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

We observed that pretreatment of male F344 rats with benzyl selenocyanate, a versatile organoselenium chemopreventive agent in several animal model systems, decreases the levels of DNA and RNA modifications produced in the liver by the hepatocarcinogen 2-nitropropane. To clarify the mechanisms involved, we pretreated male F344 rats with either benzyl selenocyanate, its sulfur analog benzyl thiocyanate, phenobarbital or cobalt protoporphyrin IX; the latter is a depletor of P450. We then determined (1) the ability of liver microsomes to denitrify 2-nitropropane, (2) effects on 2-nitropropane-induced liver DNA and RNA modifications and (3) amount of nitrate excreted in rat urine following administration of the carcinogen. Pretreatment with benzyl selenocyanate or phenobarbital increased the denitrification activity of liver microsomes by 217 and 765%, respectively, increased liver P4502B1 by 31- and 435-fold, respectively, decreased the levels of 2-nitropropane-induced modifications in liver DNA (29-70% and 17-30%, respectively) and RNA (67-85% and 30-50%, respectively), and increased the 24-h urinary excretion of nitrate by 157 and 209%, respectively. Pretreatment with benzyl thiocyanate had no significant effect on any of these parameters. Pretreatment with cobalt protoporphyrin IX decreased liver P4502B 1 by 87%, decreased the denitrification activity of liver microsomes by 76%, decreased the 24 h urinary excretion of nitrate by 88.5%, but increased the extent of 2-nitropropane-induced liver nucleic acid modifications by 17-67%. These results indicate that the metabolic sequence from 2-nitropropane to the reactive species causing DNA and RNA modifications does not involve the removal of the nitro group. Moreover, they suggest that benzyl selenocyanate inhibits 2-NP-induced liver nucleic acid modifications in part by increasing its detoxication through induction of denitrification, although it is evident that other mechanisms must also be involved.
Carcinogenesis 1997 Sep
PMID:Inhibition of 2-nitropropane-induced rat liver DNA and RNA damage by benzyl selenocyanate. 932 79

Recent developments in cell culture techniques have made it possible to study the cellular mechanisms involved in carcinogenesis and to apply these methods as screening tools in vitro. This study investigated and compared the ability of the metals most commonly used in orthopedic implants to induce toxicity and neoplastic transformation in the C3H10T1/2 mouse fibroblast cell line. Eight metals (cobalt, chromium, nickel, iron, molybdenum, aluminium, vanadium and titanium) and their alloys (stainless steel, cobalt-chrome alloy and titanium alloy) were tested, both as soluble salts and as solid particles. There were marked differences between the various metals in terms of both toxicity and transforming ability. Significant increases in the incidence of cell transformation were seen with soluble forms of cobalt, chromium, nickel and molybdenum but not with iron, aluminium, vanadium or titanium. For most of the metals. transforming ability was directly related to toxicity, although this correlation did not hold for either molybdenum or vanadium. The physical form of the metal was critically important in determining its effects, and transformation occurred only with soluble metal salts.
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PMID:Neoplastic transformation of cells by soluble but not particulate forms of metals used in orthopaedic implants. 966 50

The mechanisms of cobalt-induced pulmonary interstitial fibrosis and cancer are incompletely understood. DNA damage, either induced by genotoxic (direct or via oxygen radicals) or co-genotoxic (e.g. inhibition of DNA repair) processes may play an important role in the initiation of cancer. The alkaline comet assay provides a sensitive tool to investigate these two processes. Cobalt metal, a mixture of cobalt with tungsten carbide and cobalt chloride, were compared for their DNA-damaging capacity. Concentrations from 0 to 6.0 microg Co-equivalent/ml were tested. All three compounds were able to induce DNA damage in isolated human lymphocytes from three donors, in a dose- and time-dependent way. A relatively large interexperimental and interdonor variability in response was observed. This was ascribed to technical parameters and unidentified individual factors. This confirms the importance of repeating experiments using the same and different donors. The DNA-damaging potential of the cobalt-tungsten carbide mixture was higher than that of cobalt metal and cobalt chloride, which had comparable responses. No significant increase of DNA migration was observed when the DNA of cells treated with cobalt metal, cobalt-tungsten carbide or tungsten carbide were incubated with the oxidative lesion-specific enzyme formamidopyrimidine DNA glycosylase. This suggests that during the short treatment period no substantial oxidative damage to DNA was produced. Cobalt metal was able to inhibit the repair of methylmethanesulphonate-induced DNA damage. This was concluded from simultaneous exposure to cobalt and methyl methanesulphonate, post-incubation and post-treatment with 1.2 microg/ml cobalt of methyl methanesulphonate-treated cells.
Carcinogenesis 1998 Nov
PMID:Evaluation of the in vitro direct and indirect genotoxic effects of cobalt compounds using the alkaline comet assay. Influence of interdonor and interexperimental variability. 985 19

