phenanthrenes and Skin-Neoplasms

Chinese hamster V79 cells were exposed to a high or low concentration of the highly carcinogenic (R,S,S,R) or the less active (S,R,R,S) bay- or fjord-region diol epoxides of benzo[a]pyrene, benzo[c]phenanthrene or dibenz[c,h]acridine. Independent 8-azaguanine-resistant clones were isolated, and base substitutions at the hypoxanthine (guanine) phosphoribosyltransferase (hprt) locus were determined. For the three (R,S,S,R) diol epoxides studied, the proportion of mutations at AT base pairs increased as the concentration of diol epoxide decreased. Concentration-dependent differences in the mutational profile were not observed, however, for the three (S,R,R,S) diol epoxides. In studies, with V-H1 cells (a DNA repair deficient variant of V79 cells), a concentration-dependent difference in the profile of mutations for the (R,S,S,R) diol epoxide of benzo[a]pyrene was not observed. These results suggest that concentration-dependent differences in the mutational profile are dependent on an intact DNA repair system. In additional studies, we initiated mouse skin with a high or low dose of benzo[a]pyrene and promoted the mice for 26 weeks with 12-O-tetradecanoylphorbol-13-acetate. Papillomas were examined for mutations in the c-Ha-ras proto-oncogene. Dose-dependent differences in the profile of c-Ha-ras mutations in the tumors were observed. In summary, (i) dose-dependent differences in mutational profiles at the hprt locus were observed in Chinese hamster V79 cells treated with several highly mutagenic and carcinogenic (R,S,S,R) bay- or fjord-region diol epoxides but not with their less active (S,R,R,S) diol epoxide enantiomers, (ii) a dose-dependent difference in the mutational profile was not observed for the (R,S,S,R) diol epoxide of benzo[a]pyrene in a DNA-repair defective V79 cell line, and (iii) a dose-dependent difference in the mutational profile in the c-Ha-ras proto-oncogene was observed in tumors from mice treated with a high or low dose of benzo[a]pyrene.

Topics: Acridines; Amino Acid Substitution; Animals; Base Sequence; Bay-Region, Polycyclic Aromatic Hydrocarbon; Benzo(a)pyrene; Carcinogens; Dose-Response Relationship, Drug; Epoxy Compounds; Genes, ras; Humans; Hypoxanthine Phosphoribosyltransferase; Molecular Sequence Data; Mutagenesis; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Proto-Oncogene Mas; Skin Neoplasms

Topics: Animals; Antineoplastic Agents; Arginase; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Cell Division; Cell Transformation, Neoplastic; Deoxyribonucleases; DNA; Fluorouracil; Humans; Liver Neoplasms; Methylcholanthrene; Mice; Mutation; Neoplasms; Neoplasms, Experimental; Nucleosides; Oncogenic Viruses; Orotic Acid; Phenanthrenes; Protein Binding; Pyrimidinones; Rats; Skin Neoplasms; Thymine; Uracil

Topics: Animals; Carcinogens; Carcinoma, Squamous Cell; Chemical Phenomena; Chemistry; Hydrocarbons; Ketones; Methylcholanthrene; Mice; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sarcoma, Experimental; Skin Neoplasms; Steroids

Melanoma is the most malignant skin tumor and is difficult to cure with the alternative treatments of chemotherapy, biotherapy, and immunotherapy. Our previous study showed that triptolide (TP) exhibited powerful tumoricidal activity against melanoma. However, the clinical potential of TP is plagued by its poor aqueous solubility, short half-life, and biotoxicity. Therefore, developing an ideal vehicle to efficiently load TP and achieving targeted delivery to melanoma is a prospective approach for making full use of its antitumor efficacy.. We applied exosome (Exo) derived from human umbilical cord mesenchymal stromal cells (hUCMSCs) and engineered them exogenously with a cyclic peptide, arginine-glycine-aspartate (cRGD), to encapsulate TP to establish a bionic-targeted drug delivery system (cRGD-Exo/TP), achieving synergism and toxicity reduction. The average size of cRGD-Exo/TP was 157.34 ± 6.21 nm, with a high drug loading of 10.76 ± 1.21%. The in vitro antitumor results showed that the designed Exo delivery platform could be effectively taken up by targeted cells and performed significantly in antiproliferation, anti-invasion, and proapoptotic activities in A375 cells via the caspase cascade and mitochondrial pathways and cell cycle alteration. Furthermore, the biodistribution and pharmacokinetics results demonstrated that cRGD-Exo/TP possessed superior tumor targetability and prolonged the half-life of TP. Notably, cRGD-Exo/TP significantly inhibited tumor growth and extended survival time with negligible systemic toxicity in tumor-bearing mice.. The results indicated that the functionalized Exo platform provides a promising strategy for targeted therapy of malignant melanoma.

Topics: Animals; Cell Line, Tumor; Diterpenes; Epoxy Compounds; Exosomes; Humans; Integrin alphaVbeta3; Integrins; Melanoma; Melanoma, Cutaneous Malignant; Mice; Peptides, Cyclic; Phenanthrenes; Skin Neoplasms; Tissue Distribution

Transcutaneous immunization (TCI) is a non-invasive vaccination strategy targeting the skin-associated lymphoid tissue. Topical application of the TLR7 agonist imiquimod as adjuvant in combination with peptide antigens activates the innate immune system and mounts cytotoxic T lymphocyte (CTL) responses.. Based on the commercial 5% imiquimod-containing drug Aldara we aimed to develop an improved formulation with superior vaccination efficiencies. The primary target was the enhancement of mast cell activation as important key for the function of the innate immune system.. We investigated the effects of 9-phenanthrol (9-phe) on the activation of mast cells in vitro and in vivo. For TCI, we applied 0.2% 9-phe in Aldara or Aldara alone as adjuvants in combination with the MHC class I - restricted peptide SIINFEKL. To monitor vaccination, mast cell degranulation, migration of DC and frequencies of epitope-specific CTL was assessed. In a transgenic tumor model, the efficiencies of prophylactic immunization against a tumor antigen were also monitored.. 9-phe induced degranulation of mast cells in vitro and upon topical application in vivo. A mixture of 0.2% 9-phe in Aldara showed superior results regarding the migration of DC and the expansion of antigen-specific CTL. Consequently, prophylactic immunization with 0.2% 9-phe in Aldara caused enhanced protection against tumor inoculation.. Our data demonstrate that a simple modification of an adjuvant formulation can yield superior results in experimental vaccination protocols by boosting critical steps leading to the generation of an efficient CTL response.

