -
Mamoru TANAKA, Yoshinori KATOH, Hidetoshi KAWASHIMA1997 Volume 110 Issue 1 Pages 11-17
Published: 1997
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSGastric ulcers were produced in male Donryu rats (8-weeks-old) by subserosal injection of 20μl of 20% acetic acid. Five days later, an indomethacin (IND)-filled osmotic pump (OP) was implanted into the dorsal subcutaneous space in the rats and maintained for 2, 3 or 4 weeks. The natural healing of the acetic acid-induced ulcers was significantly (P<0.05) delayed by administration of IND via OP implanted for 4 weeks. Two, 3 and 4 weeks after OP implantation, the plasma IND level was 1.87±0.13, 2.43±0.16 and 0.74±0.26 (μg/ml), respectively, showing that a steady state IND plasma level was maintained for 3 weeks. The gastric mucosal PGE2 levels in rats with ulcers for 3 weeks after implantation of OP were significantly (P<0.05) reduced by IND (IND(-):576.6±83.9 pg/mg, IND(+):355.6±34.7 pg/mg). Repeated administration of enprostil, famotidine and rabeprazole at 25 μg/kg, 100 mg/kg and 10 mg/kg (p.o., b i d), respectively, showed anti-ulcer activity. Teprenone and rebamipide had only slight anti-ulcer activity. These findings indicated that this model of delayed healing of acetic acid ulcers by IND using OP is useful for investigating the anti-ulcer activity of drugs.View full abstractDownload PDF (4765K) -
Naoko YATO, Takashi MURATA, Nobuko SAITO, Atsuko SAKAI, Matsuo KIKUCHI ...1997 Volume 110 Issue 1 Pages 19-29
Published: 1997
Released on J-STAGE: January 30, 2007
JOURNAL FREE ACCESSThe anti-allergic activity of betotastine besilate (betotastine), a new anti-allergic drug, was investigated in several allergy models of rats in comparison with other anti-allergic drugs. 1) Orally administered betotastine (0.1-30 mg/kg) inhibited homologous passive cutaneous anaphylaxis (PCA) in rats in a dose-dependent manner (ID30-value: 0.38 mg/kg). The inhibitory activity of betotastine was significant at 1 mg/kg and was more potent than that of ketotifen, terfenadine, cetirizine and epinastine. The PCA-inhibitory activity of betotastine lasted more than 8 hr after administration, and the repeated administration of betotastine for 8 days did not induce drug-tolerance. 2) Orally administered betotastine inhibited the histamine-induced skin reaction in rats in a dose-dependent manner (ID30: 0.10 mg/kg), and the inhibitory activity lasted more than 4 hr after the administration. Its inhibitory activity was significant at 0.1 and 1 mg/kg and was more potent than those of ketotifen, terfenadine, cetirizine and epinastine. 3) Betotastine suppressed histamine release from rat peritoneal mast cells at a high concentration (10-3 M). 4) In concanavalin A-induced rat pleurisy, orally administered betotastine (30 mg/kg) suppressed the decrease of histamine content in pleural cells. 5) Betotastine suppressed the leukotoriene B4 and 5-HETE production in rat peritoneal cells at a high concentration (10-3 M). These results suggest that betotastine has a potent and long acting anti-allergic activity, and these effects are mainly due to histamine antagonistic activity.View full abstractDownload PDF (7325K)
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