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 relationship between treatment with 3-methoxy-benzamide (MBA), a potent inhibitor of ADP-ribosylation reactions, and the response of C3H10T1/2 cells to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) has been examined. Quiescent cells effected potentially lethal damage repair (PLDR) over a 48-h period following MNNG and the repair was coincident with the removal of DNA strand breaks. MBA had no effect on PLDR but was very co-cytotoxic with MNNG in dividing cells. The presence of MBA caused the appearance of an additional number of DNA strand breaks following MNNG in both quiescent and dividing cells. These results suggest that ADP-ribosylation is required for normal cell cycle progression following DNA damage in dividing cells.
Carcinogenesis 1985 May
PMID:Cellular recovery of dividing and confluent C3H10T1/2 cells from N-methyl-N'-nitro-N-nitrosoguanidine in the presence of ADP-ribosylation inhibitors. 298 8

Poly ADP-ribosylation of two mouse lymphoma cell lines, L5178Y (LS) and the radiation and alkylating agent resistant derivative AII, was investigated by uptake of [3H]NAD by permeabilised cells into acid-precipitable material that was sensitive to phosphodiesterase but insensitive to DNase and RNase. Basal activities in both lymphoma lines were 3-4-fold greater than in mouse L1210 leukaemia cells. However, total endogenous poly (ADP-R) polymerase activity in both L5178Y cell lines, stimulated by a large excess of DNase in the presence of Triton X-100, was less than half the activity in L1210 cells. Doses of N-methyl-N-nitrosourea (MNU) that produced 20-50% survival of colony-forming units increased poly (ADP-R) in both lymphoma lines by only 25% compared with 377% in L1210 cells when synthesis was measured immediately after a 30-min exposure of MNU. During the first 24 h after MNU AII cells produced a peak of activity that was not seen with LS cells. A second peak was seen in both cell lines between 24 and 48 h following MNU. Concentrations of 3-aminobenzamide (3AB) above 2.5 mM inhibited colony-forming ability of lymphoma cells and equally inhibited uptake of [14C]formate into protein, RNA and DNA indicating that 3AB behaves as a general metabolic poison. Concentrations of 3AB in the toxic range of 3-10 mM inhibited poly (ADP-R) synthesis but no degradation of the polymer was observed. Non-toxic concentrations of 3AB potentiated cell killing by MNU to a similar degree in both lymphoma cell lines. In conclusion, we have found little evidence to support the hypothesis that the differential sensitivity of LS and AII is related to poly ADP-ribosylation. Compared with other mouse cells, L5178Y cells appear deficient in poly (ADP-R) polymerase and poly (ADP-R) glycohydrolase activities.
Carcinogenesis 1985 Jul
PMID:Poly (ADP-ribose) metabolism in alkylated mouse L5178Y cells. 299 Jul 53

The levels of adenosine diphosphate ribosyl transferase (ADPRT) have been quantified in Ficoll-Isopaque isolated marrow cells from 36 patients with acute myeloid leukemia (AML). The in vitro growth pattern in agar at diagnosis was also determined, and in 16 patients the in vitro drug sensitivity of the clonogenic cells (CFU-GM) to cytosine arabinoside and daunorubicin was measured. The ADPRT activities of the various marrow cell preparations correlated to the morphological diagnoses, in vitro growth patterns, in vitro drug sensitivities to cytosine arabinoside, and to the prognoses of the AML patients. Hence, ADPRT may be a useful marker for the pathophysiology associated to AML.
Carcinogenesis 1985 Jul
PMID:Adenosine diphosphate ribosyl transferase in marrow cells of patients with acute myeloid leukemia is related to differentiation and drug sensitivity. 299 Jul 54

