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)

In addition to being a potent hepatocarcinogen, aflatoxin B1 (AFB1) is a pulmonary carcinogen in experimental animals and epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. Since point mutations at codons 12, 13 and 61 of the K-ras protooncogene are often implicated in chemically induced mouse lung tumors and in human lung adenocarcinomas, we undertook an investigation of the role of K-ras activation in AFB1-induced pulmonary carcinogenesis. Female AC3F1 (A/J x C3H/HeJ) mice were treated with AFB1 (150 mg/kg i.p., divided into 24 doses over 8 weeks), and 6-14 months after the completion of dosing mice were killed and pulmonary adenomas and carcinomas removed. Of the 76 AFB1-induced lung tumors analyzed by single strand conformation polymorphism (SSCP) and direct sequencing, 75 possessed K-ras codon 12 mutations (46 GTT, 14 GAT, 13 TGT and 2 TTT; normal, GGT) and one had a GGC-->CGC mutation in codon 13. The observation that K-ras mutations occurred only at G:C base pairs is in agreement with N7-guanine being the primary site of AFB1-DNA adduct formation and with guanine residues being targets for AFB1-induced oxidative DNA damage via formation of 8-hydroxydeoxyguanosine (8-OHdG). The AFB1-specific nature of the observed K-ras mutation spectrum and the fact that 100% of the tumor samples examined contained K-ras mutations is consistent with K-ras activation being an early, critical event in AFB1-induced pulmonary carcinogenesis in AC3F1 mice. The parental origin of the observed K-ras mutations was determined by allele-specific PCR amplification of AFB1-induced lung tumor DNA followed by SSCP analysis. In the vast majority of tumors (73/76), the mutated K-ras allele was derived from the lung tumor susceptible A/J parent. This finding supports the existence of a link between K-ras and differences in mouse lung tumor susceptibility.
Carcinogenesis 1996 Aug
PMID:Activation of K-ras in aflatoxin B1-induced lung tumors from AC3F1 (A/J x C3H/HeJ) mice. 876 34

8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a mutation-prone (G:C to T:A transversion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversions are observed in the p53 and ras genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sunlight. In the current study, 8-OHdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m2 of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OHdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OHdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OHdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogenesis.
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PMID:8-hydroxy-2'-deoxyguanosine is increased in epidermal cells of hairless mice after chronic ultraviolet B exposure. 887 58

Fullerene C60 dissolved in polyvinylpyrrolidone was mutagenic for Salmonella strains TA102, TA104 and YG3003 in the presence of rat liver microsomes when it was irradiated by visible light. The mutagenicity was elevated in strain YG3003, a repair enzyme-deficient mutant of TA102. The mutation was reduced in the presence of beta-carotene and parabromophenacyl bromide, a scavenger and an inhibitor, respectively, of phospholipase. The results suggest that singlet oxygen was generated by irradiating the C60 by visible light and that the mutagenicity was due to oxidized phospholipids in rat liver microsomes. Of the phospholipids in rat liver microsomes, the linoleate fraction isolated by high performance liquid chromatography was a major component, and played an important role in mutagenicity. Methyl linoleate, which was prepared for gas chromatographic analysis, was readily oxidized to hydroperoxymethyl linoleate, and associated with both 10- and 12-hydroxyl derivatives with a double bond in chemical structure by singlet oxygen: radicals to the hydroxyl function were probably generated. Because of the instability of the hydroxymethyl linoleate radicals, guanine residues generated radicals. The results of ESR spectrum analysis suggested generation of radicals at the guanine base but not thymine, cytosine and adenine bases as estimated with the g value of 2.0150. On the other hand, the singlet oxygen-generating C60 formed 8-hydroxydeoxyguanosine (8-OH-dG) upon treatment with 2' deoxyguanosine and microsomes or linoleate. The formation of 8-OH-dG was highly elevated in the presence of microsomes and linoleate. The level of 8-OH-dG formed with and without the microsome fraction was 47 and 9.6 units, respectively, per 10(4) deoxyguanosine. It was considered that the mechanism is indirect action of singlet oxygen due to lipid peroxidation of linoleate that causes oxidative DNA damage.
Carcinogenesis 1996 Oct
PMID:Mutagenicity of the fullerene C60-generated singlet oxygen dependent formation of lipid peroxides. 889 84

Treatment of isolated DNA with crocidolite and man-made vitreous fibre-21 (MMVF-21) significantly increased the concentration of 8-hydroxydeoxyguanosine (8-OHdG) in isolated DNA above background levels and co-treatment with glutathione (GSH) eliminated this effect. Crocidolite, MMVF-21 and chrysotile fibres increased the number of revertants in Salmonella typhimurium TA100 and GSH-deficient strains, TA100/NG-54 and TA100/NG-57, over background levels. This increase was small in TA100 but was greater in the GSH-deficient strains. When these bacterial strains were further depleted of GSH by co-culture with buthionine sulfoximine, all fibres tested caused a significant increase in the number of revertants over the parent strains. Pre-treatment with the GSH precursor N-acetyl-L-cysteine reduced the number of revertants to below that of the parent strain. Previous studies have shown a mechanistic role for iron-catalyzed production of oxygen radicals in the mutagenicity of fibres and this study suggests a protective role for GSH against such oxidative damage possibly by acting as a radical scavenger.
Carcinogenesis 1996 Oct
PMID:Glutathione modulates the formation of 8-hydroxydeoxyguanosine in isolated DNA and mutagenicity in Salmonella typhimurium TA100 induced by mineral fibres. 889 1

