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

The 1,2-dithiol-3-thiones are a class of five-membered cyclic sulfur compounds which have chemotherapeutic and chemoprotective properties. The parent 1,2-dithiol-3-thione nucleus and a series of six substituted analogs all induced NAD(P)H: quinone reductase (EC 1.6.99.2) activity and elevated glutathione levels in Hepa 1c1c7 murine hepatoma cells in culture thereby enhancing detoxification potential. These analogs included monosubstituted derivatives with phenyl, p-methoxyphenyl or 2-pyrazinyl groups at C-4 or C-5, and disubstituted compounds bearing phenyl or 2-pyrazinyl moieties at C-5 and an additional methyl group at C-4. This system can be used as an in vitro model for the study of the specificity and mechanism of action of the 1,2-dithiol-3-thiones as already demonstrated for several other classes of chemoprotective agents. The 1,2-dithiol-3-thiones also elevated quinone reductase and glutathione levels in the Hepa 1c1c7 cell mutants (BPrc1 and TAOBPrc1) that are defective in aryl hydrocarbon receptor functions. We conclude that the 1,2-dithiol-3-thiones are largely concerned with the stimulation of metabolic inactivation of electrophiles.
Carcinogenesis 1986 Jun
PMID:1,2-Dithiol-3-thione analogs: effects on NAD(P)H:quinone reductase and glutathione levels in murine hepatoma cells. 370 58

The activities of aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as coenzymes were determined in normal liver, hepatocyte nodules and hepatocellular carcinomas from male Wistar rats. Hepatocyte nodules were produced by intermittent exposure of rats to 0.05% 2-acetylaminofluorene or by initiation with diethylnitrosamine followed by selection using 2 weeks of dietary exposure to 0.02% 2-acetylaminofluorene and partial hepatectomy. The activities of propionaldehyde:NAD and benzaldehyde:NADP aldehyde dehydrogenases were increased in hepatocyte nodules of all types as well as in most hepatocellular carcinomas. The most prominent elevation of enzyme activity was found in the cytosol of persistent hepatocyte nodules (35-60 times) and some hepatocellular carcinomas (92 times) using benzaldehyde and NADP. The benzaldehyde:NADP aldehyde dehydrogenase activity varied considerably between different nodules suggesting the existence of a subpopulation of hepatocyte nodules with very high enzymatic activities. The activity of propionaldehyde:NAD aldehyde dehydrogenase activity as well as of gamma-glutamyltransferase did not show substantial internodular variations. The activity of benzaldehyde:NADP aldehyde dehydrogenase in individual carcinomas investigated in these experiments varied extensively. The data did not support the idea that all hepatomas had been developed from pre-neoplastic nodules with very high activity of this enzyme.
Carcinogenesis 1985 Dec
PMID:Aldehyde dehydrogenase activities in hepatocyte nodules and hepatocellular carcinomas from Wistar rats. 406 45

The resistant hepatocyte model was used to study expression of tumor-associated aldehyde dehydrogenase (ALDH) activity during the course of rat hepatocarcinogenesis. The hepatic ALDH phenotype was determined at intervals over 280 days by histochemical analysis, total ALDH activity assays and gel electrophoresis, using propionaldehyde and NAD (P/NAD) to characterize normal liver ALDH activity or benzaldehyde and NADP (B/NADP) to determine tumor-associated ALDH activity. By total activity assays and gel electrophoresis, no significant changes in ALDH activity occurred until day 70. However, histochemical analysis clearly demonstrated changes in ALDH activity early in neoplastic development. Intense focal hepatocyte staining with P/NAD and/or B/NADP was first detectable at day 28. The number of P/NAD-positive foci increased until day 35 then declined until day 70. The number of B/NADP-positive foci also increased until day 35, but then remained relatively constant for the remainder of the experiment. GGT activity of serial sections indicated that early ALDH-positive lesions represent a small subpopulation (9%) of all GGT-positive foci. However, by day 168 a significant portion (80%) of persistent GGT-positive neoplastic nodules were also B/NADP-positive histochemically. In addition, virtually all hepatocellular carcinomas (96%) generated by this protocol possessed significantly elevated levels of tumor-associated ALDH by histochemical analysis, total ALDH activity and gel electrophoresis. These results indicate that early appearing ALDH-positive lesions may define one early subpopulation of all initiated cells that have a high probability of progressing to the ultimate neoplasm.
Carcinogenesis 1984 Dec
PMID:Expression of tumor-associated aldehyde dehydrogenase during rat hepatocarcinogenesis using the resistant hepatocyte model. 614 20