Topics: Adjuvants, Immunologic; Administration, Cutaneous; Aminoquinolines; Animals; Calcium; Cell Degranulation; Cell Movement; Dendritic Cells; Humans; Imiquimod; Immunity, Innate; Mast Cells; Melanoma; Mice; Mice, Inbred C57BL; Mice, Transgenic; Phenanthrenes; Protein Kinase Inhibitors; Skin; Skin Neoplasms; T-Lymphocytes, Cytotoxic; TRPM Cation Channels; Vaccination; Xenograft Model Antitumor Assays

Melanoma is the most serious type of skin cancer because it is highly frequency of drug resistance and can spread earlier and more quickly than other skin cancers. The objective of this research was to investigate the anticancer effects of cryptotanshinone on human melanoma cells in vitro, and explored its mechanisms of action. Our results have shown that cryptotanshinone could inhibit cell proliferation in human melanoma cell lines A2058, A375, and A875 in a dose- and time-dependent manner. In addition, flow cytometry assay showed that cryptotanshinone inhibited the proliferation of human melanoma cell line A375 by blocking cell cycle progression in G2/M phase and inducing apoptosis in a concentration-dependent manner. Moreover, western blot analysis indicated that the occurrence of its apoptosis was associated with upregulation of cleaved caspases-3 and pro-apoptotic protein Bax while downregulation of anti-apoptotic protein Bcl-2. Meanwhile, cryptotanshinone could decrease the levels of reactive oxygen species (ROS). Furthermore, cryptotanshinone also blocked A375 cell migration and invasion in vitro which was associated with the downregulation with MMP-9. Taken together, these results suggested that cryptotanshinone might be a potential drug in human melanoma treatment by inhibiting proliferation, inducing apoptosis via ROS-mitochondrial apoptotic pathway and blocking cell migration and invasion.

Topics: Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Shape; Cell Survival; G2 Phase Cell Cycle Checkpoints; Humans; Melanoma; Mitochondria; Neoplasm Invasiveness; Phenanthrenes; Reactive Oxygen Species; Signal Transduction; Skin Neoplasms; Tumor Stem Cell Assay

Numerous studies have demonstrated that triptolide induces cell cycle arrest and apoptosis in human cancer cell lines. However, triptolide-induced DNA damage and inhibition of DNA repair gene expression in human skin cancer cells has not previously been reported. We sought the effects of triptolide on DNA damage and associated gene expression in A375.S2 human malignant melanoma cells in vitro. Comet assay, DAPI staining and DNA gel electrophoresis were used for examining DNA damage and results indicated that triptolide induced a longer DNA migration smear based on single cell electrophoresis and DNA condensation and damage occurred based on the examination of DAPI straining and DNA gel electrophoresis. The real-time PCR technique was used to examine DNA damage and repair gene expression (mRNA) and results indicated that triptolide led to a decrease in the ataxia telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR), breast cancer 1, early onset (BRCA-1), p53, DNA-dependent serine/threonine protein kinase (DNA-PK) and O6-methylguanine-DNA methyltransferase (MGMT) mRNA expression. Thus, these observations indicated that triptolide induced DNA damage and inhibited DNA damage and repair-associated gene expression (mRNA) that may be factors for triptolide-mediated inhibition of cell growth in vitro in A375.S2 cells.

Topics: Antineoplastic Agents, Alkylating; Ataxia Telangiectasia Mutated Proteins; BRCA1 Protein; Cell Cycle Proteins; Cell Line, Tumor; Cell Survival; Comet Assay; Diterpenes; DNA Damage; DNA Modification Methylases; DNA Repair; DNA Repair Enzymes; DNA-Activated Protein Kinase; DNA-Binding Proteins; Down-Regulation; Epoxy Compounds; Gene Expression; Humans; Melanoma; Phenanthrenes; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; RNA, Messenger; Skin Neoplasms; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Triptolide, a diterpenoid obtained from Tripteryglum wilfordii Hook.f, has attracted interest for its anti- tumor activities against human tumor cell lines in recent years. This report focuses on anti-proliferative and pro-apoptotic activities in human melanoma A375 cells assessed by CCK8 assay, Hoechst 33258 staining and flow cytometry. In addition, triptolide-induced arrest in the S phase was also observed. Caspase assays showed the apoptosis induced by triptolide was caspase-dependent and probably through intrinsic apoptotic pathways. Furthermore, expression of NF-κB (p65) and its downstream factors such as Bcl-2, Bcl-XL was down-regulated. Taken together, the data indicate that triptolide inhibits A375 cells proliferation and induces apoptosis by a caspase-dependent pathway and through a NF-κB-mediated mechanism.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; bcl-X Protein; Caspase 3; Caspase 9; Cell Line, Tumor; Cell Proliferation; Diterpenes; Down-Regulation; Epoxy Compounds; Humans; Melanoma; NF-kappa B; Phenanthrenes; Proto-Oncogene Proteins c-bcl-2; S Phase Cell Cycle Checkpoints; Skin Neoplasms

To date, Kaposi sarcoma has not been mentioned among the adverse effects of triptolide/tripdiolide, ethyl acetate extracts or polyglycosides of the Chinese herbal remedy Tripterygium wilfordii Hook F.. A patient was diagnosed with rheumatoid arthritis at the age of 29 years. She underwent treatment with corticosteroids, methotrexate and gold sodium thiosulfate, and was chronically taking ketoprofen. At the age of 59 years she started to take a powder (≈2 g/day) from a Chinese physician for treatment of rheumatoid arthritis. This powder was supplied to her regularly for 10 years. At the age of 69 years, multiple soft, violaceous to dark-red patches, plaques, nodules and blisters of varying sizes appeared on a background of severely edematous skin on her legs, and later on her arms. Biopsy specimens of the leg lesions were diagnostic for human herpesvirus 8-associated Kaposi sarcoma. Triptolide (235 µg/1 g) and tripdiolide were found in the Chinese powder by the use of Liquid Chromatography Electrospray Ionization Mass Spectrometry. Administration of the powder was stopped and medication with paclitaxel was introduced. General condition of the patient improved and skin lesions diminished significantly.. This case indicates a possible association between triptolide/tripdiolide chronic intake and development of human herpesvirus 8-associated Kaposi sarcoma. Triptolide/tripdiolide could contribute to development of Kaposi sarcoma by reactivation of latent human herpesvirus 8, permitted by immunosuppression induced by triptolide.

