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)

Organic isothiocyanates block the production of tumors induced in rodents by diverse carcinogens (polycyclic aromatic hydrocarbons, azo dyes, ethionine, N-2-fluorenylacetamide, and nitrosamines). Protection is afforded by alpha-naphthyl-, beta-naphthyl-, phenyl-, benzyl-, phenethyl-, and other arylalkyl isothiocyanates against tumor development in liver, lung, mammary gland, forestomach, and esophagus. Many isothiocyanates and their glucosinolate precursors (beta-thioglucoside, N-hydroxysulfate) occur naturally and sometimes abundantly in plants consumed by humans, e.g., cruciferous vegetables. Nevertheless, the possible contributions of isothiocyanates and glucosinolates to the well recognized protective effects against cancer of high consumptions of vegetables are unclear. The anticarcinogenic effects of isothiocyanates appear to be mediated by tandem and cooperating mechanisms: (a) suppression of carcinogen activation by cytochromes P-450, probably by a combination of down-regulation of enzyme levels and direct inhibition of their catalytic activities, which thereby lower the levels of ultimate carcinogens formed; and (b) induction of Phase 2 enzymes such as glutathione transferases and NAD(P)H: quinone reductase, which detoxify any residual electrophilic metabolites generated by Phase 1 enzymes and thereby destroy their ability to damage DNA. Since isothiocyanates block carcinogenesis by dual mechanisms and are already present in substantial quantities in human diets, these agents are ideal candidates for the development of effective chemoprotection of humans against cancer.
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PMID:Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. 813 23

Poly(ADP-ribose) polymerase, which catalyzes the formation of poly(ADP-ribose) polymers, is an enzyme involved in cell proliferation, differentiation and transformation as well as in recovery from DNA damage. Poly(ADP-ribose) polymers are rapidly synthesized from the ADP-ribose moieties from intracellular NAD+, which, as a consequence, is depleted. It has been shown that DNA strand breaks are required for enzyme activation and it is suggested that one of the functions of poly(ADP-ribosylation) is to improve accessibility of damaged sites to other DNA repair enzymes. The aim of this study was to investigate whether poly(ADP-ribosylation) is involved in repair of (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene [(+/-)-anti-BPDE]-induced DNA damage in human lymphocytes in vitro. Results show that (+/-)-anti-BPDE is capable of inducing poly(ADP-ribosylation), NAD+ depletion and inhibition of proliferation in phytohemagglutinin-stimulated human peripheral blood lymphocytes. Also, repair of (+/-)-anti-BPDE induced DNA damage was confirmed by both unscheduled DNA synthesis and (+/-)-anti-BPDE-deoxyguanosine adduct removal. Based on these findings, it is concluded that poly(ADP-ribosylation) is involved in (+/-)-anti-BPDE-induced DNA repair in these cells. In addition, these results confirm the possible relation between poly(ADP-ribosylation), NAD+ depletion and inhibition of proliferation, after induction of DNA damage.
Carcinogenesis 1994 Apr
PMID:Increased poly(ADP-ribose) polymerase activity during repair of (+/-)-anti-benzo[a]pyrene diolepoxide-induced DNA damage in human peripheral blood lymphocytes in vitro. 814 90

Recently, oxidation products of linoleic acid such as 13-hydroxyoctadecadienoic acid (HODE) have been implicated in the regulation of cellular physiology including the proliferative response to growth factor treatment. In addition, an NAD(+)-dependent 13-HODE dehydrogenase was recently described. To evaluate the contribution of this enzyme to cellular processes we have examined the behavior of the enzyme under different conditions. In the present report, changes in the activity of 13-hydroxyoctadecadienoic acid dehydrogenase during in vitro differentiation of two different cell lines were examined. The cell line HT-29 undergoes induced differentiation via manipulation of the medium while the Caco-2 line undergoes spontaneous differentiation upon attainment of confluence. In both cell lines, longer culture times were accompanied by increases in 13-HODE dehydrogenase activity. The increase in enzyme activity continued even after cell proliferation had ceased. Cellular differentiation was verified by the observation of increases in sucrase and alkaline phosphatase activities. In addition, the activity of 13-HODE dehydrogenase was measured in growing, early confluent and late confluent cultures of undifferentiating Swiss mouse 3T3 fibroblasts. In the fibroblast line, no significant changes in 13-HODE dehydrogenase activity were observed during the course of the experiment. The specific activity of 13-HODE dehydrogenase was also significantly different between the three cell lines, consistent with the extent of differentiation. Highest levels of activity were found in Caco-2 cells (200-400 pmol/min/mg) and barely detectable levels in the fibroblasts (0.6-2 pmol/min/mg). The correlation between 13-HODE dehydrogenase and cell differentiation suggests the enzyme may have a role to play in the partitioning of cells between proliferation and differentiation pathways.
Carcinogenesis 1993 Nov
PMID:Increases in 13-hydroxyoctadecadienoic acid dehydrogenase activity during differentiation of cultured cells. 824 49

