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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Co-incubation of benzo[a]pyrene (BaP) and coal-derived complex organic mixtures has been shown to decrease the metabolism and mutagenic activity of BaP. Because of these influences, five mixtures were co-administered dermally to mice to initiate tumor development. Results from these studies demonstrated that BaP tumor-initiating activity was decreased substantially by four of the five mixtures. When one of the mixtures was separated into chemical class fractions, the polycyclic aromatic hydrocarbon (PAH) and nitrogen-containing polycyclic aromatic compound fractions were the most effective, and the aliphatic and hydroxy-PAH fractions were the least effective as inhibitors of BaP-induced tumor initiation. Binding of [3H]BaP to epidermal DNA under conditions identical to those used for tumor initiation was decreased by co-administration of all five mixtures. Calculations of the number of tumors produced/micrograms BaP bound to DNA demonstrated that co-administration of this carcinogen with the mixtures consistently increased the effectiveness of the bound BaP at producing tumors by approximately a factor of 2. The HPLC radioactivity profiles of enzyme-hydrolyzed, adducted DNA indicated that, in the presence of the mixtures, the predominant adducts were derived from BaP-diol epoxide (BPDE); however, the mixtures decreased the ratios of the anti-BPDE-deoxyguanosine to syn-BPDE-deoxy-guanosine adducts. These data indicate that the prevailing influences of the mixtures (i.e. decreased DNA binding and adduct shifts) were similar to those observed with other bioassays following co-administration of binary mixtures. Furthermore, the data demonstrate that both DNA binding and adduct profiles are important in determining the contribution of a known carcinogen to tumor initiation by complex organic mixtures.
Carcinogenesis 1989 Jan
PMID:Influences of complex organic mixtures on tumor-initiating activity, DNA binding and adducts of benzo[a]pyrene. 249 65

Macrophages and their immortalized cell lines can be activated to form nitrite and nitrate via oxidation of arginine and this is accompanied by the formation of N-nitroso compounds. The mechanism of nitrosamine formation has been investigated through the use of compounds which are known either to inhibit or enhance acid-catalyzed nitrosation. The range of nitrogen acceptors has been expanded to include ureas as well as amines of varying pKa and structure. The results are consistent with a mechanism in which NO is oxidized to N2O3 and N2O4, which are capable of nitrosating amines, but not ureas or amides, at neutral pH. This is in agreement with a recent observation that macrophage cell-free extracts can oxidize arginine to NO. The effect of ascorbic acid on intact activated macrophages is complex since nitrite formation is enhanced over a very wide range of ascorbate concentrations (5-500 microM) while nitrosation is inhibited at ascorbate concentrations greater than 50 microM.
Carcinogenesis 1989 Mar
PMID:Nitrosation by stimulated macrophages. Inhibitors, enhancers and substrates. 249

A novel route for the microsomal generation of nitrogen mustard from its N-oxide nitromin is demonstrated. The mustard was trapped as an adduct with diethyldithiocarbamate and estimated by capillary GLC. The enzyme responsible for this reduction could utilize either NADPH or NADH. Reduction occurred preferentially under anaerobic conditions. Purified cytochrome P450 reductase could carry out this reaction. Similar activities were seen using microsomal fractions from rat liver or liver derived BL8, JB1 or Walker 256 carcinoma cells, when these were expressed on a per mg of protein basis. Unscheduled DNA synthesis (UDS) was used as an index of activation of nitromin in these cell systems. In all instances, greater induction of UDS occurred in cells incubated with nitromin under anaerobic conditions.
Carcinogenesis 1989 Nov
PMID:Reduction of nitromin to nitrogen mustard: unscheduled DNA synthesis in aerobic or anaerobic rat hepatocytes, JB1, BL8 and Walker carcinoma cell lines. 250 92