Topics: Adult; Aged; Arthritis, Rheumatoid; Diterpenes; Edema; Epoxy Compounds; Female; Humans; Immunosuppressive Agents; Leg; Middle Aged; Phenanthrenes; Powders; Sarcoma, Kaposi; Skin Neoplasms

Snail1 is a master regulator of the epithelial-mesenchymal transition (EMT) and has been implicated in key tumor biological processes such as invasion and metastasis. It has been previously shown that poly(ADP-ribose) polymerase-1 (PARP-1) knockdown, but not PARP inhibition, downregulates the expression of Snail1. In this study we have characterized a novel regulatory mechanism controlling Snail1 protein expression through poly(ADP-ribosyl)ation. The effect is not only limited to repression of Snail1 transcription but also to downregulated Snail1 protein stability. PARP-1 (but not PARP-2) poly(ADP) ribosylates Snail1, both in vivo and in vitro, and interacts with Snail1, an association that is sensitive to PARP inhibitors. PARP inhibition has also clear effects on EMT phenotype of different tumor cells, including Snail1 downregulation, E-cadherin upregulation, decreased cell elongation and invasiveness. Therefore, this study reveals a new regulatory mechanism of Snail1 activation through poly(ADP-ribosyl)ation with consequences in malignant transformation through EMT.

Topics: Cadherins; Cell Line, Tumor; Enzyme Inhibitors; Epithelial-Mesenchymal Transition; Fluorobenzenes; Humans; Melanoma; Neoplasm Invasiveness; Phenanthrenes; Phthalazines; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Protein Stability; Skin Neoplasms; Snail Family Transcription Factors; Transcription Factors

To investigate the effect of triptolide on the proliferation and apoptosis of human epidermal squamous cell carcinoma cell line A431 in vitro.. Human epidermal squamous cell carcinoma cell line A431 was cultured. After the treatment with triptolide, the inhibition of cellular growth was determined by measuring MTT dye absorption of the living cells. Light microscope showed morphological changes. The cell cycle and apoptosis rate were assessed by flow cytometry.. Triptolide could significantly inhibit the proliferation of A431 cells in a dose- and time-dependent manner. Triptolide could also cause cell morphological changes (the number of floating cells and nuclear pyknosis increase), induce cell apoptosis, and change the distribution of cell cycle phase in A431 cells. Compared with the control group, the G( 0) /G( 1) phase A431 cell rate increased and the rate of S phase cell decreased in TP-treated group. Cell cycles were obviously inhibited by triptolide in G( 0) /G( 1) phase ( both P<0.05).. TP could play an anti-tumor role by effectively inducing cell apoptosis and inhibiting the proliferation of A431 cells.

Topics: Antineoplastic Agents, Alkylating; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Diterpenes; Epoxy Compounds; Humans; Phenanthrenes; Skin Neoplasms

Natural resin acids present in rosin of Pinus spez., including isopimaric acid (1), mercusic acid (2), neoabietic acid (3), dehydroabietic acid (4), and podocarpic acid (8), as well as resin acid derivatives 8β,9α,13α-H-tetrahydroabietic acid (5), 8α,9α,13α-H-tetrahydroabietic acid (6), 13α-H-Δ(8)-dihydroabietic acid (7), maleopimaric acid (9), and fumaropimaric acid (10), were studied for their possible inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Compounds 1, 3, 4, 7, and 10 (IC(50): 352, 330, 311, 340, and 349, respectively) exhibited strong inhibitory effects compared to the other compounds. Among these, 1, 4, and 7 were selected to examine their effects on in vivo two-stage mouse skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene (DMBA) as initiator and TPA as promoter. Treatment with compounds 4 and 7 (85 nmol) along with DMBA/TPA inhibited papilloma formation up to week 8 and the percentage of papilloma bearers in these two groups was approximately 80% at week 20. The average number of papillomas formed per mouse was 4.4 and 4.2 even at week 20 (p>0.05). Compounds 4 and 7 exhibited high activity in the in vivo anti-tumor-promoting test. In addition, rosin was examined in vivo for its chemopreventive effect. Treatment with rosin (50 μmol) along with DMBA (100 μg)/TPA (1 μg) inhibited papilloma formation up to week 8 and the percentage of papilloma bearers in this group was less than 80% at week 20. The average number of papillomas formed per mouse in the rosin-treated group was 3.8 even at week 20 (p>0.05). The in vivo two-stage mouse skin carcinogenesis test revealed that rosin possessed a pronounced anticarcinogenetic effect, and its high activity is due to the synergism of the diterpenes contained in it.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Anticarcinogenic Agents; Antigens, Viral; Carboxylic Acids; Carcinogenicity Tests; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Inbred ICR; Papilloma; Phenanthrenes; Pinus; Resins, Plant; Skin Neoplasms; Tetradecanoylphorbol Acetate

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

A methanol extract of the leaves of the plant Rosmarinus officinalis L. (rosemary) was evaluated for its effects on tumor initiation and promotion in mouse skin. Application of rosemary to mouse skin inhibited the covalent binding of benzo(a)pyrene [B(a)P] to epidermal DNA and inhibited tumor initiation by B(a)P and 7,12-dimethylbenz[a]anthracene (DMBA). Topical application of 20 nmol B(a)P to the backs of mice once weekly for 10 weeks, followed 1 week later by promotion with 15 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) twice weekly for 21 weeks, resulted in the formation of 7.1 tumors per mouse. In a parallel group of animals that were treated topically with 1.2 or 3.6 mg of rosemary 5 min prior to each application of B(a)P, the number of tumors per mouse was decreased by 54 or 64%, respectively. Application of rosemary to mouse skin also inhibited TPA-induced ornithine decarboxylase activity, TPA-induced inflammation, arachidonic acid-induced inflammation, TPA-induced hyperplasia, and TPA-induced tumor promotion. Mice initiated with 200 nmol DMBA and promoted with 5 nmol TPA twice weekly for 19 weeks developed an average of 17.2 skin tumors per mouse. Treatment of the DMBA-initiated mice with 0.4, 1.2, or 3.6 mg of rosemary together with 5 nmol TPA twice weekly for 19 weeks inhibited the number of TPA-induced skin tumors per mouse by 40, 68, or 99%, respectively. Topical application of carnosol or ursolic acid isolated from rosemary inhibited TPA-induced ear inflammation, ornithine decarboxylase activity, and tumor promotion. Topical application of 1, 3, or 10 mumol carnosol together with 5 nmol TPA twice weekly for 20 weeks to the backs of mice previously initiated with DMBA inhibited the number of skin tumors per mouse by 38, 63, or 78%, respectively. Topical application of 0.1, 0.3, 1, or 2 mumol ursolic acid together with 5 nmol TPA twice weekly for 20 weeks to DMBA-initiated mice inhibited the number of tumors per mouse by 45-61%.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Abietanes; Animals; Anticarcinogenic Agents; Antioxidants; Arachidonic Acid; Benzo(a)pyrene; Dermatitis, Contact; DNA; Drug Interactions; Enzyme Induction; Epidermis; Female; Hyperplasia; Magnoliopsida; Mice; Mice, Inbred Strains; Ornithine Decarboxylase; Phenanthrenes; Plant Extracts; Skin; Skin Neoplasms; Spices; Tetradecanoylphorbol Acetate; Triterpenes; Tritium; Ursolic Acid

