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)

1,N6-Ethenodeoxyadenosine (edA) and 3,N4-ethenodeoxycytidine (edC) are two mutagenic adducts associated with exposure to ethyl carbamate (urethane) and vinyl chloride. We have recently developed two ultrasensitive methods for determining the molecular dose of these adducts in cellular DNA. In both methods, purified DNA was first enzymatically digested to 2c-deoxyribonucleotide 3c-monophosphates. Etheno-modified nucleotides were then separated from normal nucleotides in one of two ways: either by reverse phase, ion-pair HPLC coupled with 260 nm UV detection, or by immunoaffinity chromatography using reusable microcolumns containing specific monoclonal antibodies coupled to Protein A-Sepharose. Fractions enriched for the adducted nucleotides were labeled using T4 poly-nucleotide kinase and [32P]ATP, and individual nucleotides were subsequently resolved by two-dimensional TLC, visualized by autoradiography, and quantified by liquid scintillation counting. When used to analyze the same sample of etheno-modified calf thymus DNA, both assays produced similar results. However, when both methods were used to analyze rat liver DNA 'spiked' with known amounts of etheno nucleotide standards, the immuno-affinity/32P TLC procedure proved to be more sensitive and more reproducible than the HPLC/32P TLC method: while the detection limit of the immunoaffinity/32P TLC technique was < 4 etheno adducts/10(9) parent deoxynucleotides, the HPLC/32P TLC method often failed to detect adducts at concentrations < 2/10(8). In other experiments, the immunoaffinity/32P TLC method was used to demonstrate formation of edA and edC in cells treated with vinyl chloride monomer. Because of its exquisite sensitivity, the immunoaffinity/32P TLC method promises to be extremely useful for measuring both background and induced levels of etheno adducts, making it possible to examine the role of these adducts in inducing mutations and/or carcinogenesis.
Carcinogenesis 1994 Aug
PMID:A comparison of two ultrasensitive methods for measuring 1,N6-etheno-2'-deoxyadenosine and 3,N4-etheno-2'-deoxycytidine in cellular DNA. 805 45

Mutations in ras oncogenes and expression of their encoded p21 protein products are believed to play an important role in carcinogenesis in humans. Detection of mutant p21 proteins in serum may be a useful molecular epidemiologic biomarker with which to study this process, and workers with heavy exposure to vinyl chloride (VC) represent a model population for such study. We studied the occurrence of a specific ras mutation (Asp 13 c-Ki-ras) by oligonucleotide hybridization and the expression of the corresponding p21 protein in tumor tissue and serum by immunohistochemistry and immunoblotting with monoclonal antibodies in five individuals with heavy exposure to VC and resultant angiosarcomas of the liver (ASL). Four of five (80 percent) of the cases of ASL were found to contain the mutation and to express the corresponding mutant protein in their tumor tissue and serum. Serum expression of the mutant protein also was examined in nine VC-exposed workers with liver angiomas and 45 VC-exposed workers with no evidence of liver neoplasia; eight of nine (89 percent) of the former and 22 of 45 (49 percent) of the latter were also positive for the mutant p21 in their serum. However, serum immunoblotting results for 28 age-gender-race matched, unexposed controls were all negative. Stratification by years of VC exposure showed a significant linear trend (P < 10(-5)) for the occurrence of the serum mutant p21 protein with increasing duration of exposure. These results suggest that detection of serum mutant p21 protein can be a valid surrogate for ras gene expression at the tissue level.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutant c-Ki-ras p21 protein in chemical carcinogenesis in humans exposed to vinyl chloride. 806 Nov 77

Mutations in the p53 tumor suppressor gene are commonly found in the major human cancers and the mutational spectrum in some cancer types is consistent with the genotoxic effects of the associated environmental risk factors. Thus far there is little information on p53 mutations in cancers of factory workers with a history of carcinogen exposure in the workplace. Occupational exposure to vinyl chloride causes liver angiosarcomas (ASL) and also increases the risk of several other cancers. Loss of p53 function in osteo- and fibrosarcomas can occur by two different mechanisms, p53 mutation and amplification of the MDM2 gene. We examined tumors from five vinyl chloride-exposed patients, four with ASL and one with hepatocellular carcinoma (HCC), for evidence of MDM2 proto-oncogene amplification or p53 mutation in exons 5-8. Amplification of MDM2 was not found, but in two of the angiosarcomas an A:T to T:A missense mutation was detected. p53 sequence analysis of vinyl chloride associated cancers may provide valuable information on the relationship between carcinogen exposure and DNA damage in cancer-related genes.
Carcinogenesis 1994 Jan
PMID:p53 mutations at A:T base pairs in angiosarcomas of vinyl chloride-exposed factory workers. 829 34

