title: Induction or suppression of SV40 amplification by genotoxic carcinogens, non-genotoxic carcinogens or tumor promoters.
abstract: Carcinogens are generally classified into two groups: genotoxic and non-genotoxic. As the final product of genotoxic and non-genotoxic carcinogens is the same, i.e., a clone of genetically altered cells, it could be possible that non-genotoxic carcinogens may yield genotoxic events as a secondary result of cell toxicity having led to mitogenesis/cellular proliferation, or that genetic alterations are induced that are normally neglected in genotoxicity tests. A genetic effect with possible relevance for the ultimate mechanism of carcinogenicity is the amplification of oncogenes. In the present experiments, amplification of SV40-virus DNA in transformed CO631-cells has been measured. In this system, two genotoxic carcinogens (positive control), two non-carcinogens (negative control), and eight non-genotoxic carcinogens have been tested. With the exception of testosterone and BVDU, all substances were tested when given alone. Testosterone and BVDU were tested in combination with either MTX or AMP in the presence or absence of S9-mix. The genotoxic carcinogens TEM and 4-NQO as well as the tumor promoters TPA, coumarin, mezerein and chrysarobin were able to induce SV40 amplification when given alone. The same was for acetamide and thioacetamide. The non-carcinogens acetone and dimethylformamide were ineffective. In case of testosterone, a co-amplification effect was seen in the absence of S9-mix, and an anti-amplification effect in presence of S9-mix. The anti-recombinogen BVDU reduced the SV40 amplification effect of AMP in experiments without addition of S9-mix. In the presence of activating S9-mix, this substance was effective at lower concentrations than without S9-mix, and showed an enhanced anti-amplification effect. Similar effects of testosterone and BVDU had been observed before in respect to stimulation or suppression of recombination. These results can be used as supportive evidence for the assumption that gene amplification is mechanistically related to recombination.
authors.affiliation: Department of Genetics, Fraunhofer-Institute for Toxicology and Aerosol Research, Hannover, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Fahrig
authors.forename: A
authors.initials: A
authors.lastname: Steinkamp-Zucht
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000096:Acetone / Q000494:pharmacology; D000873:Anthracenes / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology*; D002461:Cell Line, Transformed; D003374:Coumarins / Q000494:pharmacology; D004279:DNA, Viral / Q000096:biosynthesis* / Q000187:drug effects*; D003857:Deoxyuridine / Q000494:pharmacology; D004126:Dimethylformamide / Q000494:pharmacology; D004224:Diterpenes; D015122:Mercaptopurine / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D009153:Mutagens / Q000494:pharmacology*; D009600:Nitroquinolines / Q000494:pharmacology; D009693:Nucleic Acid Hybridization; D013539:Simian virus 40 / Q000187:drug effects* / Q000235:genetics; D013729:Terpenes / Q000494:pharmacology; D013739:Testosterone / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013853:Thioacetamide / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000081:Acetamides; D000873:Anthracenes; D002273:Carcinogens; D003374:Coumarins; D004279:DNA, Viral; D004224:Diterpenes; D009153:Mutagens; D009600:Nitroquinolines; D013729:Terpenes; D013853:Thioacetamide; D000096:Acetone; C011309:mezerein; D013739:Testosterone; C013883:chrysarobin; D004126:Dimethylformamide; C030686:acetamide; C030123:coumarin; D015122:Mercaptopurine; D013755:Tetradecanoylphorbol Acetate; D003857:Deoxyuridine; D008727:Methotrexate