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)

The generation of superoxide and hydroxyl radicals is known to be implicated in the hydroxylation of 2'-deoxyguanosine (dG) at the C-8 position and of guanine base residues in DNA. It was also shown previously that in the presence of horseradish peroxidase, hydrogen peroxide and Fe3+ - EDTA complex, diethylstilbestrol (DES) induces single strand breaks in DNA, caused by the production of superoxide anion (O2-) and hydroxyl (OH.) radicals. By means of high-pressure liquid chromatography and electrochemical detection a strong indication is adduced that dG is oxidized to 8-hydroxy-2'-deoxyguanosine during peroxidative in vitro metabolism of DES, which might be at the basis of DES induced cell transformation.
Carcinogenesis 1989 Feb
PMID:Peroxidative in vitro metabolism of diethylstilbestrol induces formation of 8-hydroxy-2'-deoxyguanosine. 291 92

Oxidants, such as those generated by metabolically activated phagocytes in inflammation, have been implicated in the metabolic activation of carcinogens, and in this study we demonstrate that the interaction of (+/-)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene (BP 7,8-dihydrodiol) with phorbol ester-stimulated polymorphonuclear leukocytes (PMNs) results in the generation of both a chemiluminescent intermediate and one that covalently binds to DNA. Cu(II)(3,5-diisopropylsalicylic acid)2 (CuDIPS), a biomimetic superoxide dismutase, and azide, a myeloperoxidase inhibitor, inhibited both of these reactions, indicating a dependency on oxygen-derived oxidants in these hydrocarbon-activation processes. Concordant with the formation of a carcinogen-DNA adduct, the admixture of BP 7,8-dihydrodiol and phorbol ester-stimulated PMNs elicited mutagenesis in Salmonella typhimurium strain TA100. 7,8-Dihydro-BP and BP cis-7,8-dihydrodiol were also mutagenic, whereas derivatives lacking a double bond at the 9,10 position were not. These results demonstrate that oxidants generated by metabolically stimulated PMNs can activate penultimate polycyclic aromatic hydrocarbons to a genotoxic metabolite and further defines a role for inflammation in carcinogenesis.
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PMID:Oxidant-dependent metabolic activation of polycyclic aromatic hydrocarbons by phorbol ester-stimulated human polymorphonuclear leukocytes: possible link between inflammation and cancer. 299 10

Diethylstilbestrol (DES) and four derivatives, viz. tetrafluoro-DES, 3'-hydroxy-DES, Z,Z-dienestrol and hexestrol, were examined for their abilities to form superoxide radicals and to induce DNA strand breaks in the presence of horseradish peroxidase/hydrogen peroxide metabolism in a cell-free system. Furthermore, the induction of strand breaks by these compounds was tested in Syrian hamster embryo (SHE) cells in vitro. Formation of superoxide radicals could be demonstrated by reduction of nitro blue tetrazolium for DES but not for its derivatives. With isolated superhelical DNA, induction of strand breaks in the presence of Fe3+ was observed for DES, tetrafluoro-DES and 3'-hydroxy-DES, while hexestrol and Z,Z-dienestrol were ineffective. In SHE cells, alkaline elution technique showed that DNA strand breaks were induced by DES and all derivatives tested, although only at cytotoxic concentrations. It is concluded that DES, under conditions of peroxidative metabolism, can give rise to superoxide generation and DNA strand breaks, and that these events may play a role in the process of DES-induced cell transformation.
Carcinogenesis 1986 Aug
PMID:Possible role of oxygen radicals in cell transformation by diethylstilbestrol and related compounds. 301 47

Subclinical flat cervical warts are commonly recognized by means of colposcopy. These warty lesions frequently contain cellular atypia of a varying degree showing all the features of cervical intraepithelial neoplasia (CIN) together with the features of wart virus infection e.g. koilocytosis. Human papillomavirus (HPV) antigens and DNA have been found in these lesions which can be called atypical condylomas. The presence of such markers in lesions regarded as having neoplastic potential implicates HPV in cervical carcinogenesis. We investigated a group of Chinese women in Singapore to see whether this hitherto unstudied group showed HPV markers, in particular, HPV antigens by means of the peroxidase-antiperoxidase (PAP) staining technique. We found that histological warty change and HPV antigens were commoner in early compared with advanced CIN. These results, which are similar to previous studies, suggest that the aetiology of cervical carcinoma is probably no different in Singapore than in the West. They also suggest that HPV infection of the cervix is endemic in non-Western countries as well as in the West and may play a role in cervical carcinogenesis in diverse racial groups.
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PMID:Atypical condylomas of the cervix uteri in Singapore women: a histopathological and immunohistochemical study. 302 Nov 7