Nickel, cadmium, cobalt, and copper are carcinogenic to humans and/or animals, but the underlying mechanisms are poorly understood. Our studies have been focused on one such mechanism involving mediation by the metals of promutagenic oxidative damage to DNA bases. The damage may be inflicted directly in DNA or in the deoxynucleotide pool, from which the damaged bases are incorporated into DNA. Such incorporation is prevented in cells by 8-oxo-2'-deoxyguanosine 5'-triphosphate pyrophosphatases (8-oxo-dGTPases). Thus, inhibition of these enzymes should enhance carcinogenesis. We have studied effects of Cd(II), Cu(II), Co(II), and Ni(II) on the activity of isolated bacterial and human 8-oxo-dGTPases. Cd(II) and Cu(II) were strongly inhibitory, while Ni(II) and Co(II) were much less suppressive. After developing an assay for 8-oxo-dGTPase activity, we confirmed the inhibition by Cd(II) in cultured cells and in the rat testis, the target organ for cadmium carcinogenesis. 8-Oxo-dGTPase inhibition was accompanied by an increase in the 8-oxo-dG level in testicular DNA.
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PMID:Inhibition of antimutagenic enzymes, 8-oxo-dGTPases, by carcinogenic metals. Recent developments. 1083 Aug 71

This study assessed the effect of chronic exposure to a 60 Hz circularly polarized magnetic field on the occurrence of ionizing radiation-induced lymphoma and other hematopoietic neoplasia in mice. Female C57BL/6 mice received lifetime exposure to either a magnetic field flux density of 1.42 mT for 18 h/day, or an ambient magnetic field of 0.13 microT. Beginning on the first day of magnetic field exposure, 1710 mice were treated with one of three levels of split-dose Cobalt-60 gamma-radiation (cumulative 3.0, 4.0 or 5.1 Gy). The remaining 570 mice received sham irradiation treatment. Sections from 10 lymphoid tissues were evaluated histopathologically for hematopoietic neoplasia. The primary statistical analysis used the Poly3 method to compare lymphoma incidences in magnetic field (MF)-exposed and control mice. Secondary analyses used the Cox proportional hazards model to analyze incidence rates for mortality and development of specific types of neoplasia. The mortality incidence rate was increased by ionizing radiation treatment, and all neoplasms were observed sooner in irradiated mice. However, the lifetime incidence of hematopoietic neoplasia was similar in all experimental groups, including those that were not exposed to ionizing radiation. Chronic exposure to MFs did not affect the mortality incidence rates and did not change the relative incidences of hematopoietic neoplasia in mice that received the same ionizing radiation treatment, with the exception of a marginally significant reduced relative risk of 0.97 (P = 0.05) for lymphoblastic lymphoma in mice exposed to a magnetic field and treated with 5.1 Gy. Lymphomas and histiocytic sarcomas were first observed approximately 50 days sooner in mice that were exposed to magnetic fields but not ionizing radiation, although this comparison was not statistically significant and the incidence of hematopoietic neoplasia in these mice was not different from that of mice in the 0 T/0 Gy group.
Carcinogenesis 2000 Jul
PMID:Hematopoietic neoplasia in C57BL/6 mice exposed to split-dose ionizing radiation and circularly polarized 60 Hz magnetic fields. 1087 17

Even though not mutagenic, compounds of the carcinogenic metals nickel, cadmium, cobalt and arsenic have been shown previously to inhibit nucleotide excision repair and base excision repair at low, non-cytotoxic concentrations. Since some toxic metals have high affinities for -SH groups, we used the bacterial formamidopyrimidine-DNA glycosylase (Fpg protein) and the mammalian XPA protein as models to investigate whether zinc finger structures in DNA repair enzymes are particularly sensitive to carcinogenic and/or toxic metal compounds. Concentrations of </=1 mM Ni(II), Pb(II), As(III) or Co(II) did not affect the activity of the Fpg protein significantly. In contrast, the enzyme was inhibited in a dose-dependent manner by Cd(II), Cu(II) or Hg(II), starting at concentrations of 50 microM, 5 microM and 50 nM, respectively. Simultaneous treatment with Cd(II) or Cu(II) and Zn(II) partly prevented the inhibitions, while no reversal of inhibition was observed when Zn(II) was added after Cd(II) or Cu(II). In the case of Hg(II), Zn(II) had no protective effect independent of the time of its addition; however, the enzyme activity was completely restored by glutathione. Regarding XPA, Hg(II), Pb(II) or As(III) did not diminish its binding to an UV-irradiated oligonucleotide, while Cd(II), Co(II), Cu(II) and Ni(II) reduced its DNA-binding ability. Simultaneous treatment with Zn(II) prevented largely the inhibition induced by Cd(II), Co(II), and Ni(II), but only slightly in the case of Cu(II). Collectively, the results indicate that both proteins were inhibited by Cd(II) and Cu(II), XPA was additionally inactivated by Ni(II) and Co(II), and Fpg but not XPA was strongly affected by Hg(II). Even though other mechanisms of protein inactivation cannot be completely excluded, zinc finger structures may be sensitive targets for toxic metal compounds, but each zinc finger protein has unique sensitivities.
Carcinogenesis 2000 Nov
PMID:Differential effects of toxic metal compounds on the activities of Fpg and XPA, two zinc finger proteins involved in DNA repair. 1106 74

