allopurinol and Papilloma

Salvia miltiorrhiza is a traditional Chinese medicine which has been well documented for its anti-cancer effects. Based on the structure of danshinone, one of the active compounds derived from Salvia miltiorrhiza, we synthesized a simplified phenolic analog, S-3-1, and tried to explore its possible actions in preventing the development of cancer. With the Ames test, S-3-1 was found to efficiently suppress the mutagenicity of benzo[alpha]pyrene. This result is consistent with the inhibitory effect of S-3-1 on the activation of benzo[alpha]pyrene by hepatic microsomal enzymes. Besides the anti-initiation effects, S-3-1 could significantly inhibit the croton oil-induced increase of mouse skin epithermal ornithine decarboxylase activity. Moreover, S-3-1 quenched both superoxide and hydroxyl free radicals whereas it inhibited lipid peroxidation in the in vitro model. These results suggest that S-3-1 might act as anti-initiation and anti-promotion agents through reversing the biochemical alterations induced by carcinogen during carcinogenesis. Therefore, we further investigated the effects of S-3-1 on carcinogenesis. In vitro, S-3-1 inhibited the benzo[alpha]pyrene-induced transformation of V79 Chinese hamster lung fibroblasts. At 10-40 mg/kg, S-3-1 was found to inhibit the development of DMBA/croton oil-induced skin papilloma in mice through decreasing the incidence of papilloma, prolonging the latent period of tumor occurrence and reducing tumor number per mouse in a dose-dependent manner. We concluded from this study that S-3-1 might be developed as a new chemopreventive drug.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Benzo(a)pyrene; Benzofurans; Bepridil; Biphenyl Compounds; Cell Transformation, Neoplastic; Cells, Cultured; Cricetinae; Croton Oil; Cysteine; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs, Chinese Herbal; Epithelial Cells; Fibroblasts; Free Radical Scavengers; Hypoxanthine; In Vitro Techniques; Iron; Lipid Peroxidation; Lung; Male; Medicine, Chinese Traditional; Mice; Mice, Inbred ICR; Microsomes, Liver; Molecular Structure; Mutagens; Ornithine; Ornithine Decarboxylase; Papilloma; Pentetic Acid; Phenanthrenes; Picrates; Plants, Medicinal; Rats; Salmonella; Skin; Skin Neoplasms; Spectrometry, Mass, Electrospray Ionization; Structure-Activity Relationship; Xanthine Oxidase

The antitumor effect of oxygen radicals produced by hypoxanthine and xanthine oxidase reaction was studied in an experimental rabbit model. VX2 carcinomas were transplanted into rabbit hind legs. Hypoxanthine was administered continuously through the ear vein, while xanthine oxidase was administered simultaneously through the femoral artery. As a result, hypoxanthine and xanthine oxidase reacted only in the hind leg, and superoxide was produced in that area. The volume of the VX2 carcinoma was measured immediately prior to treatment and 7 days later. As an index of lipid peroxidation, thiobarbituric acid-reactive substances in the tumor tissue were measured 60 min following infusion of hypoxanthine and xanthine oxidase. Tumor growth was suppressed significantly by the hypoxanthine-xanthine oxidase reaction, and thiobarbituric acid-reactive substances in the tumor tissue infused with hypoxanthine and xanthine oxidase were significantly increased. In addition, the antitumor effect of the hypoxanthine and xanthine oxidase reaction was significantly inhibited by the administration of superoxide dismutase and catalase. Pathological examination showed that oxygen radicals produced by hypoxanthine and xanthine oxidase reaction were selectively more destructive for VX2 carcinoma tissue than muscle tissue surrounding the tumor region. These results suggest that oxygen radicals produced by hypoxanthine and xanthine oxidase reaction produce an anticancer effect and that the VX2 carcinoma used in this study was more sensitive to oxygen radicals than normal muscle tissue.

Topics: Animals; Carcinoma, Squamous Cell; Catalase; Cattle; Free Radical Scavengers; Humans; Hypoxanthine; Hypoxanthines; Male; Muscles; Papilloma; Rabbits; Recombinant Proteins; Superoxide Dismutase; Superoxides; Thiobarbituric Acid Reactive Substances; Xanthine Oxidase

The activities of several enzymes involved in reactive oxygen production and detoxification were quantified in murine skin during the ontogeny of chemically induced skin cancer. Relative to solvent-treated controls, the specific activities of epidermal superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) were reduced approximately 45, approximately 60 and approximately 24% respectively, 24 h after the fourth or tenth topical application of 1 microgram of 12-O-tetradecanoylphorbol-13-acetate (TPA) to the dorsal skin of SENCAR mice. The specific activity of epidermal xanthine oxidase (XO) increased approximately 350% during the same period. SOD and CAT specific activities in papillomas and carcinomas generated in an initiation-promotion protocol were approximately 15 and approximately 40% respectively of the activities measured in age-matched, non-treated mice. CAT and SOD activities were also significantly suppressed in the skin adjacent to the papillomas for several weeks following the cessation of TPA promotion, but eventually recovered to the levels measured in age-matched controls. XO specific activities in papillomas and squamous cell carcinomas (SCC) were approximately 85-350% greater than the activities determined in skin adjacent to the tumors. The increases in XO and the decreases in SOD and CAT activities measured in the tumors were independent of continued treatment with TPA, and thus characteristic of the tumor phenotype. GPX activities in papillomas were comparable to normal, untreated skin, but reduced approximately 22-41% in SCC. Collectively, these studies demonstrate that TPA orchestrates changes in the activities of several enzymes involved in reactive oxygen metabolism that are characteristic of the papilloma and SCC phenotype.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Catalase; Female; Glutathione Peroxidase; Mice; Mice, Inbred Strains; Oxygen; Papilloma; Phenotype; Skin; Skin Neoplasms; Superoxide Dismutase; Tetradecanoylphorbol Acetate; Xanthine Dehydrogenase; Xanthine Oxidase