Previous studies showed that 5,6-dimethylchrysene (5,6-diMeC) and 5,7-diMec were significantly less tumorigenic than 5-methylchrysene (5-MeC). These results were unexpected based on the known mechanism of metabolic activation of 5-MeC and indicated the presence of critical steric requirements for tumorigenicity at the 6 and 7 positions of 5-MeC. In this study, the structure activity relationships were further extended by comparing the tumor-initiating activities on mouse skin of 5-MeC, 6,7-cyclopentano-5-MeC, 5,6-diMeC, 6,7-diMeC, 5,7-diMeC, chrysene and 6,7-cyclopentanochrysene. 5-MeC was the most tumorigenic compound, with activity significantly higher than all other compounds tested. Among the other compounds. Only 5,6-diMeC was significantly tumorigenic. The results demonstrate that substitution of methyl or methylene groups at the 6 or 7 positions of 5-MeC leads to a significant reduction of tumor initiating activity.

Topics: Animals; Biotransformation; Carcinogens; Chemical Phenomena; Chemistry; Chrysenes; Female; Mice; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship

Polycyclic aromatic hydrocarbons (PAHs) with a methylene-bridge spanning the bay region are often detected in higher concentrations in the environment than PAHs which have a bay-region methyl substituent. The tumor-initiating activity of methylene-bridged bay-region derivatives of chrysene and benz[a]anthracene was evaluated on the skin of female CD-1 mice. 4,5-Methylenechrysene elicited twice as many tumors as chrysene at each of the doses tested. At total initiation doses of 1.5, 0.5 and 0.15 mumol/mouse 4,5-methylenechrysene gave rise to 8.5, 6.8 and 1.1 tumors/animal respectively. There was a 100% incidence of tumor-bearing mice at the two higher doses and a 65% incidence at the lowest dose. This methylene-bridged hydrocarbon was less tumorigenic than 5-methylchrysene at each dose tested. Animals treated with 1,12-methylenebenz[a]anthracene developed 7.6, 4.9 and 1.6 tumors/animal at total initiating doses of 4.0, 2.0 and 0.5 mumol/mouse. The incidence of tumor-bearing mice was 90% at the higher doses and 75% at the lowest dose tested. 12-Methylbenz[a]anthracene was more tumorigenic than the methylene-bridged derivative at each dose. The keto-derivative of 1,12-methylenebenz[a]anthracene did not display significant (P greater than 0.05) tumor-initiating activity at these dose levels. Results from these bioassays indicate that methylene-bridged bay-region derivatives of chrysene and benz[a]anthracene contribute to the overall genotoxicity of environmentally occurring PAHs.

Topics: Animals; Benz(a)Anthracenes; Carcinogens; Chrysenes; Female; Mice; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship

Cyclopenta[cd]pyrene (CPP) was a potent tumorigen when tested over a 5-fold dose range in the newborn mouse assay. A 20-fold increase in lung tumor multiplicity and a nearly 8-fold increase in tumor incidence was observed at the lowest total dose tested (1.55 mumol) with the dose-response relationship indicating a saturation of tumor multiplicity at approximately 7 tumors/animal. No liver nodules or lymphatic system tumors were noted. Analysis of dose-response data for benzo[a]-pyrene (BaP) and 6-nitrochrysene (6-NC) showed that tumor multiplicity for BaP also saturated at approximately 7 tumors/animal, whereas no similar saturation was found for 6-NC at up to 40 tumors/animal. Progression of lung adenomas to adenocarcinomas, as measured by the incidence of mice bearing malignant tumors, was essentially a linear function of dose. To facilitate comparison and maximize quantitative data obtainable from the newborn mouse assay-parameters were defined for tumor incidence (ED50), tumor multiplicity (TM1.0) and tumor malignancy (malignancy index). Values for the ED50 and TM1.0 were similar for the same compound and a tumorigenic potency series of 6-NC greater than BaP greater than CPP was obtained corresponding to a ratio of approximately 1:10-25:76.5-135, respectively. The malignancy index, however, indicated increased adenocarcinoma induction in the order CPP greater than 6-NC greater than BaP as expressed by the ratio 1:1.4:8.3, respectively.

Topics: Adenoma; Animals; Animals, Newborn; Benzo(a)pyrene; Biological Assay; Carcinogens; Chrysenes; Dose-Response Relationship, Drug; Female; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; Phenanthrenes; Pyrenes; Skin Neoplasms

The stereochemistry of diol epoxide formation in mouse epidermis upon topical application of [3H]-1R,2R-dihydroxy-1,2-dihydro-5-methylchrysene ([3H]-5-MeC-1R,2R-diol) and [3H]-6-MeC-1R,2R-diol, and the tumorigenicity in mouse skin and in newborn mice of the R,S,S,R and S,R,R,S enantiomers of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (5-MeC-1,2-diol-3,4-epoxide), 5-MeC-7,8-diol-9,10-epoxide, and 6-MeC-1,2-diol-3,4-epoxide were examined. Analysis of tetraols and their derived tetraacetates present in mouse epidermis, 2 h after application of [3H]-5-MeC-1R,2R-diol or [3H]-6-MeC-1R,2R-diol, demonstrated greater than 90% stereoselectivity in formation of 5-MeC-1R,2S-diol-3S,4R-epoxide and 6-MeC-1R,2S-diol-3S,4R-epoxide. Taken together with previous data, these results demonstrate that there is a high degree of stereoselectivity for formation of R,S,S,R enantiomers of 5-MeC- and 6-MeC-1,2-diol-3,4-epoxides in mouse skin. The results of the tumorigenicity studies in mouse skin and in newborn mice clearly demonstrated that 5-MeC-1R,2S-diol-3S,4R-epoxide was the most tumorigenic of the diol epoxide enantiomers tested; 6-MeC-1R,2S-diol-3S,4R-epoxide was inactive. The results of this study show that the high tumorigenicity of 5-MeC compared to 6-MeC is due to the remarkable tumorigenic activity of 5-MeC-1R,2S-diol-3S,4R-epoxide which, in contrast to 6-MeC-1R,2S-diol-3S,4R-epoxide, has a methyl group in the same bay region as the epoxide ring. We propose that such methyl bay region diol epoxides of other carcinogenic methylated polynuclear aromatic hydrocarbons will also show unique tumorigenic properties.