Heavy metal-tungsten alloys (HMTAs) are dense heavy metal composite materials used primarily in military applications. HMTAs are composed of a mixture of tungsten (91-93%), nickel (3-5%) and either cobalt (2-4%) or iron (2-4%) particles. Like the heavy metal depleted uranium (DU), the use of HMTAs in military munitions could result in their internalization in humans. Limited data exist, however, regarding the long-term health effects of internalized HMTAs in humans. We used an immortalized, non-tumorigenic, human osteoblast-like cell line (HOS) to study the tumorigenic transforming potential of reconstituted mixtures of tungsten, nickel and cobalt (rWNiCo) and tungsten, nickel and iron (rWNiFe). We report the ability of rWNiCo and rWNiFe to transform immortalized HOS cells to the tumorigenic phenotype. These HMTA transformants are characterized by anchorage-independent growth, tumor formation in nude mice and high level expression of the K-ras oncogene. Cellular exposure to rWNiCo and rWNiFe resulted in 8.90 +/- 0.93- and 9.50 +/- 0.91-fold increases in transformation frequency, respectively, compared with the frequency in untreated cells. In comparison, an equivalent dose of crystalline NiS resulted in a 7.7 +/- 0.73-fold increase in transformation frequency. The inert metal tantalum oxide did not enhance HOS transformation frequency above untreated levels. The mechanism by which rWNiCo and rWNiFe induce cell transformation in vitro appears to involve, at least partially, direct damage to the genetic material, manifested as increased DNA breakage or chromosomal aberrations (i.e. micronuclei). This is the first report showing that HMTA mixtures of W, Ni and Co or Fe cause human cell transformation to the neoplastic phenotype. While additional studies are needed to determine if protracted HMTA exposure produces tumors in vivo, the implication from these in vitro results is that the risk of cancer induction from internalized HMTAs exposure may be comparable with the risk from other biologically reactive and insoluble carcinogenic heavy metal compounds (e.g. nickel subsulfide and nickel oxide).
Carcinogenesis 2001 Jan
PMID:Neoplastic transformation of human osteoblast cells to the tumorigenic phenotype by heavy metal-tungsten alloy particles: induction of genotoxic effects. 1115 49

Carcinogenesis is a multistage process involving dysregulation of signal transduction and cell cycle pathways. This dysregulation results in specific molecular and genetic alterations, including gene amplification, mutations, and chromosomal rearrangements. These aberrations can be measured to provide a novel means to assess carcinogenic risk or as targets for chemointervention. Recent human and in vivo studies have demonstrated that genetic alterations, such as oncogenes and oncoproteins, were observed in preneoplastic tissues or serum following exposure to chemical carcinogens or low-level radiation (LLR). Identification of preneoplastic changes following radiation exposure may provide information that will allow development of LLR chemopreventive strategies. Radiation carcinogenesis studies in vivo with a lung tumor model showed that a low-dose cobalt-60 radiation exposure induced persistent time-dependent genetic alterations, such as elevated ras expression. This radiation exposure also resulted in lung tumor formation in 26% of the irradiated animals at 232 days after irradiation. A significant and progressive increase in ras oncogene expression was measured using Northern blot analysis in 80% of the irradiated animals over the duration of the experiment. Pharmacological intervention strategies are being tested using buthionine-[S,R]-sulfoximine (BSO). BSO has been previously shown to down-regulate ras expression. Administration of BSO prevented radiation-induced changes in ras mRNA levels in this lung tumor model. Further studies are being conducted with an LLR-induced leukemia model in which detection of circulating levels of oncoproteins will be more feasible. Based on these preliminary results and on its clinical efficacy and low clinical toxicity, BSO warrants further study as an LLR chemopreventive agent. Furthermore, this strategy to target LLR-induced preneoplastic alterations may be an effective means of developing modulators of LLR-induced cancers.
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PMID:Development of chemopreventive strategies for radiation-induced cancer: targeting radiation-induced genetic alterations. 1187 17

