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

Hydrazine sulfate is a genotoxic hepatocarcinogen for the hamster. A study was conducted to follow changes in DNA maintenance methylation in selected genes in liver DNA during the 21-month induction of liver adenomas and hepatocellular carcinomas by demonstrating changes in restriction fragment length polymorphism. Male Syrian golden hamsters were exposed to hydrazine sulfate in the drinking water at three concentrations (170, 340 and 510 mg/l) shown previously to result in a dose-dependent induction of liver tumors. Liver DNA from animals exposed to the high concentration for 6, 12, 16, 20 and 21 months and animals exposed to the low or mid concentration for 21 months was digested with EcoRI, MspI, HindIII or BamHI, or a combination of one of these endonucleases and a methyl-sensitive restriction enzyme, HpaII or HhaI. The DNA digests were subjected to Southern analysis using a c-DNA probe for one of the following genes: DNA methyltransferase (DMT), c-Ha-ras, c-jun, c-fos, and c-myc proto-oncogenes, p53 tumor suppressor gene or gamma-glutamyltranspeptidase. Alteration in DNA restriction by methyl-sensitive endonucleases was detected in four (DMT, c-Ha-ras, p53 and c-jun) of the seven genes examined and as early as 6 months in animals exposed to the highest concentration of hydrazine sulfate; alteration of recognition sites in c-Ha-ras was also detected in DNA from animals exposed for 21 months to the intermediate concentration of hydrazine sulfate. Early changes in recognition sites, presumed to indicate altered methylation status of DNA cytosine and/or guanine mutations, were seen using c-DNA probes for DMT, c-Ha-ras and c-jun; in the p53 tumor suppressor gene alteration of such sites was a late event relevant to appearance of liver adenomas and hepatocellular carcinomas. Evidence for hypomethylation in the p53 and c-jun genes and hypermethylation of the c-Ha-ras and DMT genes is provided. This study supports the induction of site-specific hypomethylation and hypermethylation during the course of hydrazine carcinogenesis.
Carcinogenesis 1996 Dec
PMID:Changes in methyl-sensitive restriction sites of liver DNA from hamsters chronically exposed to hydrazine sulfate. 900 10

To evaluate the anti-cancer effects of folic acid at the molecular level, we determined plasma folic acid concentration by radioimmuno-assay and the degree of total genomic DNA methylation by incubating DNA with 3H-S-adenosylmethionine (3H-SAM) in the presence of a methylase, and analyzed the methylation status of the c-myc and c-Ha-ras oncogenes by Southern blotting in 21 patients with advanced gastric cancer. The degree of total genomic DNA methylation of cancerous tissues was significantly lower than that of paracancerous and non-cancerous tissues; c-myc and c-Ha-ras oncogenes from cancerous (10/21, 5/10) and paracancerous (13/21, 4/10) tissues were hypomethylated. The plasma folic acid concentration in patients who showed hypomethylation was lower than that patients showing normal methylation. These findings suggest that a decrease in folic acid, and the subsequent DNA hypomethylation, may be involved in human gastric carcinogenesis.
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PMID:Relationship of plasma folic acid and status of DNA methylation in human gastric cancer. 908 63

In order to study the role of DNA damage processing in the development of cutaneous squamous cell carcinoma (SCC), we assessed the ability of six keratinocyte cell lines from a multistage-tumor progression model to repair three types of DNA damage: pyrimidine dimers, oxidative DNA lesions and DNA double strand breaks (DSB). The model comprised the spontaneously immortalized, non-tumorigenic human keratinocyte cell line HaCaT, four different c-Ha-ras transfectants of HaCaT (non-, benign- and two malignant-tumorigenic) and a SCC-derived cell line. Host cell reactivation assays with UVB-treated plasmid vectors pRSVcat showed no significantly altered repair of UVB-induced pyrimidine dimers in the tumorigenic cell lines, compared with the non-tumorigenic lines. Using the singlet oxygen-treated plasmids pRSVcat the Ha-ras-HaCaT-clones and the SCC-cells, exerted a DNA repair efficiency that was not significantly different from HaCaT cells. In order to assess the ability of the cells to ligate free DNA ends (repair of DSB), we used a plasmid shuttle vector assay with linearized plasmid pZ189. We found a significant increase of DNA end joining ability in the non-tumorigenic, the benign and in one of the malignant HaCaT-clones II-4. The malignant HaCaT-clone II-3, however, exerted a significantly lower rate of rejoining the linearized plasmid. This cell line also showed a highly and significantly elevated rate of micronuclei, which reflects a pronounced chromosomal instability. The SCC-cells exhibited a more efficient repair of DNA DSB than the HaCaT cells. We conclude that in the examined model, progression of human keratinocytes from the non-tumorigenic to the highly tumorigenic phenotype, is not accompanied by a decrease in the cell's capacity to repair UVB- and singlet oxygen-induced DNA lesions. However, an acquired deficiency in repairing DNA double strand breaks can be one mechanism promoting progression towards malignancy, possibly through impairing chromosomal stability.
Carcinogenesis 1997 Apr
PMID:Processing of three different types of DNA damage in cell lines of a cutaneous squamous cell carcinoma progression model. 911 Nov 96

