Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fusarin C (FC) is a potent mutagen which has been isolated from Fusarium moniliforme culture extracts (FME). We have confirmed that the mutagenicity of these extracts is enhanced by phenobarbital- or Aroclor-induced microsomes and shown that: (i) additional, direct-acting, mutagens are present in crude extracts from F. moniliforme cultures; (ii) Salmonella typhimurium TA 100 exposed to FME in the presence of S9 mixtures shows an increased number of DNA strand breaks as detected by intercalation of ethidium bromide; (iii) exposure of polyoma-transformed rat fibroblast cells to HPLC-purified FC induced asynchronous replication of polyoma DNA sequences, a phenomenon also observed when these cells were exposed to a variety of other carcinogens; (iv) FME can alkylate 4-(p-nitrobenzyl)pyridine in the absence of S9 mix, although less efficiently than styrene oxide; and (v) these additional direct-acting mutagens, present in crude extracts from F. moniliforme cultures, may be responsible for the DNA adducts formed by reaction with calf thymus DNA in the absence of metabolic activation and detected by the 32P-postlabeling assay. All of these observations suggest that significant health effects may be associated with human exposure to F. moniliforme and that further studies on its metabolites are needed.
Carcinogenesis 1988 Sep
PMID:Fusarium moniliforme metabolites: genotoxicity of culture extracts. 284 81

When a single topical application of 12-O-tetradecanoylphorbol-13-acetate (TPA) was performed 12 h before the second application, ornithine decarboxylase (ODC) induction by the second application of TPA was markedly suppressed (refractory state). However, at intervals of 96 h between the first and the second application, the ODC activity induced by the second application of TPA was higher (enhanced state) than the activity induced by the single application. When various anti-tumor promoting agents, i.e. p-bromophenacyl bromide, nordihydroguaiaretic acid, quercetin, 1-tosylamide-2-phenylethyl chloromethyl ketone, retinoic acid and palmitoylcarnitine, were applied concurrently with the first TPA application, the ODC induction in the refractory state was restored only by palmitoylcarnitine, but not by other antitumor promoting agents. None of these anti-tumor promoting agents affected the ODC induction in the enhanced state. Stearoylcarnitine also had the restorative effect but was less effective than palmitoylcarnitine. Acetylcarnitine and palmitic acid were not effective. Pretreatment of mice with TPA 12 h or 96 h before the second TPA application resulted in the reduction or the increase in the Vmax values of ODC both for ornithine and pyridoxal-5'-phosphate, respectively. Palmitoylcarnitine restored these reduced Vmax values to the control values. Twelve hours after TPA treatment, the epidermal protein kinase C activity of both cytosol and particulate fractions decreased moderately. At 96 h after TPA application, protein kinase C activities of both cytosol and particulate fractions were fully or at least partially restored to the control levels. Protein kinase C activities both in the cytosol and the particulate fractions tended to be restored by palmitoylcarnitine, but the effect was not always reproducible. The TPA-induced refractory state and the enhanced state for ODC induction appear to result from the changes in the protein kinase C activities caused by TPA. However, it is not known whether such changes in the protein kinase C activities are the major causes for the TPA-induced refractory and/or enhanced state for ODC induction and whether or not the restorative effect of palmitoylcarnitine is due to its modulating action on protein kinase C activity.
Carcinogenesis 1988 Feb
PMID:Palmitoylcarnitine reverses 12-O-tetradecanoylphorbol-13-acetate-induced refractory state for the TPA-caused ornithine decarboxylase induction in mouse epidermis. 333 15

Chloroacetaldehyde, the stable metabolite of the human carcinogen vinyl chloride, forms interstrand cross-links in vitro in salmon sperm DNA and in the alternating copolymer, poly(deoxyadenylate-deoxythymidylate) [poly(dA-dT)]. Formation of the cross-link was a function of both time of reaction and concentration of chloroacetaldehyde. Cross-linking in chloroacetaldehyde-treated poly(dA-dT) was detected initially by changes in renaturation hysteresis [Singer et al., Carcinogenesis (Lond.), 5: 1165-1171, 1984]. This has been confirmed and quantitated using the relative fluorescence of ethidium bromide after denaturation and reannealing at 40 degrees C. Three percent cross-linking was detected after 10 min reaction with 20 mM chloroacetaldehyde at 24 degrees C. In DNA the relative fluorescence of ethidium bromide after denaturation and rapid cooling was used to estimate the number of cross-links formed. Three times as much cross-linking occurs in DNA compared to poly(dA-dT) under identical reaction conditions. The postulated structure for an interstrand cross-link in poly(dA-dT) is a hydroxyethyl bridge across the strands between the N6-amino groups of alternate adenine residues. In DNA, other amino groups in the proper configuration can be involved.
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PMID:Formation of interstrand cross-links in chloroacetaldehyde-treated DNA demonstrated by ethidium bromide fluorescence. 340 21