The N-heterocyclic aromatic pollutant, 7H-dibenzo[c,g]carbazole (DBC), is a potent carcinogen having both local and systemic effects. The overall objective of this research was to investigate the nature of the covalent binding of DBC with nucleic acids in vitro. DBC was shown to bind to polynucleotides, RNA and DNA in an in vitro rat or hamster microsomal enzyme assay, exhibiting a preferential binding to polyguanylic acid (poly[G]). Benzo[a]pyrene (BaP) binding to these same nucleic acids was determined simultaneously and was approximately 10-fold higher than DBC binding under identical experimental conditions. DBC-nucleic acid binding was shown to be dependent upon the presence of a microsomal activating system, the results being similar for rat or hamster liver microsomes. This microsome-dependent binding was unaffected by the addition of epoxide hydrase activity modifiers but was almost completely inhibited by alpha-naphthoflavone. The nature of DBC-nucleic acid binding was investigated using fluorescence spectroscopy. Benzo[c]carbazole and 5,5,6,6-tetrahydrodibenzo[c,g]carbazole were synthesized as representatives of the effect of disruption of the DBC pi-electron system on fluorescence excitation and emission. DBC-poly[G] adducts were isolated from binding assay mixtures and separated by HPLC. Results indicated that there are at least three different DBC-poly[G] adducts formed in vitro. The emission spectra of isolated adducts were similar in shape to that of DBC; however, the adduct spectra were shifted 5-10 nm toward longer wavelengths. This suggests that the bound DBC species have intact pi-electron systems. Results are consistent with binding through the nitrogen position as well as binding through the 1,2,3,4-ring of the molecule.
Carcinogenesis 1989 Dec
PMID:Binding of 7H-dibenzo[c,g]carbazole to polynucleotides and DNA in vitro. 259 Oct 8

A select group of non-histone proteins becomes complexed to DNA after Chinese hamster ovary (CHO) cells are treated with potassium chromate. The most abundant complexed protein has a mol. wt of approximately 45 kd and is thought to be actin. An antiserum to the chromate-induced DNA-protein complexes (DPCs) was prepared to facilitate the study of these complexes. Rather than detecting the predominant silver-stained proteins of DPCs described in an earlier study, this antiserum reacts primarily with an acidic 95-kd protein (p95) that does not silver stain. The antiserum can be used routinely to assay for the induction of p95-DNA complexes produced by chromate and perhaps by other carcinogens. Immunofluorescent staining of CHO cells and immunoblotting of cell fractions show the reactive antigens are within the cell nucleus. Blotting experiments with the antiserum indicate the chromate-induced p95-DNA complex dissociates in the presence of 2-mercaptoethanol, suggesting similarity to the DPCs formed by carcinogenic platinum compounds. A reduced species of chromium (probably Cr3+) may form DPCs by binding to the nitrogen, oxygen or sulfur atoms of proteins and DNA. These results illustrate the usefulness of immunological detection methods to study specific DNA-protein interactions induced by carcinogens. The possible relevance of DPCs in the carcinogenic process is discussed.
Carcinogenesis 1989 Apr
PMID:Immunological detection of DNA-protein complexes induced by chromate. 264 65