Poly(ADP-ribose) (polymer) is enzymatically synthesized on nuclear proteins in response to DNA strand breaks. NAD+ is the substrate for this reaction, which is catalyzed by poly(ADP-ribose)polymerase. This post-translational modification occurs in response to DNA strand breaks and is thought to play an important role in DNA repair. Polymer synthesis resulting from DNA damage has been described in cultured cells, but measurement is more difficult in animal tissues. In this study, modifications were made to an earlier method to measure carcinogen-induced increases in polymer levels in vivo. RNase I was added to the enzyme mixture used to digest polymer to ribosyladenosine (RAdo). This prevented the inhibition of snake venom phosphodiesterase by RNA. The HPLC analysis was improved, allowing elimination of the second boronate affinity chromatography step traditionally used to purify epsilon RAdo. Using this technique, we have studied the effect of i.p. diethylnitrosamine (DEN) injection on hepatic NAD+ and poly(ADP-ribose) levels in Fischer-344 rats. Hepatic polymer levels rose 8-fold from 26 to 218 pmol/g liver wet weight, 10 h following 200 mg DEN/kg body weight (n = 4-5). Liver NAD+ decreased concurrently, to 61% of basal levels at 16 h post-treatment (n = 4-5). Erythrocyte NAD+ concentrations remained unchanged, despite carcinogen administration. The DEN-induced effects on tissue polymer and NAD+ levels were dose dependent from 0 to 200 mg DEN/kg body weight (n = 4).
Carcinogenesis 1993 Dec
PMID:Diethylnitrosamine administration in vivo increases hepatic poly(ADP-ribose) levels in rats: results of a modified technique for poly(ADP-ribose) measurement. 826 20

We have studied the effect of the chemotherapeutic drug VP-16 (etoposide) on the metabolism of HeLa cells by analysing different cellular parameters; in particular we have focused on changes in cellular morphology that are considered as markers of apoptosis. By immunofluorescence experiments we have shown that VP-16 causes the complete disruption of nucleoli and induces chromatin margination and fragmentation. Agarose gel electrophoresis of DNA from cells treated with 10-100 microM VP-16 showed the appearance of a characteristic ladder due to the internucleosomal DNA cleavage. The effect of etoposide on DNA integrity was not prevented by preincubation of cells with the protein synthesis inhibitor cycloheximide. These results provide experimental evidence indicating that the typical features of apoptosis are visible in HeLa cells exposed to VP-16. In this experimental system we have investigated whether the ADP-ribosylation process could be regulated by the presence of DNA fragments. By means of the activity gel technique, which allows the direct evaluation of automodified poly(ADP-ribose)polymerase, we have observed that in extracts from cells where etoposide-induced DNA fragmentation occurred, the autoribosylated form of the enzyme is greatly increased. Ribosylated poly(ADP-ribose)polymerase has been isolated by affinity chromatography on boronate column from cells permeabilized and labelled with [32P]NAD. Drug exposure caused a strong augmentation of modified enzyme. These observations suggest that activation of ADP-ribosylation process occurs in cells that show the typical features of apoptosis.
Carcinogenesis 1993 Dec
PMID:The effect of the chemotherapeutic drug VP-16 on poly(ADP-ribosylation) in apoptotic HeLa cells. 826 27