Topics: Animals; Animals, Newborn; Carcinogens; Chrysenes; Epoxy Compounds; Ethers, Cyclic; Methylation; Mice; Phenanthrenes; Skin; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship

During the past decade substantial progress has been made in elucidating factors that determine the tumorigenic activity of bay-region diol epoxides, major ultimate carcinogenic metabolites derived from polycyclic aromatic hydrocarbons. Neither high nor low chemical reactivity of the diol epoxides (as measured by rates of uncatalyzed solvolysis) is required for high tumorigenic response. In contrast, aspects of molecular structure such as conformation and absolute configuration strongly influence tumorigenic activity. The role of conformation is illustrated by the observation that those diol epoxides whose hydroxyl groups are pseudoaxial are weak or inactive as tumorigens. Absolute configuration is an important determinant of biological activity of bay-region diol epoxides: in all cases studied to date, the predominantly formed (R,S)-diol-(S,R)-epoxides are generally the most tumorigenic of the four metabolically possible configurational isomers. In the course of investigating the effects of structural factors on tumorigenic activity, we identified the (4R,3S)-diol-(2S,1R)-epoxide of benzo(c)phenanthrene as the most potent tumorigen (in initiation-promotion experiments on mouse skin) of the diol epoxides studied to date. Studies of all four configurationally isomeric diol epoxides derived from benzo(c)phenanthrene led to the striking observation that these diol epoxides exhibit an exceptionally high efficiency of covalent binding, relative to hydrolysis, when allowed to react with calf thymus DNA in aqueous solution. Thus, these diol epoxides should provide an excellent tool for the detailed study of such binding. When the four isomeric benzo(c)phenanthrene diol epoxides are compared, there appears to be no simple correlation between tumorigenic response and either the extent of binding to DNA or the major types of deoxyribonucleoside adducts formed. Deoxyribonucleoside adducts of benzo(c)phenanthrene diol epoxide have also been identified from the DNA of cultured rodent embryo cells after treatment of the cells with tritium-labeled benzo(c)phenanthrene. The distribution of adducts is consistent with predominant metabolic formation of the (4R,3S)-diol-(2S,1R)-epoxide; deoxyadenosine is the major site in the cellular DNA attacked by this epoxide, just as it is in DNA in solution. Further experiments are in progress which we hope will identify more subtle aspects of the DNA binding of benzo(c)phenanthrene diol epoxides that may be uniquely correlated with t

Topics: Animals; Animals, Newborn; Carcinogens; Circular Dichroism; Deoxyadenosines; DNA; Epoxy Compounds; Ethers, Cyclic; Lung Neoplasms; Mice; Molecular Conformation; Nucleic Acid Conformation; Phenanthrenes; Polycyclic Compounds; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship

6-Nitro-5-methylchrysene was prepared by nitration of 5-methylchrysene and the mutagenic and tumorigenic activities of the two compounds were compared. Whereas 5-methylchrysene was a strong tumor initiator on mouse skin, no tumors were observed in the mice treated with 6-nitro-5-methylchrysene. In Salmonella typhimurium TA100, both compounds were mutagenic in the presence, but not in the absence, of rat liver 9000 g supernatant. The major metabolite of 6-nitro-5-methylchrysene in rat liver in vitro was trans-1,2-dihydro-1,2-dihydroxy-6-nitro-5-methylchrysene. In view of the ready conversion of 6-nitro-5-methylchrysene to a 1,2-dihydrodiol, its apparent lack of tumorigenicity in mouse skin was intriguing.

Topics: Animals; Chromatography, High Pressure Liquid; Chrysenes; Liver; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Mutagenicity Tests; Phenanthrenes; Rats; Rats, Inbred F344; Skin Neoplasms; Structure-Activity Relationship

Tumorigenic activities of the (+)- and (-)-enantiomers of the diastereomeric, bay-region benzo(c)phenanthrene 3,4-diol-1,2-epoxides were evaluated in two mouse tumor models. In an initiation-promotion experiment on mouse skin, a single topical application of 10, 25, or 75 nmol of the compounds was followed by 20 weeks of promotion with 12-O-tetradecanoylphorbol-13-acetate. Of the four optical isomers of the bay-region diol epoxides, (-)-(R,2S,3S,4R)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrogenzo(c )phenanthrene [(-)-diol epoxide-2] and (+)-(1R,2S,3R,4S)-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(c) -phenanthrene [(+)-diol epoxide-1] had equally high tumor-initiating activity while (+)-[1S,2R,3R,4S]-3,4-dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo (c)phenanthrene [(+)-diol epoxide-2] had less than one-half of the activity of (-)-diol epoxide-2 and (+)-diol epoxide-1. (-)-(1S,2R,3S,4R)-3,4-Dihydroxy-1,2-epoxy-1,2,3,4-tetrahydrobenzo(c) -phenanthrene [(-)-diol epoxide-1] was inactive at the doses tested. In newborn mice, (-)-diol epoxide-2 was almost 10-fold more active in producing lung tumors (average number of lung tumors/mouse) than the next most active compound, (+)-diol epoxide-2, at a total dose of 10 nmol. The enantiomers of diol epoxide-1 were inactive at this dose. When the total dose of each optical isomer was increased to 50 nmol, (-)-diol epoxide-1 was still inactive, and (+)-diol epoxide-1 produced a significant number of lung tumors (0.9 lung tumor/mouse), but this isomer still had less than 10% of the activity of the (+)- and (-)-diol epoxide-2 isomers. (-)-Diol epoxide-2, but none of the other optical isomers, also produced a significant incidence of hepatic tumors at the higher dose, and this compound was found to be the most tumorigenic bay-region diol epoxide ever tested in newborn mice. Racemic diol epoxide-1 had approximately 1% of the tumorigenic activity of racemic diol epoxide-2 in newborn mice, but both racemates had equal tumor-initiating activity on mouse skin. These results dramatically illustrate the complexities involved in ranking the relative tumorigenic activities of compounds in different tumor models.

Topics: Animals; Animals, Newborn; Epoxy Compounds; Ethers, Cyclic; Female; Isomerism; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship

5-Methylchrysene, (+/-)-trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene, (+/-)-trans-7,8-dihydro-7,8-dihydroxy-5-methylchrysene, (+/-)-trans-1,2-dihydroxy-anti-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (anti-DE-I), (+/-)-trans-1,2-dihydroxy-syn-3,4-epoxy-1,2,3,4-tetrahydro-5-methylchrysene (syn-DE-I), and (+/-)-trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-5-methylchrysene (anti-DE-II) were tested for tumorigenicity in newborn mice and for tumor-initiating activity on mouse skin. In newborn mice, a total dose of 56 nmol of anti-DE-I induced 4.6 lung tumors/mouse and 1.2 liver tumors/mouse. These incidences were significantly higher than observed for any of the other metabolites, tested at equimolar doses. The results indicate that anti-DE-I, but not syn-DE-I or anti-DE-II, is a major ultimate carcinogen of 5-methylchrysene in the newborn mouse. Anti-DE-I was also more tumorigenic than anti-DE-II on mouse skin, inducing 4.4 tumors/mouse after an initiating dose of 100 nmol, compared to zero tumors per mouse induced by anti-DE-II. However, anti-DE-I was less tumorigenic on mouse skin than was its metabolic precursor, trans-1,2-dihydro-1,2-dihydroxy-5-methylchrysene or its parent hydrocarbon, 5-methylchrysene.