Novobiocin inhibits DNA topoisomerases. It also inhibits excision repair of DNA photodamage, blocking both repair synthesis and the earlier step of incision at u.v. damage sites (as measured by the accumulation of DNA strand breaks in u.v.-irradiated interphase cells treated with DNA synthesis inhibitors such as hydroxyurea or cytosine arabinoside). It has been supposed, therefore, that novobiocin affects repair by blocking a putative topoisomerase step prior to incision. But we find that novobiocin also has a marked dose- and time-dependent effect on mitochondria: in cells exposed to novobiocin, mitochondria swell and their cristae become disrupted, and the intracellular ATP:ADP ratio is lowered, though the membrane potential is maintained as judged by rhodamine 123 fluorescence. Mitotic cells are more resistant to mitochondrial disruption by novobiocin than are interphase cells. This correlates with a relative resistance of u.v.-irradiated mitotic cells to the inhibition of incision by novobiocin. The chromosomal decondensation that results from the accumulation of DNA breaks due to incision when u.v.-irradiated mitotic cells are treated with hydroxyurea and cytosine arabinoside is largely suppressed by novobiocin. Furthermore, the suppression of induced strand break accumulation is partly due to a suppression by novobiocin of the uptake and phosphorylation of cytosine arabinoside; breaks accumulated in u.v.-irradiated cells in the presence of aphidicolin, an inhibitor of DNA polymerase alpha that does not require phosphorylation, are less novobiocin-sensitive. We conclude that the effects of novobiocin on excision repair are more likely to be due to a non-specific effect on ATP metabolism than to a specific effect on a repair-related topoisomerase.
Carcinogenesis 1985 Sep
PMID:Novobiocin inhibition of DNA excision repair may occur through effects on mitochondrial structure and ATP metabolism, not on repair topoisomerases. 299 34

We have demonstrated that carcinogen damage to DNA induces the production of cellular factors that act in trans to enhance the asynchronous replication of polyoma viral DNA. Exposure of a polyoma virus-transformed rat cell line to benzo[a]pyrene-7,8-diol-9,10-oxide (BPDE), the ultimate carcinogenic metabolite of benzo[a]pyrene, led to the accumulation of heterogeneously sized free viral DNA molecules which contain polyoma origin sequences as well as cellular sequences that flank the integrated viral DNA. When the sequence gpt was linked to the polyoma early region and transfected into rat cells, it underwent asynchronous replication in response either to direct treatment of the transfected cells with BPDE, or to fusion of untreated transfected cells with normal cells previously exposed to BPDE. Transient arrest of the cell cycle by hydroxyurea, isoleucine deprivation or methotrexate caused a slight enhancement of viral DNA replication when compared with BPDE. Both aphidicolin, an inhibitor of DNA polymerase alpha, and 3-aminobenzamide, an inhibitor of poly[ADP]ribosyl transferase, caused marked inhibition of BPDE-induced viral DNA synthesis. The induction of a trans-acting factor in response to damage of cellular DNA may be relevant to synergistic interactions between environmental chemicals and DNA viruses in cell transformation and to the general phenomenon of gene amplification.
Carcinogenesis 1986 Jun
PMID:Carcinogen induced asynchronous replication of polyoma DNA is mediated by a trans-acting factor. 301 4

Inhibition of poly(ADP-Rib) by benzamide (BA) or 3-amino-benzamide (3AB) for a limited period (i.e., when ADP-ribosylation is elevated) during and shortly following X-ray or MNNG-induced DNA damage of BALB/3T3 cells significantly (3- to 30-fold) enhanced transformation frequency by these agents. Individual Type III foci isolated from benzamide, X-ray, or X-ray plus benzamide treated cultures were established and characterized for growth in soft agar and for tumor induction in nude mice. DNA isolated from representative transformed lines established as a result of BA, X-ray or X-ray and BA treatments was transfected onto NIH/3T3 cells. Transformation efficiencies ranging from 0.17 to 0.28 foci/micrograms of DNA were observed suggesting the possibility that dominant transforming gene(s) were responsible for the oncogenic phenotype of radiation and benzamide transformed DNA.
Carcinogenesis 1986 Feb
PMID:Relationship between DNA strand breaks and inhibition of poly (ADP-ribosylation): enhancement of carcinogen-induced transformation. 308 Dec 74

The response of cellular NAD+ metabolism to DEN and/or ABA and the carcinogenesis of the liver initiated by DEN and ABA were studied in rats. The liver NAD+ level was depleted by an ip injection of 20 mg or 200 mg/kg body weight of DEN. ABA, administered ip at a dose of 600 mg/kg simultaneously with or 4 hours after DEN, prevented the depletion of NAD+ by DEN. These biochemical findings correlated with the changes of conspicuous intranuclear immunofluorescence of poly(ADP-ribose), which were studied by immunohistochemistry. When initiated by 20 mg/kg body weight DEN and 600 mg/kg ABA and then processed to selection pressure, the liver was found to be capable of developing hepatocellular carcinomas with or without PB promotion. These results suggest that the inhibition of poly(ADP-ribosylation) might lead to irreversible initiation of liver carcinogenesis by DEN in rats.
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PMID:Possible model of liver carcinogenesis using inhibitors of NAD+ ADP ribosyl transferase in rats. 310 Nov 58