4-Methyl-5-pyrazinyl-3H-1,2-dithiole-3-thione (oltipraz) and several other dithiolethiones protect against the acute toxicities of many xenobiotics and are effective inhibitors of experimental carcinogenesis. These protective effects are mediated, in part, through elevation of glutathione S-transferase, NAD(P)H: quinone reductase and UDP-glucuronosyltransferase activities in the liver and other target tissues. The induction of these phase 2 enzymes by oltiprax results from enhanced transcription. In the present study, the molecular mechanisms of these inductions were analyzed utilizing a construct containing a 41 bp enhancer element derived from the 5'-upstream region of the mouse liver glutathione S-transferase Ya subunit gene ligated to the 5' end of the isolated promoter region of this gene, and inserted into a plasmid containing a human growth hormone reporter gene. When this construct was transfected into murine Hepa 1c1c7 hepatoma cells, the concentrations of 25 dithiolethiones and related analogs required to double growth hormone production were determined and spanned a range nearly three orders of magnitude. Concentrations of dithiolethiones required to double the specific activity of NAD(P)H: quinone reductase were also determined in Hepa 1c1c7 cells. There was a positive correlation (r = 0.78) between the potencies of the 21 active compounds as inducers of both NAD(P)H: quinone reductase activity and growth hormone production. Moreover, no dithiolethiones were inactive in only one system. It is probable, therefore, that the induction of NAD(P)H: quinone reductase and other phase 2 enzymes by oltipraz and other dithiolethiones is mediated entirely through the 41 bp enhancer element.
Carcinogenesis 1994 Feb
PMID:Regulation of phase 2 enzyme induction by oltipraz and other dithiolethiones. 831 5

The exposure of rats to the carcinogen 2-acetylaminofluorene (2-AAF) results in the accumulation of DNA-damaging adducts. The inability of cells to repair such damage adequately is a putative causal event in chemical carcinogenesis. It has been shown that one cellular response to DNA damage that leads to DNA repair is poly(ADP-ribosyl)ation of nuclear proteins. To examine the possible existence of an altered poly(ADP-ribosyl)ation response to 2-AAF-mediated damage of rat liver DNA, tissue ADP-ribose polymer levels were determined during various stages of 2-AAF-mediated carcinogenesis. 2-AAF was administered to rats in a discontinuous feeding regimen comprised of five consecutive cycles, each cycle consisting of 3 weeks on 2-AAF diet followed by 1 week of recovery on a control diet without 2-AAF. During cycle one of 2-AAF administration, rat liver ADP-ribose polymer levels increased 3-fold over that found in livers of rats fed only the control diet. In contrast, when rats were administered the non-genotoxic liver mitogen 4-AAF for one cycle, no significant elevation occurred in ADP-ribose polymer levels. Elevated ADP-ribose polymer production was also observed during cycles two and three of 2-AAF administration. However, during cycles four and five of 2-AAF administration, a period when rats administered 2-AAF acquire a high risk for hepatocarcinogenesis, an altered pattern of ADP-ribose polymer production occurred in rat livers. ADP-ribose polymer levels in these rat livers remained low, similar to levels found in control rat livers, despite the administration of 2-AAF. When the livers from rats fed either one or five cycles of 2-AAF were analyzed for possible decreases in the levels of tissue NAD+, the substrate for poly(ADP-ribose) polymerase, no changes in relative abundance were found. In addition, analysis of poly(ADP-ribose) polymerase activity showed no decrease at five cycles of 2-AAF administration. These results indicated that at late stages of 2-AAF-induced hepatocarcinogenesis, 2-AAF does not induce an expected increase in ADP-ribose polymer levels, and suggested that significant changes in DNA repair may occur at a time just preceding an increased risk for developing liver cancer.
Carcinogenesis 1993 Jul
PMID:Changes in levels of ADP-ribose polymers in rat liver during 2-acetylaminofluorene-induced hepatocarcinogenesis. 833 Mar 62

It has been reported that several naturally occurring and related synthetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine were determined in male F344 rats and found to be 250, 250, 1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing N-acetylcysteine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase activities in colonic mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diallyl disulfide, compared to those fed the control diet. N-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diallyl disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase in the liver and colon.
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PMID:Chemoprevention of colon carcinogenesis by organosulfur compounds. 833 52

