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

Regulation of P(1)450 gene expression in mouse hepatocytes from responsive (C57BL/6) and non-responsive (DBA/2) strains in primary culture was investigated with respect to aryl hydrocarbon hydroxylase (AHH) activity and P450 transcript levels. Although significant induction of AHH activity in C57BL/6 mouse hepatocytes after exposure to benz[aanthracene (BA) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was observed 24 h after the beginning of cultivation, the response was more prominent after longer periods. AHH induction in DBA/2 mouse hepatocytes by TCDD was also evident after 24 h treatment, but that by BA was delayed, only becoming significant after 3 days. Limited treatment with cycloheximide (CHI) for the initial 8 h affected AHH activity measured after 24 h; BA-induced AHH activity was decreased if the treatment started day 1 after seeding of the cells from either strain, whereas if started at day 3 the enzyme activities in hepatocytes from C57BL/6 strain were approximately doubled and those from DBA/2 increased to 130%. Treatment with dibutyryl cAMP or forskolin, a specific activator for adenyl cyclase, increased BA-induced AHH activities. 3-Methoxybenzamide, a specific inhibitor of poly(ADP-ribose) polymerase, significantly increased both basal and BA-induced AHH activities of hepatocytes from both strains at days 3 and 5, reduction of P(1)450 transcripts also being evident in the latter case. The observations indicate qualitatively similar but quantitatively different regulation of AHH induction in both responsive and non-responsive mouse strains. Furthermore the regulation changed with increasing cultivation period. Previously described regulation mechanisms in cultured cells were observed to operate a few days after seeding, possibly after adaptation of hepatocytes to the culture conditions.
Carcinogenesis 1991 Apr
PMID:Regulation of mouse P(1)450 gene expression in monolayer-cultured hepatocytes from responsive and non-responsive strains. 184 69

Poly(ADP-ribose) is a naturally occurring nuclear macromolecule resembling nucleic acids. It is synthesized from NAD+ on histones and a few other nuclear proteins. Its function, although not completely understood, might be to alter chromatin structure and to regulate the activity of proteins involved in the metabolism of DNA strand breaks such as ligase II, and topoisomerase I. In addition, poly(ADP-ribose) modifies proteins involved in gene expression such as acetylated histones. HMG proteins, and T antigen. The enzyme poly(ADP-ribose) polymerase responsible for this modification has the unique property of requiring nicks or free ends on the DNA for its activity and of being automodified. The automodified enzyme, presumably found at the vicinity of DNA strand breaks at damaged chromatin sites, could remove histones from DNA and attract enzymes that have an affinity for poly(ADP-ribose) such as ligase II or poly(ADP-ribose) glycohydrolase, the polymer-degrading enzyme. Alterations in chromatin structure alter gene expression and seem to be involved in repair, replication, and recombination and in changing DNA superhelical density, intermediate steps in molecular carcinogenesis. Experiments with cells in culture and laboratory animals show that inhibition of poly(ADP-ribosylation) alters transformation and tumorigenicity brought about by a great number of carcinogenic agents. Cancer can be caused by the accumulation of unrepaired DNA strand breaks in the cell accelerating gene rearrangements, deletions, insertions and amplifications. Repair of DNA strand breaks shows an absolute dependence upon the rapid synthesis and degradation of poly(ADP-ribose). The polymer has a very short half life indeed. Data are reviewed on changes in chromatin structure and function caused by histone and nonhistone poly(ADP-ribosylation). The link of this modification to transformation, tumorigenesis, development, replication and gene expression is examined. A model is proposed to explain the effect of poly(ADP-ribosylation) on chromatin structure at the molecular level. Mono- and oligo(ADP-ribosylated) histones present in nuclei under physiological conditions are proposed to functions, like acetylated histones, in maintaining chromatin loops into transcriptionally active structures. On the other hand, poly(ADP-ribosylated) histones and poly(ADP-ribosylated) enzymes such as DNA and RNA polymerases, suggested to be modified from in vitro studies, might only appear in cells that have been heavily damaged by carcinogen. Their function might be to remove histones from DNA in order to facilitate repair and to shut down transcription and replication.
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PMID:Relation between carcinogenesis, chromatin structure and poly(ADP-ribosylation) (review). 190