NAD(P)H:quinone reductase exhibits broad specificity in the reduction of endogenous and exogenous quinones and quinone imines, such as those derived from polycyclic aromatic carcinogens, phenolic steroids, vitamin K, and numerous therapeutic drugs. This enzyme is found in several cell compartments and is widely distributed among tissues. In contrast to several other flavoprotein dehydrogenases, quinone reductase catalyzes obligatorily two electron reductions. Extensive studies by Huggins and by others have shown that the quinone reductase in liver and some other tissues of rats is inducible by various polycyclic hydrocarbons and aromatic amines, as well as by certain azo dyes. Huggins perceived that the relative effectiveness of such compounds in inducing quinone reductase correlated with their abilities to protect against toxicity and carcinogenesis. Certain antioxidants are also known to protect against the tumorigenic and toxic effects of carcinogens. Studies on the mechanisms underlying the protective effects of BHA, BHT, ethoxyquin, and disulfiram have revealed that these compounds alter the activity profiles of several enzymes which metabolize carcinogenic and toxic compounds. We have observed that quinone reductase specific activity is increased markedly in mouse liver and several extrahepatic tissues in response to dietary BHA, ethoxyquin, and disulfiram, whereas BHT has been shown by others to enhance this enzymatic activity in rat liver. These findings confirm and extend the correlation between the ability to elevate quinone reductase activity and to confer protection against carcinogenesis and toxicity. The broad specificity of quinone reductase, its apparent inability to catalyze one electron reductions of quinones, its widespread distribution, and its inducibility by a variety of structurally dissimilar protective compounds, suggest that quinone reductase may play a significant local protective role in various regions of the cell.
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PMID:Elevation of quinone reductase activity by anticarcinogenic antioxidants. 618 Jun 7

Poly(ADP-Rib) polymerase is activated by strand breaks in DNA and appears to play an important role in DNA repair. The enzyme catalyses the poly ADP-ribosylation of histones and non-histone proteins, yet the contribution of these major alterations in chromatin composition have, as yet, not been critically evaluated with regard to DNA strand breaks. In the present study, the effects of N-methyl-N-nitrosourea (MNU) upon the poly ADP-ribosylation of nuclear protein acceptors have been identified and quantified at the oligonucleosomal level of chromatin. Treatment of HeLa cells with MNU (4.5 mM) for 1 h resulted in a reduction in the cellular NAD pool (30%), a 2-3 fold stimulation of poly ADP-ribosylation in isolated nuclei and in isolated oligonucleosomes. Of acceptors modified, the automodification of the polymerase was stimulated at least 3-fold. Analysis of the acid-soluble acceptors showed a stimulation in the modification of the core histones and a 2-fold increase in histone H1 poly ADP-ribosylation. This modification causes a novel crosslinking of the latter histone, and this has been studied as it relates to DNA strand breaks in the present work. In vivo treatment with MNU resulted in the synthesis of longer chain or more complex polymer species at the expense of the shorter chained ADP-ribose moieties.
Carcinogenesis 1982
PMID:Acceptors for the poly ADP-ribosylation modification of chromatin structure are altered by carcinogen-induced DNA damage. 629 34