The inhibitors of the nuclear enzyme ADP-ribosyl transferase (ADPRT) had been shown to block the stimulation of quiescent lymphocytes with mitogens suggesting the involvement of the enzyme in the control of gene expression and cell differentiation. By means of the activity-gel assay we have analysed the intensity and the molecular mass of the catalytic bands of the enzyme at early and late times after stimulation of human lymphocytes by phytohemagglutinin. We observed that the increase in the activity of ADPRT is concurrent with the onset of DNA synthesis and is maintained for up to 10 days after lymphocyte stimulation, when DNA replication is over but the capacity to perform repair synthesis is still elevated. The analysis of ADPRT in stimulated lymphocytes by Western blots indicated that the increase in enzyme activity is due to the de novo synthesis of enzyme protein. The response of ADPRT to the treatment of human lymphocytes with DNA-damaging agents was studied at various dose-ranges, using the activity-gel technique. The results obtained indicate that dimethyl sulfate is 10 times as active as methyl methane sulfonate in stimulating ADPRT activity and that, at very high doses, the activity band of the enzyme tends to disappear. Very similar observations were obtained when Chinese hamster ovary cells were treated with the same agents, although the concentrations of the mutagens eliciting maximal ADPRT activation were 10 times higher than in human lymphocytes. When analysed by Western blots, no significant difference of the protein band of the enzyme was observed in comparing control and treated cells. This suggests that the activity-gel system can detect two different phenomena: the increase in enzyme protein, as in the case of stimulated lymphocytes, and the enzyme-activating effect of DNA-damaging agents, which occurs without changing the number of enzyme molecules. Of particular interest is the observation that mitomycin C is capable of activating ADPRT in human lymphocytes, thus suggesting that cross-linking agents are involved in promoting ADP-ribosylation reactions. We have also analysed the variations of the enzyme throughout the cell cycle in HeLa cells synchronized in S phase or in mitosis. No significant changes in the levels of the enzyme activity were revealed by the activity-gel assay during the progression of the cycle, although an overall increase of active polypeptides of larger size in concomitance with the S period was observed.
Carcinogenesis 1987 Sep
PMID:Response of mammalian ADP-ribosyl transferase to lymphocyte stimulation, mutagen treatment and cell cycling. 311 54

We have studied the effects of plasma and of cumene hydroperoxide (CUM) on adenosine diphosphate ribosyl transferase (ADPRT) from mononuclear leukocytes (HML) of patients with colonic adenomatous polyps (n = 22), with colonic hyperplastic polyps (n = 5) and with neither type of polyp (controls) (n = 6). ADPRT was measured after incubation of HML with plasma alone (termed the plasma value), and with plasma plus CUM (50 microM) (the activated value); the difference elicited by CUM was termed the induced value. There was no significant difference in values between the control and hyperplastic polyp groups: these were combined for further analysis. The plasma (P = 0.038), activated (P = 0.009) and induced (P = 0.0024) values of the combined group all differed significantly from those of the adenoma group. At low exposures, CUM stimulated both ADPRT and unscheduled DNA synthesis and, at higher exposures, inactivated both. Pretreatment of HML with vitamin E protected against these effects of CUM, while pretreatment with diamide (which depletes GSH) accentuated the effects. This study demonstrates a differential reaction of ADPRT in patients harboring colonic adenomas and suggests that the origin of this difference may lie in cellular responses to oxidative stress.
Carcinogenesis 1988 Mar
PMID:Effects of cumene hydroperoxide on adenosine diphosphate ribosyl transferase in mononuclear leukocytes of patients with adenomatous polyps in the colon. 312 91

Benzamides are potent inhibitors of nuclear ADP-ribosyltransferase and have been extensively used to demonstrate the involvement of ADP-ribosylation in cellular function. When permeabilized L1210 cells are treated with 50 microM 3-acetylamidobenzamide (3-aab) the enzyme is inhibited. However, when 50 nM 3-aab is used a two-fold stimulation of enzyme activity is produced. This anomalous stimulation is obtained with benzamides and nicotinamides and is correlated with their activity as inhibitors. Strikingly the steady-state level of poly(ADP-ribose) in intact cells is increased by these low levels of inhibitors. The mechanisms of this effect and its consequences for the experimental use of benzamides are discussed.
Carcinogenesis 1988 Nov
PMID:Benzamides can stimulate as well as inhibit the activity of nuclear ADP-ribosyltransferase. 314 Oct 76


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