A large proportion of the metabolites formed from benzo[a]pyrene (BP) in cell cultures from rodents, fish and humans result from conjugation of an oxidized metabolite of BP with sulfate, glucuronic acid or glutathione (GSH). To improve the analysis of these metabolites, a reversed-phase ion-pair h.p.l.c. system using a step gradient of methanol:tetrabutyl-ammonium bromide in ammonium formate buffer has been developed for the separation of these three classes of conjugates. This system separated 3-hydroxy-BP glucuronide and sulfate conjugates and resolved them from GSH conjugates of BP 4,5-oxide, 7,8-oxide and 7,8-diol-9,10-epoxide. Cultures of early passage Syrian hamster, Wistar rat and Sencar mouse embryo cells, a bluegill fry (BF-2) cell line and a human hepatoma cell line (HepG2) were exposed to [3H]BP for 24 h. Medium samples from each were extracted with chloroform: methanol:water, and the water-soluble metabolites were analyzed by ion-pair h.p.l.c. The largest peak of metabolites in the media from cell cultures from rodents and the bluegill fry cell line co-eluted with the glucuronic acid conjugate of 3-hydroxy-BP. These phenol-glucuronides represented 48-62% of the total water-soluble metabolites in the fish and rodent cell cultures. Treatment of this material with beta-glucuronidase released 3-hydroxy-BP and 9-hydroxy-BP in ratios from 3:4 to 13.3:1 in various cultures. Media from the bluegill fry cell line and the mouse embryo cell cultures also contained a peak of BP-diol glucuronides; treatment of these peaks with beta-glucuronidase released mainly BP-7,8-diol. In HepG2 cells, 40% of the water-soluble metabolites were identified as sulfate conjugates of 3-hydroxy-BP and 9-hydroxy-BP. No glucuronic acid conjugates of BP metabolites were detected in HepG2 cells. Only small amounts of the water-soluble metabolites from these cell cultures eluted in the same volumes as the synthetic GSH conjugate of BP-4,5-oxide, BP-7,8-oxide and BP-7,8-diol-9,10-oxide. These studies indicate that conjugation with glucuronic acid represents a major pathway of formation of water-soluble metabolites from BP in cells derived from a number of species and demonstrate the value of this ion-pair h.p.l.c. system for the analysis of conjugates formed from BP.
Carcinogenesis 1987 Jan
PMID:Separation by ion-pair high-performance liquid chromatography of the glucuronide, sulfate and glutathione conjugates formed from benzo[a]pyrene in cell cultures from rodents, fish and humans. 380 96

Incubation of human leukocytes with the synthetic estrogen and known human carcinogen, diethylstilbestrol (DES), for 40 min caused extensive DNA strand breakage (clastogenesis), as measured by a fluorometric assay. The level of DNA clastogenesis was dose dependent above an apparent threshold of 10 microM. Clastogenesis was increased by addition of cysteamine, a reducing agent and hydroxyl radical scavenger, and was blocked by low concentrations of plasma. DES epoxide, a weakly estrogenic derivative, was about one-tenth as potent as a DNA clastogen. Unexpected and paradoxical findings were observed when cells were treated with DES in the presence of a hydrogen peroxide-generating system plus a peroxidase. At the subthreshold concentration of 10 microM DES, the oxidizing system increased DNA clastogenicity, yet at 30 microM DES the oxidizing system decreased clastogenicity. The addition of superoxide dismutase to the oxidizing system increased clastogenicity at both concentrations of DES. DNA damage was largely blocked by arsenite, N-ethylmaleimide, iodoacetamide and bromophenacyl bromide. These experiments provide further indication of the complex nature of reactions involving DES which can lead to DNA damage and which may be relevant to DES-induced carcinogenesis.
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PMID:DNA clastogenic activity of diethylstilbestrol. 387 97

Dose-response studies were undertaken to investigate the enhancing activity of potassium bromate (KBrO3), a food additive, on renal tumorigenesis initiated by N-ethyl-N-hydroxyethylnitrosamine (EHEN). A total of 180 male 6-week-old F344 rats were divided into 12 groups. EHEN was given in the drinking water for the first 2 weeks at a concentration of 500 ppm for initiation of carcinogenesis. Thereafter, the rats were treated orally either with KBrO3 at a concentration of 500, 250, 125, 60, 30 or 15 ppm, or with potassium bromide (KBr) at a concentration of 1750 or 350 ppm for 24 weeks. The mean numbers of kidney dysplastic foci were significantly increased in a dose-related manner in rats treated with more than 30 ppm KBrO3. The mean number of renal cell tumors was significantly higher after treatment with KBrO3 at the highest concentration of 500 ppm. On the other hand, KBr had no effect. It was concluded that KBrO3 at doses higher than 30 ppm in the drinking water has an enhancing effect on renal tumorigenesis.
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PMID:Dose-related enhancing effect of potassium bromate on renal tumorigenesis in rats initiated with N-ethyl-N-hydroxyethyl-nitrosamine. 392 54

