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

To test whether vinyl chloride-induced mutagenesis might involve ambiguous base pairing of 1,N6-etheno-adenine (epsilon A) during DNA synthesis, we examined the base pairing potential of epsilon dATP during DNA synthesis catalyzed by Escherichia coli DNA polymerase I (Klenow fragment). An electrophoretic assay of chain elongation was used to assess the degree to which epsilon dATP could substitute for each of the normal dNTPs during elongation of a primer annealed to a bacteriophage template. Despite the fact that the etheno bridge completely blocks normal Watson-Crick pairing of epsilon A with T, we observed that epsilon dATP could substitute for dATP during primer elongation (although inefficiently). In addition, detectable substitution of epsilon dATP for dGTP and dCTP occurred, indicating that epsilon A exhibits ambiguous base pairing properties. The relative ease of epsilon dAMP incorporation (opposite template T, C and G) appeared to vary considerably at different positions along the template. The major form of epsilon A incorporation (replacement of A) was confirmed by measurements of epsilon dATP----epsilon dAMP turnover (a commonly used method for detecting misincorporation), and also by the demonstration that epsilon A was present in enzymatic hydrolysates prepared from DNA that was synthesized with epsilon dATP replacing dATP. A model for ambiguous base pairing of epsilon dATP is proposed, in which incorporation occurs via the protonated, syn form of epsilon dATP.
Carcinogenesis 1986 Sep
PMID:Utilization of 1,N6-etheno-2'-deoxyadenosine 5'-triphosphate during DNA synthesis on natural templates, catalyzed by DNA polymerase I of Escherichia coli. 352 67

Published results and work from this laboratory permit the characterization of the possible promutagenic lesions induced by chloroethylene oxide (CEO) and chloroacetaldehyde (CAA), both known as bifunctional alkylating metabolites of vinyl chloride (VC). The mutagenic effectiveness of CEO and CAA in Escherichia coli, when compared to their nucleophilic selectivity, suggests that the critical target site in DNA bases is not an oxygen atom, and/or that the reaction mechanism of CEO and CAA is different from a simple alkylation. CEO-mutagenicity in E. coli is recA-independent, and CEO preferentially induces GC----AT transitions; accordingly, the mutagenicity of CEO in bacteria may result mainly from a miscoding guanosine or cytosine adduct. Two observations argue against the role of 1,N6-ethenoadenine (epsilon A) and 3,N4-ethenocytosine (epsilon C) in VC-induced mutagenesis/carcinogenesis: i) the lack of detection in double-stranded DNA in vivo and in vitro; ii) the inconsistency between mutational specificity of CEO and miscoding properties of epsilon A and epsilon C. The lack of miscoding properties of 7-(2-oxoethyl)guanine (oxet-G), the major in-vivo VC-DNA adduct, suggests a minor miscoding base adduct. Several lines of evidence point to N4-(2-chlorovinyl)cytosine as one possible putative promutagenic lesion produced by VC, but this compound has yet to be identified in DNA.
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PMID:Mutagenic and promutagenic properties of DNA adducts formed by vinyl chloride metabolites. 353 90

N2,3-Ethenoguanine (N2,3-epsilon G) was recently identified in the liver of vinyl chloride-exposed rats. We have now synthesized the nucleoside and the 5'-diphosphate which was copolymerized with CDP. The deoxypolynucleotide complement, synthesized by AMV reverse transcriptase contained, in addition to dG, dC and dT. The total pyrimidine content was approximately equivalent to the N2,3-epsilon G content of the template. Incorporation of dC is neither lethal nor mutagenic, while dT incorporation represents a mutagenic event, occurring with approximately 20% frequency. N2,3-epsilon G X dT base pairs can have two hydrogen bonds with minimal helical distortion, as is also the case for N2,3-epsilon G X C base pairs. N2,3-epsilon G is the only derivative formed in vivo by the human carcinogen, vinyl chloride, that can be shown to have a high probability of causing transitions which could initiate malignant transformation.
Carcinogenesis 1987 May
PMID:The vinyl chloride-derived nucleoside, N2,3-ethenoguanosine, is a highly efficient mutagen in transcription. 358 34