The present study was initiated to determine if DNA damage induced by the bifunctional anti-tumor alkylating agents melphalan, nitrogen mustard, a spontaneously activated derivative of cyclophosphamide or chlorambucil inhibits transcription in vitro, and to determine if the potential sites of transcription termination correlate with the sites of N7 guanine adducts predominantly formed by these agents. To assess drug effects on in vitro transcription, linearized plasmid DNA containing the 420-bp PstI fragment of exon two of the human c-myc oncogene was incubated with various concentrations of the drugs. After drug removal and further drug-free incubation, the sense strand of the c-myc insert was transcribed with either of two bacteriophage RNA polymerases in the presence of [32P]UTP. The labeled products of the reaction were electrophoresed next to the labeled products of RNA sequencing reactions, and the location of transcription termination along the DNA template was determined. The sites of transcription termination were then compared with the sites of drug-induced guanine N7 alkylation in the template, as determined by modified Maxam-Gilbert sequencing. At the drug exposures examined, all the drugs were shown to alkylate any guanine in the template. Transcription of this alkylated DNA, however, resulted in RNA molecules truncated not at every alkylated guanine, but at various discrete sites throughout the template. Transcription was terminated at every adenine pair examined in the melphalan-treated template, at selected guanine pairs in the nitrogen-mustard-treated template, and at selected adenine-guanine and guanine-adenine pairs in the chlorambucil-treated template. Transcription of cyclophosphamide-derivative-treated DNA was unaffected. These results suggest that only some bifunctional alkylating agents induce DNA damage capable of terminating transcription in vitro, and that these agents do so in a sequence-specific, drug-specific manner inconsistent with patterns of guanine N7 alkylation.
Carcinogenesis 1989 Jul
PMID:Transcription-terminating lesions induced by bifunctional alkylating agents in vitro. 273 21

O6-alkylguanine-DNA-alkyltransferase (ATase)-deficient murine haemopoietic stem cells were transfected, following electroporation, with a G418-selectable expression vector containing the protein coding region of the Escherichia coli ATase gene ada. Clones of cells that were resistant to G418 or the chloroethylating agent mitozolomide (Mz) were selected and most were shown to express very high levels of bacterial gene-encoded ATase. In comparison with control cells that were transfected with the parent vector, the ATase-expressing clones were considerably more resistant to the toxic effects of the methylating agents N-methyl-N-nitrosourea and methylmethanesulphonate or the chloroethylating agents Mz or taurine chloroethylnitrosourea, but unchanged in their susceptibility to the bis-chloroethylating agent nitrogen mustard. Thus alkylation damage in DNA that can be repaired by the E. coli ATase constitutes the principal lethal lesion produced by alkylating agents in murine haemopoietic stem cells and the ATase deficiency in these cells can be complemented by electroporation-mediated gene transfection.
Carcinogenesis 1988 Jan
PMID:Transfection of murine multi-potent haemopoietic stem cells with an E. coli DNA alkyltransferase gene confers resistance to the toxic effects of alkylating agents. 282 35

Certain DNA-binding proteins that regulate gene expression contain single or multiple copies of short polypeptide sequences, approximately 30 residues long, consisting of combinations of four Cys or His residues at defined spacing, so that Zn++ is complexed in tetrahedral coordination with the respective thiol-sulfur and/or imidazole-nitrogen atoms. The Zn++ ion evidently serves as a strut that stabilizes folding of the domain into a 'finger-loop', which is capable of site-specific binding to double-stranded DNA. This article reviews the evidence (a) that finger-loop domains have been highly conserved during evolution, (b) that they furnish one of the fundamental mechanisms for regulating gene expression, and (c) that a metal ion (e.g., Zn++) is required for binding of finger-loops to DNA and for their biological functions. The authors' search of amino acid sequences of 38 transforming proteins identified possible finger-loop domains in the myc, fms, fps, raf-1, rfp, src, syn, yes, erbA, int-1, and TGF-alpha gene-products. The search incidentally revealed possible finger-loop domains in human insulin receptor, which may provide a mechanistic explanation for recent observations that insulin, after binding to its cell surface receptor, is translocated to hepatocyte nuclei and becomes bound to chromatin. Zn++-coordination sites in finger-loop domains are proposed as potential targets for metal toxicity; substitution of Ni++, Co++, or Cd++ for Zn++ in finger-loops of transforming proteins is suggested as an hypothetical mechanism for metal carcinogenesis.
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PMID:Finger-loops, oncogenes, and metals. Claude Passmore Brown memorial lecture. 284