Topics: Animals; Animals, Newborn; Carcinogens; Chrysenes; Female; Male; Mice; Mice, Inbred ICR; Phenanthrenes; Sex Factors; Skin Neoplasms; Stereoisomerism; Structure-Activity Relationship

A series of methylene-bridged and keto-bridged bay region derivatives of chrysene and phenanthrene were prepared and evaluated for mutagenic activity in Salmonella typhimurium TA100 and for tumor-initiating activity on CD-1 mouse skin. The compounds included in this series were 4H-cyclopenta[def]phenanthrene, 4H-cyclopenta[def]phenanthrene-4-one, 1-methyl-4H-cyclopenta[def]phenanthrene, 1-methyl-4H-cyclopenta[def] phenanthren-4-one, 4H-cyclopenta[def] chrysene, and 4H-cyclopenta[def] chrysen-4-one. Among these compounds only 4H-cyclopenta[def]phenanthrene and 1-methyl-4H-cyclopenta[def]phenanthren-4-one were not significantly mutagenic when assayed with metabolic activation using Aroclor-induced rat liver homogenate. None of the compounds assayed were active without metabolic activation. 4H-Cyclopenta[def]chrysene was the most tumorigenic of the methylene-bridged bay region PAH tested on mouse skin. At a dose of 1.0 mg this compound resulted in 100% of the animals bearing papillomas with 5.63 papillomas/animal. 4H-Cyclopenta[def]chrysen-4-one and 1-methyl-4H-cyclopenta[def]phenanthrene displayed weak tumorigenic activity at a total initiating dose of 1.0 mg.

Topics: Animals; Biotransformation; Chrysenes; Female; Male; Mice; Mice, Inbred Strains; Mutagens; Phenanthrenes; Rats; Rats, Inbred F344; Salmonella typhimurium; Skin Neoplasms; Structure-Activity Relationship

Topics: Animals; Carcinogens, Environmental; Chemical Phenomena; Chemistry; Female; Mice; Mutagenicity Tests; Neoplasms, Experimental; Phenanthrenes; Rats; Risk; Skin Neoplasms

Topics: Animals; Carcinogens, Environmental; Chemical Phenomena; Chemistry; Female; Mice; Mutagenicity Tests; Neoplasms, Experimental; Phenanthrenes; Risk; Skin Neoplasms

Topics: Animals; Carcinogens, Environmental; Chemical Phenomena; Chemistry; Chrysenes; Cocarcinogenesis; Female; Male; Mice; Mutagenicity Tests; Neoplasms, Experimental; Phenanthrenes; Risk; Skin Neoplasms

Topics: Animals; Carcinogens, Environmental; Chemical Phenomena; Chemistry; Female; Mice; Mutagenicity Tests; Neoplasms, Experimental; Phenanthrenes; Risk; Skin Neoplasms

Topics: Animals; Carcinogens, Environmental; Chemical Phenomena; Chemistry; Chrysenes; Male; Mice; Mutagenicity Tests; Neoplasms, Experimental; Phenanthrenes; Risk; Skin Neoplasms

Topics: Animals; Animals, Newborn; Carcinogens; Chemical Phenomena; Chemistry; Chrysenes; Female; Mice; Phenanthrenes; Pregnancy; Skin; Skin Neoplasms; Stereoisomerism

6-Nitrobenzo[a]pyrene, 6-nitrochrysene, 3-nitroperylene, 1-nitropyrene, and the corresponding parent hydrocarbons were tested for tumor initiating activity on mouse skin with promotion by tetradecanoylphorbol acetate. The initiating doses of 6-nitrobenzo[a]pyrene and benzo[a]pyrene were 0.05 mg each; for all other compounds the initiating doses were 1.0 mg. 6-Nitrochrysene induced tumors in 60% of the mice (2.1 tumors per mouse), but was significantly less tumorigenic than chrysene. 3-Nitroperylene induced tumors in 42% of the mice (0.5 tumors per mouse) and was significantly more active than perylene. Neither 1-nitropyrene nor 6-nitrobenzo[a]pyrene exhibited significant tumorigenic activity in the concentrations tested.

Topics: Animals; Benz(a)Anthracenes; Benzo(a)pyrene; Benzopyrenes; Carcinogens; Chrysenes; Female; Mice; Mice, Inbred Strains; Neoplasms, Experimental; Nitro Compounds; Perylene; Phenanthrenes; Pyrenes; Skin Neoplasms

The tumor-initiating activity of several polymethylated phenanthrenes was determined in mouse skin. Among the compounds assayed were 1,4-, 1,9-, 2,7-, 3,6-, 4,5-, 4,9-, and 4,10-dimethylphenanthrene. Only the 1,4- and 4,10-dimethylphenanthrenes were active as tumor initiators. Initiating doses of 300 micrograms and 1.0 mg of 1,4-dimethylphenanthrene after promotion with tetradecanoylphorbol acetate induced 80 and 100% incidences of skin tumors in mice, respectively, 4,10-Dimethylphenanthrene assayed under identical conditions induced skin tumors in 35 and 55% of the mice. The in vitro metabolism of 1,4-, 3,6-, 4,9-, and 4,10-dimethylphenanthrene was studied by incubation of the compounds with the 9000 x g supernatant from the livers of Aroclor-pretreated rats. The major dihydrodiol metabolite of both 1,4- and 4,10-dimethylphenanthrene was the 7,8-dihydrodiol, the requisite precursor for the formation of bay-region dihydrodiol-epoxides. Dihydrodiols were not observed among the metabolites of 4,9-dimethylphenanthrene. In the case of 3,6-dimethyphenanthrene, the major diol metabolite formed in vitro was the 9,10-dihydrodiol. These results support previously proposed structural requirements which favor the carcinogenic activity of methylated polynuclear aromatic hydrocarbons. These studies indicate that tumorigenic activity of methylated phenanthrenes requires inhibition of dihydrodiol formation at the K-region (9,10-positions) in addition to a bay-region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.