The genetic toxicity profiles of vinyl chloride (VCl), vinyl bromide (VBr), ethyl carbamate (EC), vinyl carbamate (VC) and some structurally related chemicals were investigated in both somatic and germ cells of Drosophila melanogaster. In the white/white+ eye mosaic assay, a screening system measuring predominantly homologous recombination in somatic cells, only marginal genotoxic activities were observed for acetyl chloride (ACl), glycolaldehyde (GCA), 2,2'-dichlorodiethyl ether (DDE) and methyl carbamate (MC), whereas VCl, 2-chloroacetaldehyde (CAA), VBr, 2-bromoacetaldehyde (BAA) and EC were clearly recombinogenic in the assay. Those chemicals proven to be recombinogenic in somatic cells were investigated further in postmeiotic male germ cells, utilizing as descriptors of their genotoxicity I(CL/RL) and M(exr-)/M(exr+) indices. The I(CL/RL) index is the rate of induced chromosome loss (CL), a clastogenic event, divided by the forward mutation rate, measured as recessive lethal (RL) mutations in 700 loci of the X-chromosome. The M(exr-)/M(exr+) mutation enhancement ratio is obtained by determining RL under excision repair deficient versus repair proficient conditions. With I(CL/RL) values (2.7-6.9) similar to those obtained for cross-linking agents, vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate are all efficient clastogenic agents in Drosophila germ cells. In the absence of excision repair, however, neither CEO nor CAA gave a hypermutability response (M(exr-)/M(exr+) approximately 1). By contrast, VCl, VBr, EC and VC showed clearly enhanced M(exr-)/M(exr+) ratios, suggesting that these compounds produce some repairable DNA modification(s) that are not generated by their epoxides. This unexpected finding points to the formation of other, yet unknown, metabolites of vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate. Our results support the concept that the epoxides chloroethylene oxide (CEO), bromoethylene oxide (BEO) and vinyl carbamate epoxide (VCO) are the most essential mutagenic intermediates. Compared to chloroethylene oxide (CEO), 2-chloroacetaldehyde (CAA) was approximately 50 times less effective in the induction of RL, whereas BAA was inactive as a mutagen. These findings are consistent with the general view that CAA and BAA play no major role in the genotoxic action of vinyl halides.
Carcinogenesis 1996 May
PMID:Characterization by two-endpoint comparisons of the genetic toxicity profiles of vinyl chloride and related etheno-adduct forming carcinogens in Drosophila. 864 Sep 17

Vinthionine (S-vinyl-DL-homocysteine) is hepatocarcinogenic in rats and mice. [Vinyl-14C]vinthionine binds covalently to rat liver DNA, RNA and protein in vivo, but not in vitro. This amino acid is directly mutagenic in Salmonella typhimurium TA100 and TA1535; the mechanism of its metabolic activation in vivo in bacteria and liver is under study. In the present study liver tumors were induced in 12-day-old male B6C3F1 mice by single i.p. injections of vinthionine or the alkylating agent 2-chloroethyl methyl sulfide (CEMS). At 10 months the gross tumors were examined for the presence of activated H-ras oncogenes. DNA was isolated from single tumors per mouse from 37 mice treated with vinthionine and from 31 mice treated with CEMS. These DNAs were screened for codon 61 mutations by restriction fragment length polymorphism of PCR-amplified H-ras gene fragments. Thirty seven of 37 vinthionine-induced hepatomas had H-ras mutations in this codon, which consisted of seven C-->A transversions in the first base, with 29 A-->T transversions and one A-->G transition in the second base. Twenty five of 31 CEMS-induced hepatomas had mutations in the same codon, which consisted of seven C-->A transversions in the first base, with eight A-->T transversions and 10 A-->G transitions in the second base. These mutation spectra are quite different to that noted by others in spontaneous hepatomas in untreated B6C3F1 mice. These data appear to result from the covalent binding of these carcinogens to the liver DNA.
Carcinogenesis 1996 Jun
PMID:Activation of H-ras oncogenes in male B6C3F1 mouse liver tumors induced by vinthionine or 2-chloroethyl-methyl sulfide. 868 56