In order to clarify the involvement of oxygen radicals in lung carcinogenesis induced by diesel exhaust particles (DEP), the relationship between lung tumour response and formation of 8-hydroxydeoxyguanosine (8-OHdG) in lung DNA was examined. The role of high dietary fat and beta-carotene on these responses was also studied. Mice were intratracheally injected with 0.05, 0.1 and 0.2 mg of DEP per animal once weekly for 10 weeks. After 12 months, the lung tumour incidence in mice treated with 0.05 mg and 0.1 mg showed similar increases (30% and 31%), but was decreased to 24% at 0.2 mg. High dietary fat enhanced the incidence of both benign and malignant tumours. beta-carotene partially prevented the tumour development. After the 10 weekly treatments of DEP, inflammatory reaction was observed in the respiratory tract and alveoli. The formation of 8-OHdG in lung DNA from mice treated with DEP showed a dose dependent increase. 8-OHdG formation was enhanced by high dietary fat and partially reduced by beta-carotene. Formation of 8-OHdG was significantly correlated with the lung tumour incidence except at 0.2 mg. These results suggest that the induction of oxidative DNA damage may be an important factor in the initiation of DEP-induced lung carcinogenesis, and that beta-carotene and high dietary fat may play a role in the regulation of tumour development via modulation of the formation of 8-OHdG.
Carcinogenesis 1997 Jan
PMID:Lung carcinogenesis and formation of 8-hydroxy-deoxyguanosine in mice by diesel exhaust particles. 905 5

Oxidative DNA damage (as 8-hydroxydeoxyguanosine; 8-OHdG), carbonyl content of proteins, and activities of superoxide dismutase (SOD) and catalase were investigated in female Sprague-Dawley rats orally treated with benzo(a)pyrene (B(a)P) (75 mg/rat). HPLC-ECD system showed that B(a)P increased the level of 8-OHdG in tissues (liver, kidney, and lung), but a statistical significance was observed only in the liver (3.5-fold increase) and kidney (two-fold increase). In the liver, the peak level (21 +/- 5 8-OHdG residues/10(5) dG) was obtained 12 h after treatment and returned close to control level (9 +/- 2 8-OHdG residues/10(5) dG) at 24 h, but 8-OHdG was persistent in the kidney. Carbonyl contents measured as an index of protein oxidation were slightly increased (23-35%) in the cytosolic fraction of tissues, but a significant increase (2.19 nmol/mg protein, 35% increase) was observed only in the liver 6 h after treatment, similar to 8-OHdG. However, the rate of increase was relatively low compared to that of 8-OHdG. In contrast to DNA and protein damages, the activities of SOD and catalase in the tissues were decreased after treatment (P < 0.01) and gradually increased to control levels. SOD and catalase activities in organs of rats were inversely correlated with oxidative damages to DNA and protein. The data suggest that B(a)P oxidatively altered DNA, protein, and antioxidant enzymes in rats and this might be associated with B(a)P carcinogenesis.
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PMID:Oxidative stress to DNA, protein, and antioxidant enzymes (superoxide dismutase and catalase) in rats treated with benzo(a)pyrene. 906 23

Oxidative damage is a proposed mechanism of asbestos-induced carcinogenesis, but the detection of oxidative DNA lesions in target cells of asbestos-induced mesothelioma has not been examined. In studies here, DNA was isolated from both rat pleural mesothelial (RPM) cells and a human mesothelial cell line (MET5A) after exposure in vitro to crocidolite asbestos at various concentrations. DNA was then examined for formation of 8-hydroxydeoxyguanosine (8-OHdG) at 24, 48 and 72 h using HPLC with electrochemical detection. In addition, steady-state mRNA levels of manganese-containing superoxide dismutase (MnSOD) were assessed as an indication of oxidative stress. Whereas RPM cells showed dose-dependent and significant increases in 8-OHdG formation in response to crocidolite asbestos or iron-chelated crocidolite fibers (but not after exposure to glass beads), MET5A cells showed decreases in 8-OHdG. Both cell types exhibited elevations in message levels of MnSOD. In comparison with human MET5A cells, RPM cells exhibited increased cytotoxicity and apoptosis in response to asbestos, as documented by cell viability assays and flow cytometry analysis using propidium iodide. Results in RPM cells indicate that asbestos causes oxidative damage that may result in potentially mutagenic lesions in DNA and/or apoptosis, despite compensatory increases in expression of an antioxidant enzyme.
Carcinogenesis 1997 Apr
PMID:Patterns of 8-hydroxydeoxyguanosine formation in DNA and indications of oxidative stress in rat and human pleural mesothelial cells after exposure to crocidolite asbestos. 911 Dec 21