Topics: Animals; Carcinogens; Female; Male; Mice; Microsomes, Liver; Neoplasms, Experimental; Phenanthrenes; Rats; Rats, Inbred F344; Skin Neoplasms; Structure-Activity Relationship

The mutagenicity, in vitro metabolism, and tumor-initiating activity of methylphenanthrenes were evaluated. The only monomethyl isomers which were mutagenic toward Salmonella typhimurium were 1- and 9-methylphenanthrenes. Among the disubstituted phenanthrenes assayed for mutagenicity, only 1,4-dimethylphenanthrene was active in the presence of metabolic activation. Studies on the in vitro metabolism of methylphenanthrenes were performed by incubation of the various isomers with the 9000 X g supernatant from Aroclor-treated rat livers. Comparison of mutagenicity with metabolites formed in vitro indicated that inhibition of 9,10-dihydrodiol formation was positively associated with mutagenic activity. Among the metabolites of 1- and 9-methylphenanthrenes, significant mutagenic activity was associated only with the 3,4- and/or 5,6-dihydrodiol. Metabolism to the 1,2- or 7,8-dihydrodiol, the requisite dihydrodiols for formation of "bay-region" dihydrodiol-epoxides, was most significant in the case of 4-methylphenanthrene. None of the isomeric methylphenanthrenes were active when assayed as tumor initiators on mouse skin. In contrast, 1,4-dimethylphenanthrene was found to have potent tumorigenic activity. These results suggest that inhibition of 9,10-dihydrodiol formation, the influence of a 4-methyl substituent in directing dihydrodiol formation at the 1,2- or 7,8-positions, and the presence of a bay-region methyl group may be responsible for eliciting a tumorigenic response for 1,4-dimethylphenanthrene.

Topics: Animals; Carcinogens; Chromatography, High Pressure Liquid; Female; Liver; Mice; Mutagens; Phenanthrenes; Salmonella typhimurium; Skin; Skin Neoplasms; Structure-Activity Relationship

The major dihydrodiols formed from 5-methylchrysene by rat liver 9000 X g supernatant were tested for tumor-initiating activity on mouse skin. The compounds tested were 1,2-dihydro-1,2-dihydroxy-5-methylchrysene, 7,8-dihydro-7,8-dihydroxy-5-methylchrysene, 9,10-dihydro-9,10-dihydroxy-5-methylchrysene, and 5-methylchrysene. Each compound was applied in a total initiating dose of 30 microgram and was followed by promotion with tetradecanoylphorbol acetate. 1,2-Dihydro-1,2-dihydroxy-5-methylchrysene was the most powerful tumor initiator, inducing tumors in 95% of the animals and 7.3 tumors per animal. 5-Methylchrysene and 7,8-dihydro-7,8-dihydroxy-5-methylchrysene induced tumors in 75 and 50% of the animals and gave 3.0 and 1.1 tumors per animal, respectively. 9,10-Dihydro-9,10-dihydroxy-5-methylchrysene was not tumorigenic. The results indicate that 1,2-dihydro-1,2-dihydroxy-5-methylchrysene is a major proximate carcinogen of 5-methylchrysene. Both 1,2-dihydro-1,2-dihydroxy-5-methylchrysene and 7,8-dihydro-7,8-dihydroxy-5-methylchrysene can theoretically form bay-region dihydrodiol epoxides, but the former was more tumorigenic than the latter. The high activity of 1,2-dihydro-1,2-dihydroxy-5-methylchrysene is typical of hydrocarbon derivatives with a methyl group in the bay region adjacent to an unsubstituted angular ring.

Topics: Animals; Biotransformation; Carcinogens; Carcinoma; Chrysenes; Dose-Response Relationship, Drug; Female; Mice; Neoplasms, Experimental; Papilloma; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship

Topics: Animals; Carcinogens; Cocarcinogenesis; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

Topics: Animals; Carcinogens; Chrysenes; Cocarcinogenesis; Drug Evaluation, Preclinical; Female; In Vitro Techniques; Male; Mice; Microsomes, Liver; Mutagens; Neoplasms, Experimental; Phenanthrenes; Rats; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

Topics: Animals; Carcinogens; Chrysenes; Cricetinae; Epoxide Hydrolases; Epoxy Compounds; Ethers, Cyclic; Female; In Vitro Techniques; Male; Mice; Mutagens; Neoplasms, Experimental; Phenanthrenes; Rats; Salmonella typhimurium; Skin Neoplasms; Structure-Activity Relationship

The tumor initiating activities of 5,11-dimethylchrysene and 5-methylchrysene on mouse skin were compared. After initiating doses of 30 microgram or 10 microgram, with promotion by 3 times weekly applications of tetradecanoylphorbol acetate, both compounds were highly tumorigenic, inducing tumors in 70--85% of the treated animals. Since 5,12-dimethylchrysene had previously been shown to be only a weak tumor initiator, these results support the generalization that the structural requirements favoring carcinogenicity among the methylated chrysenes and other polynuclear aromatic hydrocarbons (PAH) are a bay region methyl group and a free peri position, both adjacent to an unsubstituted angular ring.

Topics: Animals; Chrysenes; Female; Methylation; Mice; Neoplasms, Experimental; Phenanthrenes; Polycyclic Compounds; Skin Neoplasms; Structure-Activity Relationship

Topics: Animals; Biotransformation; Chrysenes; Female; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms; Structure-Activity Relationship; Tetradecanoylphorbol Acetate

The tumor-initiating activities of chrysene and the three metabolically possible trans-dihydrodiols at the 1,2-, 3,4-, and 5,6-positions of chyrsene were determined on the skin of female CD-1 mice. A single topical application of 0.4, 1.25, or 4.0 mumol of each compound was followed 7 days later by twice-weekly applications of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate for 25 weeks. The most potent tumor initiator was chrysene 1,2-dihydrodiol, which had approximately twice the tumorigenic activity of the parent hydrocarbon chrysene at all doses tested. Chrysene 3,4-dihydrodiol and chrysene 5,6-dihydrodiol had no significant tumorigenic activity. 1,2-Dihydroxy-1,2,3,4-tetrahydrochrysene, a compound related to chrysene 1,2-dihydrodiol but with the conjugated nonaromatic double bond removed from the 3,4-position of the molecule, had less than 25% of the tumorigenic activity of chrysene 1,2-dihydrodiol. These results indicate that chrysene 1,2-dihydrodiol is a proximate carcinogenic metabolite of chrysene and that a chrysene 1,2-diol-3,4-epoxide, in which the epoxide group forms part of the bay region in the molecule, is a likely candidate as an ultimate carcinogenic metabolite of chrysene.