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-forming chemicals were developed and applied to humans and animal models. The aims were to identify hitherto unknown sources and mechanisms of exogenous and endogenous DNA damage, to examine the effect of drug polymorphism on BP adduct levels, and to develop QSAR between tumorigenic potency, heritable genetic damage and structural elements of alkylating carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring (+)-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmonary CYP1A1-related catalytic activity (AHH) and the level of lung BPDE-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carcinogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3-alkAde in urine, for which a detection method was developed (Friesen et al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Carcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC-MS analysis. The usefulness of 3-alkAde analysis for the determination of the whole-body dose of alkylating agents derived from exogenous and endogenous sources was demonstrated. (iii) Etheno-DNA adduct-forming agents: Etheno(epsilon)-DNA base adducts (epsilon A, epsilon dC, epsilon dG) are promutagenic DNA lesions that are formed by occupational (vinyl halides) and environmental (urethane) carcinogens. An ultrasensitive detection method was developed (Nair et al. (1995) Carcinogenesis, 16, 613-617), based on immunoaffinity purification and 32P-postlabelling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexposed rats, mice and from human samples contained background levels of epsilon dA and epsilon dC (Bartsch et al. (1994) Drug. Metab. Rev., 26, 349-371). As formation of epsilon dA and epsilon dC adducts by lipid peroxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative stress. Results from testing this hypothesis are presented.
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PMID:DNA adducts in human carcinogenesis: etiological relevance and structure-activity relationship. 869 83

DNA ethenobases are promutagenic lesions formed by carcinogens such as vinyl chloride (VC). Their formation was investigated in 6-week old, male Sprague-Dawley rats exposed to 500 p.p.m. VC by inhalation (4 h/day, 5 days/ week) for 1, 2, 4 or 8 weeks and in 7- and 14-week old, matched control animals. 1,N6-Ethenoadenine (epsilon A) and 3, N4-ethenocytosine (epsilon C) deoxyribonucleotides were analysed by immunoaffinity purification and 32P-postlabelling. This postlabelling method was compared with a radio-immunoassay method, which yielded similar results. Background levels of ethenobases were found in DNA from the liver, lungs, kidneys and circulating lymphocytes of unexposed, control rats. In the liver, the following background molar ratios of ethenobase to parent base in DNA were detected (mean values x 10(-8)): epsilon A/A, 0.04-0.05; epsilon C/C, 0.06-0.07. In the lungs, kidneys and circulating lymphocytes, background levels of epsilon A and epsilon C ranged from 1.7 to 4.2 x 10(-8) and from 4.8 to 11.2 x 10(-8), respectively. Following a 5-day exposure to VC, a significant increase of epsilon A and epsilon C was measured in hepatic DNA from rats sacrificed immediately after treatment. Further, a dose-dependent increase of both etheno adducts was observed in liver DNA of VC-treated rats. Compared to the 5-day exposure, approximately 4-fold higher levels of epsilon A and epsilon C were observed in the liver of animals after 8 weeks of exposure. In contrast, there was an accumulation of epsilon C but not of epsilon A in lungs and kidneys. In circulating lymphocytes, no significant increase of ethenobase levels above control values was observed after 2 months of exposure to VC. Both etheno adducts were found to be persistent in liver DNA, after 2 months following the termination of VC exposure. These results further support the notion that DNA etheno-bases are critical lesions in VC-induced carcinogenesis. The possible contribution of lipid peroxidation products that also yield ethenobases, on the formation and persistence of these DNA adducts, remains to be clarified.
Carcinogenesis 1996 Aug
PMID:Formation and accumulation of DNA ethenobases in adult Sprague-Dawley rats exposed to vinyl chloride. 876 9