Two hair dye components, carcinogenic 4-nitro-2-aminophenol and 5-nitro-2-aminophenol, induced Cu(II)-dependent DNA cleavage frequently at thymine and guanine residues in DNA fragments obtained from the c-Ha-ras-1 protooncogene. When the p53 tumor suppressor gene was used, 4-nitro-2-aminophenol caused Cu(II)-dependent piperidine-labile sites at poly G sequences. In the presence of Cu(II), both components increased 8-oxo-7,8-dihydro-2'-deoxyguanosine formation in DNA. The inhibitory effects of catalase and bathocuproine on DNA damage suggest the involvement of H2O2 and Cu(I). It is speculated that nitro-2-aminophenols undergo Cu(II)-mediated autoxidation to generate active oxygen species causing DNA damage which leads to their carcinogenesis.
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PMID:Metal-mediated oxidative DNA damage induced by nitro-2-aminophenols. 956 50

Ornithine decarboxylase (ODC) is aberrantly regulated in tumor cells and results in high basal levels of ODC and polyamines in many epithelial tumors. To determine if elevated ODC/polyamine levels can co-operate with a mutant Ha-ras gene in mouse skin tumorigenesis, double transgenic mice were generated by breeding K6/ODC transgenic mice with TG.AC v-Ha-ras transgenic mice. A K6 keratin promoter drives the ODC transgene in K6/ ODC transgenic mice, which results in elevated ODC/ polyamine levels directed to the outer root sheath cells of hair follicles. TG.AC transgenic mice carry a v-Ha-ras transgene while still retaining two normal c-Ha-ras alleles. Transgenic mice that possess only the K6/ODC or the v-Ha-ras transgene did not develop tumors unless treated with either a carcinogen or a tumor promoter, respectively. However, a high percentage of double transgenic mice possessing both the K6/ODC and v-Ha-ras transgenes developed spontaneous tumors. All tumors were well-differentiated keratoacanthomas, some of which progressed to carcinomas within 2 months. The development and the maintenance of these ODC/ras tumors was ODC-dependent since alpha-difluoromethylornithine (DFMO), a specific ODC inhibitor, prevented the formation and caused the regression of these tumors. These findings indicate that ODC overexpression and an activated Ha-ras are sufficient to produce a high rate of malignant transformation in an animal model. The ODC/ras double transgenic mouse provides a simple in vivo model without the use of chemical carcinogens or tumor promoters in which to test downstream effectors that play a key role in mediating the development of epithelial tumors resulting from the cooperation between ODC and v-Ha-ras.
Carcinogenesis 1998 Aug
PMID:Co-operation between follicular ornithine decarboxylase and v-Ha-ras induces spontaneous papillomas and malignant conversion in transgenic skin. 974 37

To clarify the mechanism of carcinogenesis by hair dyes, we compared the extent of DNA damage induced by mutagenic m-phenylenediamine and 4-methoxy-m-phenylenediamine, using 32P-5'-end-labeled DNA fragments obtained from the human c-Ha-ras-1 protooncogene and the p53 tumor suppressor gene. Carcinogenic 4-methoxy-m-phenylenediamine caused DNA damage at thymine and cytosine residues in the presence of Cu(II). Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited 4-methoxy-m-phenylenediamine-induced DNA damage, suggesting the involvement of H2O2 and Cu(I). Superoxide dismutase (SOD) enhanced the DNA damage. Formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) was induced by 4-methoxy-m-phenylenediamine in the presence of Cu(II). UV-visible spectroscopic studies have shown that Cu(II) mediated autoxidation of 4-methoxy-m-phenylenediamine and SOD accelerated the autoxidation. On the other hand, non-carcinogenic m-phenylenediamine did not cause clear DNA damage and significant autoxidation even in the presence of Cu(II). These results suggest that carcinogenicity of m-phenylenediamines is associated with ability to cause oxidative DNA damage rather than bacterial mutagenicity.
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PMID:DNA damage induced by m-phenylenediamine and its derivative in the presence of copper ion. 980 51