Topics: Animals; Carcinogens; Chemical Phenomena; Chemistry; Chrysenes; Female; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms

Fifty-four polycyclic compounds, 29 of the cyclopenta[a]phenanthrene series, 11 chrysenes, and 14 benz[a]anthracenes, have been tested for mutagenicity by Ames's method, using Salmonella typhimurium TA100. Without exception all 37 carcinogens and a known initiator were mutagens. Of the 16 noncarcinogens 7 were mutagenic, but none of these has yet been tested for initiating, as opposed to carcinogenic, activity. There appeared to be little quantitative correspondence between carcinogenic and mutagenic potency, however, and possible reasons for this are discussed. The aryl hydrocarbon hydroxylase inhibitor 7,8-benzoflavone strongly inhibited the mutagenicity of certain compounds when it was added to the incubations.

Topics: Animals; Benz(a)Anthracenes; Carcinogens; Chrysenes; Cyclopentanes; Drug Evaluation, Preclinical; Mice; Mutagens; Neoplasms, Experimental; Phenanthrenes; Salmonella typhimurium; Skin Neoplasms

The mean latent period for skin tumor production by the carcinogen 15, 16-dihydro-11-methylcyclopenta [alpha] phenanthren-17-one (Compound IVb) in the mouse was 30 weeks for a dose of 60 mug/week and about 45 weeks for 60 mug/week, while at 0.6 mug/week, no tumors were observed during 100 weeks. Simultaneous administration of the closely related noncarcinogen (IVa) (54 mug/week) together with the carcinogen at 60 mug/week had no effect on the mean latent period. Simultaneous administration of a threefold quantity of the microsomal enzyme inhibitor 7, 8-benzoflavone (I) with the carcinogen at the highest dose increased the mean latent period to 38 weeks, while at the intermediate dose it completely suppressed tumor formation. Neither ketone IVa nor IVb bound covalently to calf thymus DNA in vitro without prior metabolic activation. After incubation with rat liver microsomes and NADPH in the presence of air, both ketones bound covalently to added DNA in vitro, the noncarcinogen (IVa) about four times more extensively than the carcinogen (IVb), roughly in proportion to the overall extents to which these ketones were metabolized. In contrast, overall metabolism of the carcinogen (IVb) was somewhat increased by the addition of a threefold quantity of the inhibitor (I) to the incubation mixture, but binding to added DNA was almost completely prevented. These results are discussed in connection with the hypothesis that cellular DNA is the target of the carcinogen (IVb) for tumor initiation.

Topics: Animals; Benzopyrans; Carcinogens; Carcinoma; Cattle; Cyclopentanes; DNA; Female; Flavonoids; In Vitro Techniques; Ketones; Male; Mice; Microsomes; Microsomes, Liver; NADP; Neoplasms, Experimental; Phenanthrenes; Rats; Skin Neoplasms; Thymus Gland; Time Factors; Tritium

Four N-Acetoxy-N-arylacetamides previously found to be local sarcomagens in the rat have been found to be initiators of tumorigenesis in mouse skin. The order of activity was: N-acetoxy-2-acetamidophenanthrene greater than N-acetoxy-4-acetamino-stilbene similar to N-acetoxy-2-acetamido-fluorene greater than N-acetoxy-4-acetamidobiphenyl. Two substituted N-benzoyloxypiperidines previously shown to yield nitrenium ions on solvolysis in methanol also had initiating activity in mouse skin.

Topics: Acetamides; Animals; Benzene Derivatives; Biphenyl Compounds; Female; Fluorobenzenes; Mice; Phenanthrenes; Piperidines; Precancerous Conditions; Skin Neoplasms; Stilbenes; Time Factors

Topics: Administration, Oral; Administration, Topical; Animals; Female; Liver Neoplasms; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred Strains; Neoplasm Metastasis; Neoplasms, Experimental; Papilloma; Phenanthrenes; Sex Factors; Skin Neoplasms

Topics: Animals; Benz(a)Anthracenes; Carcinogens; Drug Synergism; Fluorenes; Male; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Pharmaceutical Vehicles; Phenanthrenes; Pyrenes; Skin Neoplasms

Topics: Animals; Benz(a)Anthracenes; Benzopyrenes; Carbon Radioisotopes; Carcinogens; Chromatography; Chromatography, Gas; Chromatography, Paper; Female; Isomerism; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms; Smoke; Smoking; Spectrophotometry, Ultraviolet; Structure-Activity Relationship

Methylchrysenes are present in tobacco smoke and are suspected to contribute to the tumorigenicity of this inhalant. Chrysene and the six isomeric methylchrysenes were obtained in high purity (99.9 percent); they were tested on mouse skin for tumor initiating activity and carcinogenicity. The 3- and 6-methylchrysenes are strong tumor initiators, whereas the other five chrysenes have moderate initiatinig activity. 5-Methylchrysene is a strong carcinogen; the other chrysenes are inactive or weak carcinogens.

Topics: Animals; Carcinogens; Carcinoma; Female; Mice; Nicotiana; Phenanthrenes; Plant Extracts; Plants, Toxic; Skin Neoplasms; Structure-Activity Relationship

Topics: Animals; Carcinogens; Cyclopentanes; Flavonoids; Mice; Neoplasms, Experimental; Phenanthrenes; Skin Neoplasms

Topics: Alkenes; Animals; Benz(a)Anthracenes; Carcinogens; Chromatography, Gas; Chromatography, Paper; Female; Fluorenes; Mass Spectrometry; Mice; Mice, Inbred Strains; Nicotiana; Phenanthrenes; Plants, Toxic; Skin Neoplasms; Smoke

Topics: Acids; Alkylating Agents; Animals; Biological Assay; Carcinogens; Carcinoma; Chemical Phenomena; Chemistry; Chromatography; Chromatography, Gas; Esters; Female; Fluorenes; Hydrocarbons; Hydrocarbons, Halogenated; Hydrogen-Ion Concentration; Insecticides; Mice; Neoplasms, Experimental; Nicotiana; Nicotine; Papilloma; Phenanthrenes; Plant Extracts; Plants, Toxic; Quinones; Skin Neoplasms; Smoke; Tars; Terpenes

Topics: Animals; Benz(a)Anthracenes; Binding Sites; Chromatography, Thin Layer; Histocytochemistry; Mice; Neoplasms, Experimental; Phenanthrenes; Skin; Skin Neoplasms

Topics: Animals; Anthracenes; Arsenic; Benz(a)Anthracenes; Benzopyrenes; Carcinogens; Hydrocarbons; Isoniazid; Methylcholanthrene; Nitrosamines; Nitroso Compounds; Pathology; Phenanthrenes; Research; Salamandridae; Skin Neoplasms; Toxicology; Urodela

Topics: Animals; Benz(a)Anthracenes; Benzene; Benzopyrenes; Croton Oil; Epidermis; Methylcholanthrene; Mice; Mice, Hairless; Phenanthrenes; Research; Skin Neoplasms; Tetrazolium Salts; Toxicology; Urethane