We reviewed the mechanism of oxidative DNA damage with reference to metal carcinogenesis and metal-mediated chemical carcinogenesis. On the basis of the finding that chromium (VI) induced oxidative DNA damage in the presence of hydrogen peroxide (H2O2), we proposed the hypothesis that endogenous reactive oxygen species play a role in metal carcinogenesis. Since then, we have reported that various metal compounds, such as cobalt, nickel, and ferric nitrilotriacetate, directly cause site-specific DNA damage in the presence of H2O2. We also found that carcinogenic metals could cause DNA damage through indirect mechanisms. Certain nickel compounds induced oxidative DNA damage in rat lungs through inflammation. Endogenous metals, copper and iron, catalyzed ROS generation from various organic carcinogens, resulting in oxidative DNA damage. Polynuclear compounds, such as 4-aminobiphenyl and heterocyclic amines, appear to induce cancer mainly through DNA adduct formation, although their N-hydroxy and nitroso metabolites can also cause oxidative DNA damage. On the other hand, mononuclear compounds, such as benzene metabolites, caffeic acid, and o-toluidine, should express their carcionogenicity through oxidative DNA damage. Metabolites of certain carcinogens efficiently caused oxidative DNA damage by forming NADH-dependent redox cycles. These findings suggest that metal-mediated oxidative DNA damage plays important roles in chemical carcinogenesis.
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PMID:The role of metals in site-specific DNA damage with reference to carcinogenesis. 1197 84

Co-exposure to cadmium, cobalt, lead and other heavy metals occurs in many occupational settings, such as pigment and batteries production, galvanization and recycling of electric tools. However, little is known about interactions between several heavy metals. In the present study we determined DNA single strand break (DNA-SSB) induction and repair capacity for 8-oxoguanine in mononuclear blood cells of 78 individuals co-exposed to cadmium (range of concentrations in air: 0.05-138.00 micro g/m(3)), cobalt (range: 0-10 micro g/m(3)) and lead (range: 0-125 micro g/m(3)). Exposure to heavy metals was determined in air, blood and urine. Non-parametric correlation analysis showed a correlation between cadmium concentrations in air with DNA-SSB (P = 0.001, R = 0.371). Surprisingly, cobalt air concentrations correlated even better (P < 0.001, R = 0.401), whereas lead did not correlate with DNA-SSB. Logistic regression analysis including 11 possible parameters of influence resulted in a model showing that cobalt in air, cadmium in air, cadmium in blood and lead in blood influence the level of DNA-SSB. The positive result with cobalt was surprising, since exposure levels were much lower compared with the TRK-value of 100 micro g/m(3). To examine, whether the positive result with cobalt is stable, we applied several logistic regression models with two blocks, where all factors except cobalt were considered preferentially. All strategies resulted in the model described above. Logistic regression analysis considering also all possible interactions between the relevant parameters of influence finally resulted in the following model: Odds ratio = 1.286(Co in air) x 1.040(Cd in air) x 3.111(Cd in blood) x 0.861(Pb in air) x 1.023(Co in air x Pb in air). This model correctly predicts an increased level of DNA-SSB in 91% of the subjects in our study. One conclusion from this model is the existence of more than multiplicative effects for co-exposures of cadmium, cobalt and lead. For instance increasing lead air concentrations from 1.6 to 50 micro g/m(3) in the presence of constant exposures to cobalt and cadmium (8 micro g/m(3) and 3.8 micro g/m(3)) leads to an almost 5-fold increase in the odds ratio, although lead alone does not increase DNA-SSB. The mechanism behind these interactions might be repair inhibition of oxidative DNA damage, since a decrease in repair capacity will increase susceptibility to reactive oxygen species generated by cadmium or cobalt. Indeed, repair of 8-oxoguanine decreased with increasing exposures and inversely correlated with the level of DNA-SSB (P = 0.001, R = -0.427). Protein expression patterns of individuals exposed to cobalt concentrations of approximately 10 micro g/m(3) were compared with those of unexposed individuals using two-dimensional gel electrophoresis. Qualitative and apparent quantitative alterations in protein expression were selective and certainly occurred in <0.1% of all proteins. In conclusion, the hazard due to cobalt exposure - that has been classified only as IIB by the IARC - seems to be underestimated, especially when individuals are co-exposed to cadmium or lead. Co-exposure may cause genotoxic effects, even if the concentrations of individual heavy metals do not exceed TRK-values.
Carcinogenesis 2003 Jan
PMID:Occupational exposure to heavy metals: DNA damage induction and DNA repair inhibition prove co-exposures to cadmium, cobalt and lead as more dangerous than hitherto expected. 1297 68


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