The induction of tumor angiogenesis is mediated in particular by an increased production of VEGF. As ras oncogene is implicated in tumorigenesis, the inhibition of farnesyl transferase activity has recently been developed. The purpose of this study was to evaluate whether expression of mutated Ha-ras oncogene is associated with an altered expression of VEGF in an in vitro model of human skin carcinogenesis and to appreciate the effect of a new farnesyl transferase inhibitor on this VEGF expression. The amounts of VEGF secreted by an HaCaT cell line and two cell clones (metastatic or not) obtained after mutated c-Ha-ras transfection were compared. Our findings showed that the release of VEGF is greater for HaCaT-ras than for HaCaT cells and could be down-regulated using a protein farnesyl transferase inhibitor, in a reversible and dose-dependent manner. These results confirm that the Ha-ras oncogene can contribute to tumor development and progression of epidermal tumors through neoangiogenesis and that farnesyl transferase inhibitors as anticancer drugs may be efficient for the reduction of skin tumor growth.
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PMID:The up-regulation of vascular endothelial growth factor in mutated Ha-ras HaCaT cell lines is reduced by a farnesyl transferase inhibitor. 1022 98

ortho-Phenylphenol (OPP) and its sodium salt, which are used as fungicides and antibacterial agents, have been found to cause carcinomas in the urinary tract of rats. To clarify the carcinogenic mechanism of OPP, we compared the DNA damage inducing ability of an OPP metabolite, phenyl-1,4-benzoquinone (PBQ) with that of another metabolite, phenylhydroquinone (PHQ). Pulsed field gel electrophoresis showed that PBQ and PHQ induced DNA strand breakage in cultured human cells, but PBQ did it more efficiently than PHQ. Significant increases in 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) were observed in cells treated with PBQ and PHQ, and the increase of 8-oxodG induced by PBQ was significantly higher than that induced by PHQ. Using 32P-5'-end-labeled DNA fragments obtained from human p53 tumor suppressor gene and c-Ha-ras-1 protooncogene, we showed that PBQ plus NADH, and also PHQ, induced DNA damage frequently at thymine residues, in the presence of Cu(II). The intensity of DNA damage by PBQ was stronger than that by PHQ, showing higher importance of PBQ than other OPP metabolites. Catalase and bathocuproine inhibited Cu(II)-mediated DNA damage by PBQ plus NADH and PHQ, suggesting that H2O2 reacts with Cu(I) to produce active species causing DNA damage. Electron spin resonance and UV-visible spectroscopic studies have demonstrated generation of semiquinone radical and superoxide from the reaction of PBQ with NADH or the Cu(II)-mediated autoxidation of PHQ. The present results suggest that these OPP metabolites cause oxidative DNA damage through H2O2 generation in cells, and the damage may lead to mutation and carcinogenesis. It is concluded that PBQ may play a more important role in the expression of OPP carcinogenicity than other OPP metabolites.
Carcinogenesis 1999 May
PMID:Oxidative damage to cellular and isolated DNA by metabolites of a fungicide ortho-phenylphenol. 1033 3