Injection of a single dose of[ethyl-1,2(-3)H]or[ethyl-1(-14C]- ethyl carbamate into 12-day old male[C57BL/6 x C3H/He]F1 mice or of[ethyl-1,2(-3H]ethyl carbamate into adult male A/Jax mice resulted in the formation of labeled 1,N6-ethenoadenosine and 3,N4-ethenocytidine adducts in the hepatic RNA. These adducts were characterized by comigration on h.p.l.c. of 3H or 14C in enzymatic hydrolysates of the RNA with synthetic standards. Both the ethenoadenosine and ethenocytidine were further characterized by their conversion to acetylated products that comigrated with acetylated synthetic standards. The ethenoadenosine was also converted by anhydrous trifluoroacetic acid to a product that comigrated with synthetic 1,N6-ethenoadenine. The levels of adducts in the hepatic RNA 12 h after a single injection of 0.5-0.6 mg of ethyl carbamate/g body weight were 6-10 and 2-3 pmol/mg RNA of ethenoadenosine and ethenocytidine, respectively. No labeled ethenoadenosine or ethenocytidine could be detected in the hepatic RNA of mice given[1-14C]ethanol, an enzymatic hydrolysis product of ethyl carbamate. These data indicate that ethyl carbamate may be metabolically activated by dehydrogenation to vinyl carbamate and subsequent epoxidation of the latter compound as previously proposed. Vinyl carbamate epoxide may form etheno derivatives in a manner analogous to that demonstrated for chloroethylene oxide, an electrophilic metabolite of vinyl chloride. Vinyl carbamate has been shown to have the same spectrum of tumor induction as ethyl carbamate but to be much more active than the latter carcinogen.
Carcinogenesis 1982
PMID:Labeled 1,N6-ethenoadenosine and 3,N4-ethenocytidine in hepatic RNA of mice given[ethyl-1,2(-3)H or ethyl-1(-14)C]ethyl carbamate (urethan). 617 29

The roles of chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) in carcinogenicity of vinyl chloride (VC) have been studied by comparing biological effects of VC exposure with those of 2,2'-dichlorodiethylether (bis(chloroethyl)ether, BCEE) as a metabolic precursor of CAA. Biological end-points investigated were covalent protein binding, nucleic acid (RNA and DNA) alkylation and the potency of the two chemicals to induce preneoplastic ATPase-deficient foci in rat liver. After exposure of rats to [1-14C]BCEE, BCEE derived radioactivity was bound to liver proteins. Analysis of hydrolysates of liver RNA and DNA gave no indication for the formation of either 7-N-(2-oxoethyl)guanine, 1,N6-ethenoadenine or 3,N4-ethenocytosine residues within the nucleic acids. After application of VC, BCEE or chloroethanol [CE), also a precursor of CAA) to young rats, only animals exposed to VC developed preneoplastic hepatocellular ATPase-deficient foci. From these investigations it is concluded, that CEO (which is not formed during metabolism of BCEE and CE), not CAA, is the ultimate carcinogenic principle in VC carcinogenicity.
Carcinogenesis 1983 Nov
PMID:Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2'-dichlorodiethylether. 619 38

In an attempt to dissociate the chemotherapeutic from the carcinogenic properties of the antischistosomal and antitrypanosomal nitrovinylfuran trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]1,2,4-oxadiazole [(SQ18506) CAS: 28754-68-9; (E)-5-amino-3-(2-(5-nitro-2-furyl)vinyl)-1,2,4-oxadiazole], potential inhibitors of carcinogenesis were administered to female outbred CD-1 mice before and during exposure to SQ18506. The compounds tested were ascorbic acid, etretinate, butylated hydroxyanisole (BHA), cysteamine hydrochloride, cysteine hydrochloride, dimercaprol, disulfiram, 1,4-dithiothreitol, reduced glutathione, and spermidine phosphate. The primary types of tumors observed were squamous cell carcinomas of the stomach and thymic and nonthymic lymphomas. BHA reduced the incidence of malignant tumors to control levels, whereas cysteine hydrochloride, spermidine phosphate, and disulfiram reduced the incidence of chemically induced tumors by 42, 34, and 32%, respectively. Although cysteamine hydrochloride and disulfiram had no or only a modest effect on the overall incidence of tumors, the data suggested possible tissue-specific anticarcinogenic properties for these agents. Of the 8 antioxidants tested, only 1 had marked anticarcinogenic properties against SQ18506. These data indicate that antioxidant properties alone cannot account for the anticarcinogenic activity of the compounds tested. Coadministration of the anticarcinogen BHA with SQ18506 also blocked the chemotherapeutic effects of this agent on female CD-1 mice infected with Schistosoma mansoni.
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PMID:Effects of multiple putative anticarcinogens on the carcinogenicity of trans-5-amino-3-[2-(5-nitro-2-furyl)vinyl]-1,2,4-oxadiazole. 620 94