The catalytic activity of the nuclear enzyme poly(ADP-ribose) polymerase (NAD+ ADP-ribosyl transferase, EC 2,4,2,30) is totally dependent upon the presence of DNA strand breaks. Having isolated a full-length cDNA for the polymerase, we have now evaluated the effect of endogenously and exogenously induced DNA strand breaks on the transcriptional control of this enzyme. During retinoic acid or dimethyl-sulfoxide-induced differentiation of HL-60 human leukemia cells, which may involve DNA breaks as well as other changes in chromatin, mRNA levels for the polymerase increased very early and remained high for up to 48 h after which it decreased to pre-induced levels. Polymerase transcript levels did not change, however, during the induction of DNA strand breaks by dimethylsulfate, a variety of other alkylating agents, X-irradiation, or UV-irradiation in several mammalian cell lines. It appears that in sharp contrast to the catalytic requirement of the polymerase, the induction of transcription of the polymerase gene may not be a strand-break-dependent process. The noninducibility of the polymerase gene following DNA damage suggested that there may be adequate levels of the polymerase in the cells to cope with DNA damage. To test this hypothesis we examined the efficacy of DNA repair in Cos cells engineered to overexpress the polymerase. Although there was a slight augmentation of the repair rate, this increase was apparent only after very high levels of DNA damage and only at early repair times. After a longer repair period, the extent of repair in control cell was similar to that in the cell overexpressing the polymerase. We thus conclude that the basal levels of the polymerase are adequate for significant amounts of DNA damage.
Carcinogenesis 1990 Jan
PMID:Expression of the poly(ADP-ribose) polymerase gene following natural and induced DNA strand breakage and effect of hyperexpression on DNA repair. 210 80

Induction of aryl hydrocarbon hydroxylase (AHH) activity was studied in primary cultures of rat hepatocytes. AHH activity was induced by treatment with benz[a]anthracene and combined treatment with cycloheximide for an initial short period during the induction enhanced benz[a]anthracene-inducible AHH activity. The enhancement was correlated to amounts of cytochrome P-450 RNA, indicating that cycloheximide treatment increased transcription of benz[a]anthracene-inducible cytochrome P-450 gene species. 3-Methoxybenzamide and 3-aminobenzamide, known to be physiologically specific inhibitors for poly(ADP-ribose) polymerase, but not the structurally related non-inhibitor, 3-aminobenzoic acid, also increased benz[a]anthracene-induced AHH activity. In addition, 3-methoxybenzamide was found to further increase the enhancing effects of cycloheximide on benz[a]anthracene induction of AHH. The effects of poly(ADP-ribose) polymerase inhibitors were not mediated by reduction of cyclic nucleotide phosphodiesterase activity. This was in clear contrast to the situation with the xanthine derivative, aminophylline, which also brought about a similar enhancement of AHH induction by benz[a]anthracene. The results suggest the participation of poly(ADP-ribose) in the regulation of expression of benz[a]anthracene-inducible cytochrome P-450 genes.
Carcinogenesis 1988 Oct
PMID:Elevation of polycyclic aromatic hydrocarbon-inducible aryl hydrocarbon hydroxylase activity in rat hepatocytes in primary culture by inhibitors of poly(ADP-ribose) polymerase. 245 55

To clarify the biological role of poly(ADP-ribose) in cancer induction in vivo, the influence of the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide (3-AB), on initiation of carcinogenesis in the colon and liver by a single application of methylazoxymethanol (MAM) acetate was investigated. Since 3-AB is rapidly metabolized and excreted in vivo when injected as a single dose, rats were given a continuous i.v. infusion of the compound (1200 mg/kg/day) for 4 days and injected with a single dose (35 mg/kg) of MAM acetate 4 h after the start of the experiment. Rats were killed 70 weeks after the beginning of the experiment. The incidence of colon tumors was significantly lower (t less than 0.025) in the 3-AB-treated group than in the carcinogen-only controls. Although significant numbers of glutathione S-transferase placental form positive foci were also induced in the liver of MAM-acetate-treated animals, 3-AB administration had no effect on their number and size. The results thus clearly demonstrated that continuous infusion of 3-AB during the initiation phase inhibited the development of MAM-acetate-induced colon tumors, but was not effective for the formation of preneoplastic foci in the liver.
Carcinogenesis 1988 Jul
PMID:Inhibition of methylazoxymethanol acetate initiation of colon carcinogenesis in rats by treatment with the poly(ADP-ribose)polymerase inhibitor 3-aminobenzamide. 313 26