Although N-acetylcysteine is an antioxidant which has been expected to be a cancer chemopreventive agent, its safety and risk assessment have not been evaluated. N-acetylcysteine increased the amount of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a characteristic oxidative DNA lesion, in human leukemia cell line HL-60, whereas the amount of 8-oxodG in HP100, which is a hydrogen peroxide (H(2)O(2))-resistant cell line derived from HL-60, was not increased. To clarify the mechanism of cellular DNA damage, we investigated DNA damage and its site specificity induced by N-acetylcysteine, using (32)P-labeled DNA fragments obtained from the human p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. N-acetylcysteine induced extensive DNA damage in the presence of Cu(II). The DNA cleavage was enhanced by piperidine treatment, suggesting that N-acetylcysteine plus Cu(II) caused not only deoxyribose phosphate backbone breakage but also base modification. N-acetylcysteine plus Cu(II) frequently modified thymine and guanine residues. Bathocuproine, a specific Cu(I) chelator, and catalase inhibited the DNA damage, indicating the participation of Cu(I) and H(2)O(2) in the DNA damage. Typical hydroxyl radical scavengers did not inhibit N-acetylcysteine plus Cu(II)-induced DNA damage, whereas methional completely inhibited it. These results suggest that reactive species derived from the reaction of H(2)O(2) with Cu(I) participates in N-acetylcysteine plus Cu(II)-induced DNA damage. The content of 8-oxodG in calf thymus DNA was increased by N-acetylcysteine in the presence of Cu(II). The present study has demonstrated that N-acetylcysteine could induce metal-dependent H(2)O(2) generation and, subsequently, damage to cellular and isolated DNA. Therefore, it is reasonable to consider that N-acetylcysteine may have the dual function of carcinogenic and anti-carcinogenic potentials. This work requires further studies on safety and risk assessment of N-acetylcysteine.
Carcinogenesis 1999 Aug
PMID:N-acetylcysteine, a cancer chemopreventive agent, causes oxidative damage to cellular and isolated DNA. 1042 96

Female CD-1 mice were treated topically with a low (25-50 nmol) or high (800 nmol) dose of benzo[a]pyrene (BP) or acetone vehicle, followed by 5 nmol 12-O-tetradecanoylphorbol 13-acetate (TPA) twice a week for 26 weeks. Selective UV radiation fractionation followed by PCR methods were used to analyze histologically defined subsets of cells (approximately 100-200 cells) on formalin-fixed, paraffin-embedded and H&E stained microscope sections. DNA samples from normal-appearing, hyperplastic or tumor regions from the skin of animals from each treatment group were isolated and amplified by PCR with c-Ha-ras-specific primers. Single-strand conformation polymorphism (SSCP) analyses were performed on both exon 1 and 2 products from each sample. DNA extracted from each aberrant band of SSCP analyses was amplified by PCR for further sequence analysis. The data indicate that c-Ha-ras mutations can be detected in normal-looking and hyperplastic epidermal cells as well as in tumor cells obtained from mice initiated with BP and promoted with TPA. The frequencies of c-Ha-ras mutations for normal-looking, hyperplastic and tumor samples were 3/20 (15%), 8/17 (47%) and 58/68 (85%), respectively, for the low dose group and 8/18 (44%), 10/20 (50%) and 64/86 (74%), respectively, for the high dose group. These observations indicate that there were no dose dependencies in the mutation frequencies for normal-looking, hyperplastic and tumor samples. For combined high dose and low dose samples, differences in mutation frequencies of the c-Ha-ras gene between the normal-looking, hyperplastic and tumor samples were highly significant (P < 0.0001, Fisher's exact test). All mutations detected were located at codons 12, 13 and 61 of the c-Ha-ras gene. With the numbers in parentheses indicating the nucleotide position in the coding sequence of the c-Ha-ras proto-oncogene, the distributions of mutations for G-->A (35), G-->T (35), G-->C (37), G-->T (38), C-->A (181), A-->T (182) and A-->G (182) in the low dose tumors were 5, 2, 11, 74, 0, 7 and 2%, respectively, and the distribution of mutations in tumors from animals treated with a high dose of BP were 3, 7, 13, 61, 15, 1 and 0%, respectively. Differences in the global mutation spectra (site and kind of all mutations) for the c-Ha-ras gene between the high and low dose group tumors were statistically significant (P < 0.004, Fisher's exact test) and the major difference between these two groups was C-->A (181) base substitutions. In summary, our data indicate that: (i) 79% of the BP/TPA skin tumors in CD-1 mice had c-Ha-ras mutations for the combined data for high dose and low dose tumors; (ii) the major mutations detected in BP/TPA skin tumors were G-->T transversions; (iii) the global mutation profile in the c-Ha-ras proto-oncogene in skin tumors obtained after initiation with a low dose of BP was different from that obtained after initiation with a high dose of BP.
Carcinogenesis 1999 Sep
PMID:Dose-dependent mutation profile in the c-Ha-ras proto-oncogene of skin tumors in mice initiated with benzo[a]pyrene. 1046 12


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