For many DNA-damaging agents, the extent of damage at any given base site is influenced by the DNA sequence surrounding that site. Most agents that alkylate the guanine N7 position, including mechlorethamine (nitrogen mustard) and benzo[a]pyrene diol epoxide, alkylate oligo-guanine sequences preferentially. Since these data suggest that guanine-cytosine(GC)-rich regions in genes could be preferred sites of damage by these agents, GenBank was searched for genes containing 30 bp sequences of greater than 90% GC (GC runs). While primate, rodent, other mammalian, vertebrate and animal virus genes constituted 57% of the annotated entries, they included 90% of the entries with the GC runs. In addition, the percentage of oncogenes in the group of the entries with GC runs was higher than that in the overall database. One gene of interest containing GC runs was the human c-Ha-ras oncogene. All seven GC runs in the c-Ha-ras gene are in the 5'-flanking region, rather than in the coding sequences. In fact, some of the GC runs are contained in Sp1-binding enhancer sequences. Gel analysis of the alkylation of cloned c-Ha-ras DNA by several carcinogenic alkylating agents strongly suggest that in this gene GC runs can be preferred sites of damage. These observations suggest mechanisms by which DNA damage at sites other than oncogene coding sequences may play a role in carcinogenesis and/or chemotherapy.
Carcinogenesis 1988 Nov
PMID:GC-rich regions in genomes as targets for DNA alkylation. 284 98

Authentic stable standards of 7H-dibenzo[c,g]carbazole (DBC), a potent environmental carcinogen, were synthesized in order to study the compound's metabolism and mutagenesis in whole cell systems. Complete characterization of 2-OH-DBC, 3-OH-DBC, 4-OH-DBC, 13c-OH-DBC and N-methyl-DBC was accomplished by UV, IR, fluorescence and high resolution NMR spectra, and by high resolution mass spectrometric procedures. Metabolites of DBC were isolated and separated by HPLC from extracts of rat liver microsomal incubations and the medium of primary cultures of rat liver cells. Identification of metabolites was accomplished by comparisons between the authentic standards and isolated metabolites by UV and fluorescence spectroscopy, mass spectral analyses, and by co-chromatographic techniques. 2-OH-DBC and 3-OH-DBC were found in all rat liver preparations as well as three other unidentified phenols. 4-OH-DBC, 13c-OH-DBC or N-methyl-DBC were not isolated under any conditions. The rates of appearance of DBC metabolites in cultures of rat liver cells were compared to those for benzo[a]pyrene (BaP) at 10, 25, 50 and 100 microM substrate. At 25 microM substrate or greater, DBC metabolites appeared in the culture medium at significantly faster rates than those of BaP. At 100 microM substrate, DBC metabolites appeared at a rate approximately 4-times the rate observed for BaP. When the mutagenic potential of DBC was compared to that of BaP under identical conditions in a co-cultivation system of rat liver cells and an epithelial cell line, DBC was found to produce significantly higher rates of mutagenesis than BaP at concentrations of 0.4, 4.0 and 40.0 microM in the culture medium. The mutagenic potential of DBC was compared to that of several derivatives of the parent compound. 3-OH-DBC, 13c-OH-DBC and N-methyl-DBC were found to be mutagenic in the co-cultivation system at 40 microM, with mutation frequencies of 4.4 +/- 0.8, 8.0 +/- 3.1 and 12.9 +/- 5.4 mutants per 10(5) survivors, respectively. The parent compound induced 8.0 +/- 2.8 mutants per 10(5) survivors at the same concentration. 2-OH-DBC and 4-OH-DBC were not mutagenic under the same conditions. The studies have shown that metabolism of 7H-DBC leads predominantly to phenols in rat liver cells. The results of the mutagenesis experiments indicate that, of the derivatives studied, those associated by induction to the nitrogen are mutagenic. The latter studies suggest that the nitrogen is involved in the activation of the parent compound through inductive mechanisms.
Carcinogenesis 1989 Mar
PMID:The chemistry and biology of 7H-dibenzo[c,g]carbazole: synthesis and characterization of selected derivatives, metabolism in rat liver preparations and mutagenesis mediated by cultured rat hepatocytes. 292 89


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