Expression of the ras oncogene product p21 (ras p21) in benign and malignant human colonic tissues was studied using the monoclonal antibody RAP-5 and the avidin-biotin-peroxidase technique. Histologically normal colonic mucosa and hyperplastic mucosa adjacent to carcinomas (transitional mucosa) were found, in most cases, to be negative for reactivity with the antibody or showed weak staining of a few epithelial cells. Similar findings were observed in hyperplastic and juvenile polyps. Of the 145 adenomas studied, 47 (32.4%) showed detectable levels of ras p21 expression. RAP-5 immunohistochemical staining was significantly associated with the degree of epithelial dysplasia (P less than 0.01) and the size of adenoma (P less than 0.05), but not with the histological type. Fifty-four of 70 primary adenocarcinomas (77.1%) were reactive with RAP-5 and usually demonstrated a higher percentage of stained cells and more intense cytoplasmic staining than that observed in adenomas. Although metastases often displayed a similar or even higher levels of ras p21 expression compared with the primary carcinomas, in 10 cases one or more metastatic lesions showed lower levels of ras p21. These results suggest that enhanced ras p21 expression may, at times, occur in the early stages of human colon carcinogenesis but are probably not associated with metastatic tumour progression.
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PMID:ras p21 oncoprotein expression in human colonic neoplasia--an immunohistochemical study with monoclonal antibody RAP-5. 304 43

The ways in which dietary polyunsaturated fats and antioxidants affect the balance between activation and detoxification of environmental precarcinogens is discussed, with particular reference to the polycyclic aromatic hydrocarbon benzo(a)pyrene. The structure and composition of membranes and their susceptibility to peroxidation is dependent on the polyunsaturated fatty acid (PUFA) content of the cell and its antioxidant status, both of which are determined to a large degree by dietary intake of these compounds. An increase in the PUFA content of membranes stimulates the oxidation of precarcinogens to reactive intermediates by affecting the configuration and induction of membrane-bound enzymes (e.g., the mixed-function oxidase system and epoxide hydratase); providing increased availability of substrates (hydroperoxides) for peroxidases that cooxidise carcinogens (e.g., prostaglandin synthetase and P-450 peroxidase); and increasing the likelihood of direct activation reactions between peroxyl radicals and precarcinogens. Antioxidants, on the other hand, protect against lipid peroxidation, scavenge oxygen-derived free radicals and reactive carcinogenic species. In addition some synthetic antioxidants exert specific effects on enzymes, which results in increased detoxification and reduced rates of activation. The balance between dietary polyunsaturated fats, antioxidants and the initiation of carcinogenesis is discussed in relation to animal models of chemical carcinogenesis and the epidemiology of human cancer.
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PMID:A role for dietary lipids and antioxidants in the activation of carcinogens. 307 48

Metabolism of benzidine was assessed with rabbit renal inner medullary slices. 3-(Glutathion-S-yl)-benzidine was identified as a product of metabolism. This thioether conjugate was shown to be identical to synthetic conjugate by chromatographically assisted hydrodynamic voltammetric and enzymatic techniques. A good correlation between PGE2 synthesis and conjugate formation was observed with a variety of incubation conditions including tissue weight, arachidonic acid concentration and incubation time. With 0-0.01 mM idomethacin, an inhibitor of the fatty acid cyclo-oxygenase component of prostaglandin H synthase (PHS), a linear relationship between conjugate formation and prostaglandin E2 synthesis was observed. In contrast, the peroxidase cosubstrates propylthiouracil, phenidone, ascorbate and methimazole inhibited arachidonic acid stimulation of conjugate formation but not prostaglandin E2 synthesis. These cosubstrates may be functioning as competitive inhibitors of benzidine co-oxidation. The results are consistent with peroxidatic metabolism of benzidine in intact tissue by a PHS-mediated process. 3-(Glutathion-S-yl)-benzidine may be a useful marker for studying peroxidatic metabolism in intact tissue and in investigating selective inhibition of this process.
Carcinogenesis 1986 Jan
PMID:Peroxidatic metabolism of benzidine by intact tissue: a prostaglandin H synthase-mediated process. 308 Feb 49