We observed a significant reduction in one specific T-cell rosetting marker after treatment of bovine lymph node lymphocytes with 12-O-tetradecanoylphorbol-13-acetate (TPA). There was a dose-dependent reduction in the formation of neuraminidase-treated sheep erythrocyte rosettes (En), but not aminoethylisothiouronium bromide-treated sheep rosettes (Ea) after as little as 10 min of incubation with TPA. A maximum of approximately 50% reduction was reached after 1 h. When several phorbol esters and mezerien were tested, we found that the reduction in En rosetting induced by the compounds correlated with their in vivo tumor-promoting activity. The reduction in En rosetting appears to be approximately 50% reversible for up to 6 h of treatment with TPA when the cells were incubated in TPA-free medium for an additional 24 h, but it was irreversible after at least 12 h of treatment. Addition of the tumor promoters directly to the rosetting assay had no detectable effect on the sheep erythrocytes or the percentage of Ea rosettes. This specific change in En rosetting marker may represent the maturation of a T-cell subpopulation to T-suppressor cells in the presence of tumor-promoting phorbol esters.
Carcinogenesis 1985 Oct
PMID:Changes in a T-cell subpopulation marker induced by tumor-promoting phorbol esters. 393 84

N-Hydroxy-N-2-fluorenylacetamide, a proximate carcinogenic metabolite of N-2-fluorenylacetamide, is oxidized largely to 2-nitrosofluorene by lactoperoxidase or extract of peroxidative activity of rat uterus in an H2O2- and Br- -dependent reaction. Evidence is presented that the oxidizing species includes OBr- (HOBr). This novel oxidation may be involved in carcinogenesis by N-arylhydroxamic acids.
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PMID:A novel oxidation of the carcinogen N-hydroxy-N-2-fluorenylacetamide catalyzed by peroxidase/H2O2/Br-. 403 95

Nucleosomes from chicken erythrocytes, with DNA containing an average of 144 base pairs, were alkylated with [3H]methylnitrosourea. The level of alkylation of the nucleosomal DNA was 48% of that of free DNA. The histones had approximately one tenth the radioactivity of the DNA. There was no statistically significant difference between alkylation of nucleosome bases in the major vs. minor groove. When the first 50 residues of the alkylated nucleosomal DNA were examined on sequencing gels, the 7-methylguanine and 3-methyladenine (3-MeA) residues were distributed randomly. The 3-MeA DNA glycosylase I of E. coli was used to measure the release of 3-MeA from nucleosomal DNA. Incubation at 37 degrees C resulted in a release which reached a plateau of approximately 33% of the 3-MeA groups of the nucleosomal DNA. A partially purified 3-MeA DNA glycosylase from rat liver gave similar results. The limited enzymatic release is most likely due to steric hindrance of the enzyme by the DNA-histone interactions on the surface of the core particle. An alteration of nucleosomal conformation has been suggested as an explanation for repair of nucleosomal DNA. Two model systems have been examined. The addition of ethidium bromide to alkylated nucleosomes increased the enzymatic release of 3-MeA to approximately 75% and altered the electron microscopic appearance. The chemical alkylation of nucleosomes also increased the enzymatic release of 3-MeA as well as decreased the sedimentation coefficient. All of these experiments indicate a limited availability of 3-MeA residues to the glycosylase and suggest that some conformational change must occur in vivo for complete repair.
Carcinogenesis 1983
PMID:The release of 3-methyladenine from nucleosomal DNA by a 3-methyladenine DNA glycosylase. 633 36

We have tested human fetal fibroblasts for development associated changes in DNA repair by utilizing nucleoid sedimentation as an assay for excision repair. Among skin fibroblasts the rate of excision repair was significantly higher in non-fetal cells than in fibroblasts derived from an 8 week fetus; this was evident by a delay in both the relaxation and the restoration of DNA supercoiling in nucleoids after irradiation. Skin fibroblasts derived at 12 week gestation were more repair proficient than those derived at 8 week gestation. However, they exhibited a somewhat lower rate of repair than non-fetal cells. The same fetal and non-fetal cells were also tested for induction of the protease plasminogen activator (PA) after u.v. irradiation. Enhancement of PA was higher in skin fibroblasts derived at 8 week than in those derived at 12 week gestation and was absent in non-fetal skin fibroblasts. These results are consistent with our previous findings that in human cells u.v. light-induced PA synthesis is correlated with reduced DNA repair capacity. Excision repair and PA inducibility were found to depend on tissue of origin in addition to gestational stage, as shown for skin and lung fibroblasts from the same 12 week fetus. Lung compared to skin fibroblasts exhibited lower repair rates and produced higher levels of PA after irradiation. The sedimentation velocity of nucleoids, prepared from unirradiated fibroblasts, in neutral sucrose gradients with or without ethidium bromide, indicated the presence of DNA strand breaks in fetal cells. It is proposed that reduced DNA repair in fetal cells may result from alterations in DNA supercoiling, and that persistent DNA strand breaks enhance transcription of PA gene(s).
Carcinogenesis 1984 Mar
PMID:DNA repair and induction of plasminogen activator in human fetal cells treated with ultraviolet light. 653 62


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