Treatment of a human lymphoblastoid line ( GM606 ) with methyl methanesulfonate (MMS) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) initially stimulates and then drastically inhibits repair synthesis. This inhibition is overcome and repair appears to be stimulated by the poly(ADP-ribose) synthetase inhibitor 3-aminobenzamide (3-AmB). The repair activity of older cultures is much diminished compared to those rapidly dividing, but the 3-AmB effect is seen in both 2- and 7-day cultures. The action of 3-AmB is very rapid and its removal results in a diminution of repair synthesis within 30 min. U.v.-induced repair synthesis was not affected by 3-AmB. However, the level of u.v.-induced repair synthesis was drastically reduced by treatment of cells with MMS. This MMS inhibition of u.v.-induced repair synthesis was completely counteracted by the presence of 3-AmB. Insofar as the effective action of 3-AmB is on poly(ADP-ribose) synthesis, the data suggest that activation of poly(ADP-ribose) synthesis by alkylation of DNA reduces the NAD and therefore the ATP level in the lymphoblastoid cells used. Reduced ATP levels result in a lessened ability to carry out u.v.-induced repair synthesis.
Carcinogenesis 1984 May
PMID:The interaction of u.v.- and methyl methanesulfonate-induced DNA repair synthesis: a role for poly(ADP-ribose)? 658 19

A significant change in hepatic aldehyde dehydrogenase activity has been observed in normal Sprague-Dawley rat liver during the promotion phase of hepatocarcinogenesis induced by brief feeding of 2-acetylaminofluorene (2-AAF) followed by tumor promotion using dietary phenobarbital (PB) exposure. Animals receiving only 2-AAF or PB do not possess this new aldehyde dehydrogenase activity. The phenotype is characterized by the appearance of a new cytosolic isozyme kinetically, electrophoretically and immunochemically distinct from the normal liver aldehyde dehydrogenase isozymes and from aldehyde dehydrogenases inducible in 2-AAF-induced hepatomas. The new isozyme is NAD-dependent, disulfiram-sensitive and cross-reacts with antiserum to a normal liver aldehyde dehydrogenase inducible in several lines of rats by PB. However, the population of animals used in this study has been shown previously to be non-responsive to aldehyde dehydrogenase induction by dietary PB. Since no animals receiving only PB express this new isozyme, the carcinogen must play a significant role in its induction. Moreover, that not all animals receiving carcinogen and promoter possess the phenotype suggests this carcinogen/promoter interaction has a genetic basis.
Carcinogenesis 1982
PMID:Sequential 2-acetylaminofluorene--phenobarbital exposure induces a cytosolic aldehyde dehydrogenase during rat hepatocarcinogenesis. 709 12

Induction of cellular detoxification enzymes can increase detoxification of carcinogens and reduce carcinogen-induced mutagenesis and tumorigenesis. To determine if the dietary anticarcinogen ellagic acid induced enzymes which detoxify xenobiotics and carcinogens, we examined the effect of ellagic acid on the expression of the phase II detoxification enzyme NAD(P)H:quinone reductase (QR). QR is induced by xenobiotics and antioxidants interacting with the xenobiotic responsive and antioxidant responsive elements of the 5' regulatory region of the QR gene. Ellagic acid is structurally related to the antioxidants which induce QR and we proposed that ellagic acid would induce QR expression through activation of the antioxidant responsive element of the QR gene. Rats fed ellagic acid demonstrated a 9-fold increase in hepatic and a 2-fold increase in pulmonary QR activity, associated with an 8-fold increase in hepatic QR mRNA. To determine if this increase in QR mRNA was due to activation of the antioxidant responsive element, transient transfection studies were performed with plasmid constructs containing various portions of the 5' regulatory region of the rat QR gene. These transfection studies confirmed that ellagic acid induces transcription of the QR gene and demonstrated that this induction is mediated through the antioxidant responsive element of the QR gene.
Carcinogenesis 1994 Sep
PMID:Ellagic acid induces NAD(P)H:quinone reductase through activation of the antioxidant responsive element of the rat NAD(P)H:quinone reductase gene. 752 86