Structural analogs of diethylstilbestrol (DES) with at least one phenolic hydroxyl group are metabolized by prostaglandin H synthase (PHS) from ram seminal vesicle microsomes (RSVM) in vitro in the presence of arachidonic acid (20:4). U.v. spectroscopy revealed the formation of p-quinoid intermediates in incubations of DES, tetrafluoro-DES and dimethylstilbestrol, and tautomerization of the quinones to the respective dien-compounds which were characterized by h.p.l.c. and GC/MS. Indomethacin inhibits the formation of these metabolites which are identical to the major metabolites formed in incubations with horseradish peroxidase/hydrogen peroxide. Covalent binding to protein was observed in incubations of PHS co-substrates. Notably, formation of reactive intermediates which bind to protein is not limited to DES-analogs which form quinone intermediates: radiolabeled hexestrol and E,E-dienestrol yield protein-bound radioactive products upon incubation with RSVM and 20:4, probably via one electron-oxidation to a phenoxy radical. PHS-catalyzed metabolism of structural analogs of DES is accompanied by a concentration-dependent increase in cyclo-oxygenase activity. The measurement of the 20:4-dependent oxygen uptake rates in vitro can serve as a convenient assay for estrogenic compounds which undergo co-oxidation. At high concentrations, however, DES structural analogs can inhibit rather than stimulate PHS. The PHS-catalyzed formation of reactive intermediates from DES structural analogs and their effect on PHS may be of importance for their biological activity in estrogen target tissues with low mono-oxygenase activity.
Carcinogenesis 1986 Jan
PMID:Co-oxidation of diethylstilbestrol and structural analogs by prostaglandin synthase. 308 Feb 50

Formic acid 2-[4-(5-nitro-2-furyl)-2-thiazolyl]-hydrazide (FNT) is a renal carcinogen in the rat. The peroxidative activity of prostaglandin H synthase oxidizes FNT into a reactive intermediate which forms 5-(S)-substituted thioether conjugates with glutathione and N-acetylcysteine. These conjugates are also formed during horseradish peroxidase oxidation of FNT. The conjugate was identified by the combined results of comparative u.v./vis. spectrophotometry, chromatographically-assisted hydrodynamic voltammetry and proton n.m.r. spectroscopy. The relative rate of PHS metabolism of FNT was similar to that observed with benzidine and 5-fold faster than ANFT, its 5-nitrofuro-2-aminothiazole analogue. These results indicate that the pathogenic effects of FNT may be caused by its peroxidative activation and that cellular thiols may attenuate the toxic effects of FNT by conjugate formation.
Carcinogenesis 1986 Sep
PMID:Metabolism of the renal carcinogen FNT by peroxidases. 309 Dec 81

Several structurally different tumor promoters altered to various degrees both glutathione (GSH) peroxidase (EC 1.11.1.9) and ornithine decarboxylase (ODC, L-ornithine carboxy-lyase, EC 4.1.1.17) activities in mouse epidermis in vivo. At 5 h after their application to the skin, the complete tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the stage 2 promoter mezerein were the most potent in inhibiting GSH peroxidase activity and inducing ODC activity. In comparison, the effects of anthralin, phorbol-12,13-didecanoate, benzoyl peroxide, H2O2, and phorbol-12,13-dibenzoate were much smaller, whereas the nontumor promoter phorbol, the hyperplastic agent ethyl phenylpropiolate, and the stage 1 promoter 4-O-methyl TPA did not alter GSH peroxidase and ODC activities. Various treatments including i.p. injections of 40 micrograms of Na2SeO3 and 100 mumol of GSH and/or topical applications of 40 mumol of D-alpha-tocopherol (vitamin E) 20 or 15 min, respectively, before tumor promoter treatment inhibited in an additive manner the effects of either TPA or mezerein on both GSH peroxidase activity and ODC induction. Moreover, these Na2SeO3, GSH, and/or vitamin E treatments inhibited in the same additive manner the tumor-promoting activity of TPA in the initiation-promotion protocol. However, when tested in the 2-stage promotion protocol with 4 doses of TPA followed by twice weekly applications of mezerein, Na2SeO3 plus vitamin E and GSH plus vitamin E treatments inhibited remarkably the tumor-promoting activity of mezerein but were ineffective in the first stage of promotion. The sequence and magnitude for the effects of 7,12-dimethylbenz[alpha]anthracene (DMBA) on GSH peroxidase and ODC activities were very different from those of the tumor promoters. In contrast with their antitumor-promoting activity, the treatments with Na2SeO3 plus vitamin E and GSH plus vitamin E failed to inhibit the carcinogenicity of a single large dose of DMBA and even enhanced the induction of skin tumors by repeated applications of subcarcinogenic doses of DMBA. These results suggest that the promoting component of DMBA carcinogenesis may be different from that of TPA. Moreover, the anticarcinogenicity of Na2SeO3, GSH, and vitamin E may be linked to their ability to facilitate or enhance the activity of the natural GSH-dependent antioxidant protective system of the epidermal cells during the later stages of skin tumor promotion.
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PMID:Effects of combined treatments with selenium, glutathione, and vitamin E on glutathione peroxidase activity, ornithine decarboxylase induction, and complete and multistage carcinogenesis in mouse skin. 309 11


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