The metabolism and mutagenicity of phenyl and 4-nitrophenyl vinyl ethers (PVE and NPVE) and their epoxide metabolites, phenoxyoxirane (PO) and 2'-(4-nitro-phenoxy)oxirane (NPO), were studied including reactions with DNA and tests for carcinogenicity. PVE and NPVE were epoxidized in dry acetone by dimethyldioxirane to give high yields (95%) of the pure epoxides. The epoxides are unstable in aqueous media and in 0.1 N phosphate buffer, pH 7.4, at 37 degrees C; they had half-lives of 2.7 min (PO) and 4.4 min (NPO). These times were reduced to 1.9 min (PO) and 2.5 min (NPO) in the presence of isotonic (154 mM) chloride ion. In neutral phosphate buffer these epoxides hydrolyze to form glycolaldehyde and the corresponding phenols; in the presence of chloride ion, chloroacetaldehyde and several unknown compounds are also formed. Glycolaldehyde was also found as a hydrolysis product of the presumed epoxides generated in the hepatic microsomal oxidation of PVE and NPVE. PO and NPO reacted with DNA to form adducts that depurinated in weak acid to form 7-(2'-oxoethyl)guanine and N(2),3-ethenoguanine. PO was weakly mutagenic in Salmonella typhimurium TA1535 while NPO was much more mutagenic under the same conditions. PO and NPO were found to have mutagenic half-lives that matched their chemical half-lives. PO and NPO were found to be tumorigenic in the skin of mice after single or five initiating doses followed by multiple doses of phorbol ester (TPA). NPO was a stronger tumor initiator than PO. NPO had appreciable activity as an initiator of hepatoma formation in infant male B6C3F1 mice. Thus PO and NPO are electrophilic, mutagenic and tumorigenic metabolites of their corresponding phenyl vinyl ethers.
Carcinogenesis 1997 Feb
PMID:The electrophilic, mutagenic and tumorigenic activities of phenyl and 4-nitrophenyl vinyl ethers and their epoxide metabolites. 905 39

Little is known about syncarcinogenic effects of occupational and environmental substances although it is supposed that different exogenous factors may play critical roles in the development of many human tumors. Epidemiologic results prove syncarcinogenesis for asbestos exposure and smoking (lung cancer), radon exposure and smoking (lung cancer), exposure to aromatic amines and smoking (bladder cancer) and alcohol abuse and smoking (oral, larynx and oesophagus cancer). Animal experiments point to additive effects in carcinogenesis for different nitrosamines and substances like benzo(a)pyrene, carbon tetrachloride, ethanol, vinyl chloride and ionising radiation. It can be concluded from modern concepts of carcinogenesis that syncarcinogenic mechanisms may not only result from genotoxicity but also from influences on cell proliferation and mitogenesis as well as toxicokinetics, DNA repair, intercellular communication, immune system and hormonal effects. New methods of molecular epidemiology seem very promising to study syncarcinogenic effects in animals and humans.
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PMID:[New data on syncarcinogenesis in tumors of exogenous origin]. 940 98

Small fragments of silicone gels injected intraperitoneally have been used to induce plasmacytomas in genetically susceptible mice. Silicone oils, in contrast to silicone gels, are apparently not tumorigenic in the mouse plasmacytoma system. The reason for this difference as well as the mechanism of silicone gel-induced plasmacytoma development is poorly understood. We chose to examine the possibility that low molecular wt silicone compounds such as siloxanes, leaking from the complex silicone gel matrix into the surrounding tissue, may be mutagenic. We postulate that this mutagenicity may be a critical determinant of the plasmacytoma inducing potency of silicone gels. Six siloxane compounds, either linear or cyclic di-, tri-, or tetrasiloxanes substituted with methyl or vinyl moieties, were selected as model compounds to study mutagenicity in Rat2lambda lacI fibroblasts in vitro. Using phage lambda-derived lacI/lacZ genes as target/reporter genes to quantitate mutagenesis, and gamma-cyclodextrin as vehicle to effectively deliver siloxanes, we found that exposure to 50 microM of tetravinyl-tetramethylcyclo-tetrasiloxane (tetravinyl D4) resulted in a modest 1.7-fold increase of mutant frequencies over controls in Rat2lambda lacI cells. In related toxicity experiments, tetravinyl D4 was shown to perturb lipid membranes leading to a loss of cytosolic glutathione (GSH), which by itself resulted in a 1.5-fold increased mutant rate in Rat2lambda lacI cells. We conclude that certain siloxanes may act as direct mutagens in mammalian cells. In addition, siloxane-induced mutagenicity may be enhanced by the depletion of intracellular GSH caused by the interaction of lipophilic siloxanes with cell membranes.
Carcinogenesis 1998 Feb
PMID:Tetravinyl-tetramethylcyclo-tetrasiloxane (tetravinyl D4) is a mutagen in Rat2lambda lacI fibroblasts. 1042 24


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