The DNA base-modified product 8-hydroxy-2'-deoxyguanosine (8-OHdG) is one of the most commonly used markers for the evaluation of oxidative DNA damage. A monoclonal antibody specific for 8-OHdG (N45.1) was characterized and applied in quantitative immunohistochemistry. N45.1 recognized both the modified base and deoxyribose structure of 8-OHdG and required a concentration two orders higher of 8-hydroxyguanosine as a competitor in the ELISA. In addition, N45.1 did not cross-react with the original four deoxyribonucleosides, other DNA base-modified products such as 8-hydroxy-2'-deoxyadenosine and O6-methyl-2'-deoxyguanosine, or urine components such as uric acid, creatine, and creatinine. A ferric nitrilotriacetate-induced rat renal carcinogenesis model was used for the evaluation of quantitative immunohistochemistry. The 8-OHdG index of quantitative immunohistochemistry, as analyzed by NIH image freeware, correlated reasonably well with the 8-OHdG amount determined by high-performance liquid chromatography with an electrochemical detector-except for a difference in peak time, which could be attributed to the selection of target location. The present method has advantages over the high-performance liquid chromatography/electrochemical detector, gas chromatography/mass spectrometry, and 32P-postlabeling methods in that it allows localization of 8-OHdG to be specified without the risk of artifactual production of 8-OHdG during the DNA extraction and hydrolytic processes.
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PMID:Quantitative immunohistochemical determination of 8-hydroxy-2'-deoxyguanosine by a monoclonal antibody N45.1: its application to ferric nitrilotriacetate-induced renal carcinogenesis model. 912 Nov 19

Deletions of loci on chromosomes 5q, 17p, 18q, and 22q, together with the incidence of p53 mutations and amplification of the double minute-2 gene were investigated in the sporadic colorectal tumors of 44 patients from a Spanish community. Chromosome deletions were analyzed by means of loss of heterozygosity analysis using a restriction fragment length polymorphism assay. Allelic losses were also detected by polymerase chain reaction (PCR)-single-stranded conformation polymorphism (SSCP) analysis of a polymorphic site in intron 2 of the p53 gene. The percentages of genetic deletions on the screened chromosomes were 39.3% (5q), 58.3% (17p), 40.9% (18q), and 40% (22q). Mutations in p53 exons 2-9 were examined by PCR-SSCP analysis and direct sequencing of the mutated region. Twenty of 44 tumor samples (45.45%) showed mutations at various exons except for exons 2, 3, and 9, the most frequent changes being G-->T transversion and C-->T transition. Because oxygen-free radicals play a role in the carcinogenesis process, we evaluated the oxidative status of the colorectal tumors. Antioxidant activities, lipid peroxidation, and DNA-damaged product concentrations in colon tumors and normal mucosa were compared. In tumor tissues, superoxide dismutase and catalase decreased fourfold and twofold, respectively, whereas glutathione peroxidase and reduced glutathione increased threefold. Malondialdehyde and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels were twofold higher in colorectal tumors than in normal mucosa. Seven of 10 DNA tumor samples (70%) showing higher values of 8-OHdG also had genetic alterations at different chromosomal loci. In these samples, the p53 gene was deleted or mutated in 71.4% of cases. We concluded that the observed changes in the oxidative metabolism of the tumor cells and the consecutive increase in DNA damage may potentiate the genomic instability of different chromosomal regions, leading to further cell malignancy and tumor expansion.
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PMID:Genetic alterations and oxidative metabolism in sporadic colorectal tumors from a Spanish community. 914 18

We have developed an experimental model of iron-induced oxidative nephrotoxicity and renal cancer. Using this model, the effect of vitamin E, a known antioxidant, was investigated. Three-week-old male Wistar rats were fed with vitamin E-sufficient (control) and vitamin E-supplemented diets throughout the experiment. After 1 month of feeding, iron-induced tissue lipid peroxidation, apoptosis, and formation of 8-hydroxydeoxyguanosine, a known DNA oxidative modification, were observed by cold Schiff staining, in situ labeling method (staining by terminal deoxynucleotidyl transferase-mediated nick end labeling), and high-performance liquid chromatography with electrochemical detection system, respectively, in the groups of rats treated with ferric nitrilotriacetate (Fe-NTA; Fe, 10 mg/kg body weight). For the vitamin E intervention study on Fe-NTA-induced renal carcinogenesis, two groups of rats fed vitamin E-sufficient and vitamin E-supplemented diets (30 and 20 rats, respectively) were treated with Fe-NTA (Fe, 7.5 mg/kg body weight once or twice a week) i.p. for 3 months and observed for 9 additional months. Five of the vitamin E-sufficient rats died during the first 3-month period. The results showed that vitamin E could inhibit tissue lipid peroxidation, apoptosis, 8-hydroxydeoxyguanosine formation, and the development of cancer [11 of 25 rats (44%) for vitamin E-sufficient versus 1 of 20 rats (5%) for vitamin E-supplemented rats, respectively]. These studies strongly suggest that in Fe-NTA-induced renal cancer, as with certain other types of cancer, oxidative stress plays an important role in carcinogenesis, and an antioxidant is an effective chemopreventive measure.
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PMID:Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney. 919 18


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