Nicotinamide adenine dinucleotide is utilized as the substrate of a chromatin-bound enzyme, poly(ADP-ribose) polymerase. The effects of diethylnitrosamine and/or 3-aminobenzamide, a potent inhibitor of poly(ADP-ribose) polymerase, on the cellular NAD levels in rat liver were investigated. 3-Aminobenzamide (600 mg/kg) administered intraperitoneally was not detectable in the liver within 12 hr after administration; the inhibitor had a calculated half life of 90 min. Diethylnitrosamine reduced the NAD levels in rat liver in a dose-dependent way. The NAD content reached a minimum level at 8 hr, returning to 78% of the control value after 48 hr. The reduction of the NAD levels caused by diethylnitrosamine was completely prevented when 3-aminobenzamide was administered either simultaneously with diethylnitrosamine or 4 hr after diethylnitrosamine treatment. Furthermore, an immunohistochemical study showed that nuclear poly(ADP-ribose) decreased 1 hr after the administration of 3-aminobenzamide. These results suggest that inhibition of poly(ADP-ribosyl)ation is involved in the initiation of liver carcinogenesis by diethylnitrosamine and 3-aminobenzamide.
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PMID:Preventive effect of 3-aminobenzamide on the reduction of NAD levels in rat liver following administration of diethylnitrosamine. 314 98

3-Aminobenzamide (3AB) is a competitive inhibitor of poly-(ADP-ribose) polymerase. It will interact synergistically with certain monofunctional alkylating agents to increase the frequency of sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells. 3AB will also increase the baseline SCE frequency in exposed cells. The extent of interaction between 3AB and monofunctional alkylating agents varies depending on the alkylating agent used and appears to be due to the different amounts of membrane damage produced by the alkylating agents. In this study, exogenously added beta-NAD+ was found to reduce substantially SCE frequency in cells that had been treated with combinations of 3AB and methyl methanesulfonate (MMS) but not in cells treated with 3AB and N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MMS produces more cell membrane damage than MNNG at equitoxic doses. beta-NAD+ is the substrate for ADP-ribosylation and normally does not freely diffuse into cells. beta-NAD+ had no significant effect on SCE induction in intact cells or in cells treated with either 3AB or alkylating agent alone. In contrast to beta-NAD+, exogenously added alpha-NAD+, which is an inhibitor of poly(ADP-ribose) polymerase, increased SCE frequency in MMS-treated cells. Thus the interaction between 3AB and certain monofunctional alkylating agents in SCE formation is apparently due to cell membrane permeabilization and the loss of intracellular NAD+ which in turn probably results in a greater inhibition of ADP-ribosylation in the presence of 3AB.
Carcinogenesis 1986 Jan
PMID:Potentiation of alkylation-induced sister chromatid exchange frequency by 3-aminobenzamide is mediated by intracellular loss of NAD+. 394 37