The expression of nitric oxide synthase (NOS) was studied by NAD(P)H diaphorase histochemical localization method in (i) individual cells of the normal colonic mucosa (n = 13) which served as control, (ii) colonic polyps (n = 14), (iii) colonic carcinoma (n = 20) and (iv) peritumoral mucosa (2 and 5 or 10 cm away from the tumor). Four of the tumor specimens had normal epithelium adjacent to the cancer, which thus served as an internal control. The expression of NOS activity in colon cancer was significantly reduced as compared to the control group of individuals (P < 0.004); undetectable in 25%, diminished in 45%, normal in 30%. On comparing the expression in normal mucosa and polyps there was a significant reduction of the expression in polyps (P < 0.027); undetectable in 14%, reduced in 35%, normal in 51%. When compared to the peritumoral mucosa at 2 and 10 cm the tumor showed a significant reduction in expression of NOS activity (P < 0.001 and P < 0.0001 respectively). There was no significant difference seen in the expression at 2 and 10 cm (P = 0.329). The peritumoral mucosa at a distance of 2 cm away from the tumor when compared to the control mucosa showed no significant difference (P = 1.000), although there is a tendency to a high normal expression of NOS activity in the mucosa at a distance of 2 cm. Similarly, there was no significant difference between the control mucosa and the peritumoral mucosa obtained at a distance of 10 cm (P = 0.383). The expression of NOS activity in all tissues examined was abolished by preincubation of tissue with the selective NOS inhibitor L-NMMA but not with D-NMMA. Our data showed extensive and significant reduction as identified by the NAD(P)H diaphorase method in the expression of NOS activity, thereby reflecting the activity of nitric oxide in colon cancer and colonic polyps. The generalized suppression of this activity, which precedes the onset of overt neoplasia, may be an important event in colon carcinogenesis. This aberrant expression could also be compatible with the selective advantage to either tumor promotion and metastatic progression or to tumoricidal activity.
Carcinogenesis 1994 Oct
PMID:Aberrant expression of nitric oxide synthase in human polyps, neoplastic colonic mucosa and surrounding peritumoral normal mucosa. 752 94

Reduction of Cr(VI) by NADH and NADPH has been shown to yield Cr(V) species, which have been detected by electron paramagnetic resonance (EPR) spectroscopy. The fine structure on the EPR signal of the Cr(V) species is consistent with the presence of two NAD(P)H ligands in a square-pyramidal arrangement with a single oxygen (oxo) group at the apex. Neither this species nor the initial Cr(VI) complex damage DNA components as evidenced by the lack of effect of these compounds on the optical and EPR signals of the Cr(VI) and Cr(V) species respectively. Addition of hydrogen peroxide to the Cr(V) species is shown to result in the formation of a further transient EPR signal, the parameters of which are consistent with an assignment to a Cr(V)-peroxide complex. Inclusion of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide in this system demonstrates that hydroxyl radicals are also generated, possibly via the decomposition of the peroxide complex. Inclusion of DNA components in this system together with the spin trap 2-methyl-2-nitrosopropane results in the detection of base- and sugar-derived radicals; the characteristic EPR signals of these species have allowed both the identification of these species and their mechanism of formation to be determined. The signals from the former species are consistent with radical addition to the base, whereas the sugar-derived species are believed to be formed via hydrogen atom abstraction. In each case, this behaviour is consistent with hydroxyl radicals being the damaging species in systems where Cr(V) is generated in the presence of hydrogen peroxide. These results therefore suggest that it may be the hydroxyl radical that is the ultimate carcinogenic species in cells and systems exposed to Cr(VI).
Carcinogenesis 1995 Apr
PMID:Direct evidence for hydroxyl radical-induced damage to nucleic acids by chromium(VI)-derived species: implications for chromium carcinogenesis. 753 82


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