Although both the epidemiologic and experimental studies have led to the identification of chemical carcinogens, the limitations in epidemiologic approaches and the need for primary prevention of cancer require a greater reliance on experimental studies. Long-term carcinogenicity studies in experimental animals have been instrumental in identifying chemicals with carcinogenic activity, and, in some cases, the experimental evidence has preceded the epidemiologic evidence (for 4-aminobiphenyl, aflatoxin B1, diethylstilbestrol, melphalan, mustard gas, and vinyl chloride). A better understanding of the multistage process of carcinogenesis and the findings from various short-term tests available more recently may provide a more solid basis for extrapolating experimental findings to man.
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PMID:Identification of chemicals carcinogenic to man. 653 57

187 workers exposed to vinyl chloride (VC) were examined. The control group consisted of workers of the same plant but not exposed to vinyl chloride. In all workers biochemical liver function tests were performed. The results showed no damaging influence of VC on the liver cells membrane. A slight increase of the aminotransferases (ALAT, AspAT) activity was noticed only in alcohol drinking persons. The most important changes of the glutamyltranspeptidase activity were found. Increased activity of this enzyme was noticed in 84 persons. The results suggest the induction of the glutamyltranspeptidase (GGTP) activity by VC after exclusion of the effects of other agents like cholestase, barbiturates, ethyl alcohol, as well as the effects of carcinogenesis.
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PMID:[Evaluation of the liver function in workers of the vinyl resin plant]. 664 35

The experimental carcinogenesis results in six compounds related to vinyl chloride are reported. Vinylidene chloride, given by inhalation, was carcinogenic in male CD-1 mice, male CD rats, Sprague-Dawley rats and male Swiss mice. Trichloroethylene, given by gavage and inhalation, was carcinogenic in the B6C3F1 mice. When given by gavage, perchloroethylene was carcinogenic in the B6C3F1 mice, and dichloroethane was carcinogenic in Osborne-Mendel rats and B6C3F1 mice. Dibromoethane, given by gavage and inhalation, was carcinogenic in B6C3F1 mice, F344 rats and Osborne-Mendel rats. Finally, epichlorohydrin was carcinogenic in male Sprague-Dawley rats and B6C3F1 mice.
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PMID:Review of experimental carcinogenesis by compounds related to vinyl chloride. 680 Jul 81

The inhibitory effect of fumaric acid (FA) on carcinogenesis by potassium 1-methyl-7-[2-(5-nitro-2-furyl)vinyl]-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate (trans, NFN) was examined histologically with male ICR/JCL mice. NFN was fed to mice at a dose level of 0.012% in the diet for 14 weeks. These mice were then divided into 2 groups. One group was given a basal diet, and the other group was given a diet containing 1% FA in the subsequent 39 weeks. In the group of 30 mice fed NFN alone, squamous cell carcinomas were found in the stomachs of 7 mice, multiple papillomas in the stomachs of 13 mice, and multiple and large papillary adenocarcinomas in the lungs of 27 animals. The administration of FA suppressed the NFN-induced stomach and lung carcinogenesis. In the group of 32 mice fed NFN and FA, no stomach tumors developed except 1 early-stage of squamous cell carcinoma. In the lungs, only a small focus of mild atypical hyperplasia and a few early-stage adenocarcinomas were noted in 7 and 11 animals, respectively.
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PMID:Inhibitory effect of fumaric acid on forestomach and lung carcinogenesis by a 5-nitrofuran naphthyridine derivative in mice. 695 8


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