3-Aminobenzamide (3AB), an inhibitor of poly(ADP-ribose) polymerase, interacts synergistically with certain monofunctional alkylating agents to increase the frequency of sister chromatid exchanges (SCEs) in Chinese hamster ovary cells (CHO). Not all alkylating agents interact with 3AB to the same extent. Because 3AB has been reported to inhibit DNA strand break rejoining, experiments were carried out to determine if 3AB interacts preferentially with alkylation-induced DNA strand breaks or some other alkylated DNA lesion in the induction of SCEs. SCE frequency was determined in CHO cells that were pretreated with methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), ethylnitrosourea (ENU) or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) for 2 h before being incubated with 3AB, and compared to the frequency of DNA strand breaks, as measured by alkaline elution, induced by these treatments. MNNG was by far the most potent DNA strand-breaking and SCE-inducing agent, followed in order of reactivity by MMS, EMS and ENU. The 3AB-enhanced SCE frequency was greatest, however, after MMS treatment. Thus the magnitude of the 3AB-mediated potentiation of SCE induction is not directly related to either the number of DNA strand breaks produced by the alkylating agent or the alkylation-induced SCE frequency. Furthermore, when MMS-treated cells were held in a non-cycling state for 2 days before release and treatment with 3AB, a procedure that results in a 60% reduction in MMS-induced SCE frequency, no synergism between MMS and 3AB in SCE induction was detected. These results suggest that 3AB does not interact with alkylation-induced DNA lesions in the induction of SCEs.
Carcinogenesis 1985 May
PMID:Different efficiencies of interaction between 3-aminobenzamide and various monofunctional alkylating agents in the induction of sister chromatid exchanges. 400 55

In the present experiments, we studied the effect of poly(ADP-ribose) polymerase inhibitors on the early stage of liver carcinogenesis by diethylnitrosamine (DEN) in rat liver in order to clarify the biological role of this enzyme in cancer induction. We used 3-aminobenzamide(ABA), 5-methylnicotinamide(MNam), and thymidine as the inhibitors and measured the numbers and sizes of gamma-glutamyltranspeptidase (gamma-GTP) positive foci as a marker of initiated cell populations. When ABA was given within 4 hr after DEN treatment, it had almost the same effect as a partial hepatectomy and caused dose-dependent enhancement of the induction of gamma-GTP positive foci. The administration of ABA at a dose of 600 mg/kg was effective to enhance the induction of the foci 1 day before to 1 day after 20 mg/kg DEN initiation. The enhancing effect of MNam and thymidine at a dose of 600 mg/kg was observed to the same extent as that of ABA. Based on these results the experiments were extended to the mechanisms of the enhancing effect of ABA. Liver cell necrosis was not detected by measuring serum GOT and GPT levels and histology after DEN and ABA administration. Further, the initiating and promoting activities of ABA in liver carcinogenesis were studied and ABA per se was not found to take part in either activity. These results indicate that poly(ADP-ribose) polymerase plays an important role in the early stage of liver carcinogenesis by DEN and provides a new avenue for studying the mechanisms of the initiation process in chemical carcinogenesis.
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PMID:Possible role of poly(ADP-ribose) polymerase on the early stage of liver carcinogenesis by diethylnitrosamine in rats. 614 Feb 58

The lethality of N-methyl-N-nitrosourea (MNU) to mouse L1210 cells, as determined by colon forming ability, was potentiated 2.8 fold by the addition of 1 mM 5'-methylnicotinamide (5MeN). When 5MeN was present throughout the expression and selection of 6-thioguanine resistant mutants, the MNU-induced mutation frequency was reduced in duplicate experiments from 15.6 and 12.0 to 7.0 mutants per 10(4) survivors per mM MNU. At the same level of survival, cells treated with 5MeN had approximately 12 times fewer mutants than untreated cells. The rate of removal of the promutagenic lesion O6-methylguanine from DNA was enhanced approximately 2-fold, whereas that of 7-methylguanine was unaffected by the incubation of MNU treated cells with 5MeN. Since 5MeN is a potent inhibitor of poly(ADP-ribose) polymerase, this may imply that in normal cells it is specific ADP-ribosylation of the repair enzyme causing the removal of O6-methylguanine, rather than a more general modification of chromatin structure, that limits the rate of repair of the promutagenic lesion. 5MeN also stimulated unscheduled DNA synthesis in MNU treated cells, implying that an earlier observation that 5MeN prevented rejoining of strand breaks induced by repair of alkyl lesions, probably resulted from inhibition of ligation and not the failure of DNA polymerase to replace bases removed by repair nucleases.
Carcinogenesis 1981
PMID:Effects of 5-methylnicotinamide on mouse L1210 cells exposed to N-methyl-N-nitrosourea: mutation induction, formation and removal of methylation products in DNA, and unscheduled DNA synthesis. 645 99


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