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], a substituted 1,2-dithiole-3-thione, protects against the acute and chronic toxicities of many xenobiotics and prevents chemically induced carcinogenicity in several target organs of rodents. The effects of dietary oltipraz, fed during the initiation and postinitiation stages, on azoxymethane-induced colon carcinogenesis and on the levels of several detoxifying enzymes, namely, glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities, were studied in male F344 rats. At 5 weeks of age, groups of animals were fed the control diet (modified AIN-76A diet) or a diet containing 200 ppm (40% maximum tolerated dose) of oltipraz. At 7 weeks of age, all animals except those in the vehicle (normal saline solution)-treated groups were given two weekly s.c. injections of azoxymethane at a dose of 15 mg/kg body weight. Three days after the second injection of azoxymethane, the groups of animals fed the oltipraz diet were transferred to the control diet (termed the initiation period) and the groups of animals receiving the control diet were transferred to the oltipraz diet (termed the postinitiation period). All groups were continued on this regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Intestinal tumors were evaluated histopathologically using routine procedures. Liver, colonic mucosa, and tumors were analyzed for glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities. The results indicate that oltipraz administered during the initiation stage significantly inhibited the incidence and multiplicity of invasive adenocarcinomas of the colon (P < 0.001), as well as the multiplicity of invasive and noninvasive adenocarcinomas (P < 0.01). Feeding of oltipraz during the postinitiation phase completely suppressed the formation of invasive adenocarcinomas (P < 0.0001) and significantly inhibited the formation of noninvasive and total adenocarcinomas, as well as the multiplicity (tumors/tumor-bearing animal, P < 0.001). Furthermore, oltipraz significantly suppressed the tumor volume when administered during the initiation phase (> 80%) or the postinitiation (> 93%) phase. Animals fed the oltipraz diet during the postinitiation stage showed increased levels of glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities (2-6-fold). Although the precise mechanism by which oltipraz inhibits colon tumor initiation and/or promotion remains to be elucidated, it is likely that the effect during the initiation stage may be due to an alteration of carcinogen metabolism.
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PMID:Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats. 849 12

N-Nitrosodimethylamine (NDMA), but not N-nitroso-N-methylurea (MNU) was more mutagenic in the Salmonella hisG428 strain, TA104, than in the hisG46 strain, TA100 in the presence of rat or hamster liver S-9 mix. As both NMDA and MNU can give rise to methyldiazonium ion (MDI) it appears that NDMA can be metabolized to an additional mutagen with a higher activity in TA104. The effects of UV and error-prone repair on NDMA and MNU-induced mutagenesis in TA104 were also different. alpha-Acetoxy-NDMA, which gives rise to the NDMA metabolite, alpha-hydroxy-NDMA, was more mutagenic in TA104 than TA100, under certain conditions. Several metabolites of NDMA (formaldehyde, 1,1-dimethylhydrazine and nitrite) were not significantly mutagenic at the concentrations that could have been generated from NDMA. It was previously reported that the microsomal-mediated mutagenesis induced by NDMA is greatly increased by cytosol in TA104, but not in TA100. The current study found that when cytosol was separated into a high and a low mol. wt fraction, neither greatly enhanced microsomal-mediated mutagenesis by NDMA in TA104. Addition of NAD to the high, but not the low mol. wt fraction resulted in greatly enhanced activation of NDMA to a mutagen in TA104. The enhancement by cytosol of NDMA-induced mutagenesis in hisG428 was only observed when both microsomes and cytosol were simultaneously present. These observations indicate that (i) the precursor to the ultimate mutagen is relatively short-lived; and (ii) the metabolism of alpha-hydroxy-NDMA to a secondary mutagenic metabolite, possibly N-nitroso-N-methylformamide, by alcohol dehydrogenase may be responsible for the ultimate mutagen with relatively high activity in TA104.
Carcinogenesis 1993 May
PMID:Effects of cytosol on mutagenesis induced by N-nitrosodimethylamine, N-nitrosomethylurea and alpha-acetoxy-N-nitrosodimethylamine in different strains of Salmonella: evidence for different ultimate mutagens from N-nitrosodimethylamine. 850 62


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