benzofurans and Papilloma

Chlorinated aromatic contaminants are active in carcinogenic processes within the skin and may have the potential to modulate ultraviolet radiation (UV)-induced skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans) during the irradiation phase of photocarcinogenesis was associated with significant (P < or = 0.001) reductions in papilloma incidence and squamous cell carcinoma multiplicity at irradiated skin sites. This protective effect was associated with significantly (P < 0.0001) reduced chronic epidermal thickening in UV and contaminant-exposed mice compared with mice exposed to UV only. Contaminant exposure was also associated with increased UV absorbance of skin methanol extracts implying a sunscreen-like effect.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dibenzofurans, Polychlorinated; Environmental Pollutants; Female; Methanol; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Papilloma; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Skin; Skin Neoplasms; Soil Pollutants; Ultraviolet Rays

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

2,3,7,8-Tetrachlorodibenzo-p-dixoin 2,3,4,7,8-pentachlorodibenzofuran (PCDF), and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are highly toxic members of a class of environmental contaminants, the polychlorinated aromatic hydrocarbons (PCAH), which exhibit a similar and highly characteristic spectrum of toxic effects. For purposes of risk assessment, it is important to be able to make accurate estimates of the relative potency of these and related compounds. Previous investigations have indicated that, in acute exposure or in vitro studies, PCDF is approximately 0.1 times as toxic and HCDF is approximately 0.01 times as toxic as TCDD. In this study, we compared the relative toxicity and tumor-promoting abilities of TCDD, PCDF, and HCDF in hairless mouse skin. Female hairless mice (HRS/J hr/hr) were treated dermally with the initiator MNNG, then dosed twice weekly for 20 weeks with acetone, TCDD (2.5-10 ng/mouse/dose), PCDF (25-100 ng/mouse/dose), or HCDF (250-1000 ng/mouse/dose) as promoter. TCDD, PCDF, and HCDF were all potent promoters for the induction of squamous cell papillomas. There was, however, no difference in the incidence or multiplicity of papilloma formation between groups. The same doses of the three PCAH, in the absence of initiator, induced no skin papillomas. TCDD produced a significant increase in liver:body weight ratio (p less than 0.001) at all doses and a decrease in thymus:body weight ratio at a dose of 10 ng (p less than 0.001). Mice treated with PCDF and HCDF had marked thymic and splenic involution, liver hypertrophy, mucous cell hyperplasia in the fundic portion of the glandular stomach, and loss of body weight. PCDF and HCDF produced a greater incidence and severity of dermatotoxic effects than TCDD. Based on data for dermal toxicity and changes in body weight and organ weights, PCDF is estimated to be 0.2 to 0.4 times, and HCDF 0.08 to 0.16 times, as toxic as TCDD following repeated dermal exposure. Therefore, toxic equivalence factors generated using data from acute and/or in vitro studies may underestimate the risk from repeated low-dose exposures to these compounds.

Topics: Animals; Benzofurans; Carcinoma, Squamous Cell; Dioxins; Female; Hypertrophy; Liver; Mice; Mice, Hairless; Papilloma; Polychlorinated Dibenzodioxins; Skin; Skin Diseases; Skin Neoplasms

Topics: Aged; Amiodarone; Benzofurans; Chemical Phenomena; Chemistry; Female; Humans; Papilloma; Skin Neoplasms

Topics: Animals; Benzofurans; Croton Oil; DNA, Neoplasm; Female; Leucine; Macromolecular Substances; Mice; Neoplasm Proteins; Neoplasms, Experimental; Nucleosides; Papilloma; RNA, Neoplasm; Skin; Skin Neoplasms; Thymidine; Tritium; Wound Healing

Topics: Aniline Compounds; Animals; Benzofurans; Biphenyl Compounds; Carcinogens; Carcinoma; Ectromelia; Female; Liver Neoplasms; Male; Mice; Neoplasms, Experimental; Papilloma; Paraffin; Urinary Bladder Neoplasms; Vaccination