Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The genetic toxicity profiles of vinyl chloride (VCl), vinyl bromide (VBr), ethyl carbamate (EC), vinyl carbamate (VC) and some structurally related chemicals were investigated in both somatic and germ cells of Drosophila melanogaster. In the white/white+ eye mosaic assay, a screening system measuring predominantly homologous recombination in somatic cells, only marginal genotoxic activities were observed for acetyl chloride (ACl), glycolaldehyde (GCA), 2,2'-dichlorodiethyl ether (DDE) and methyl carbamate (MC), whereas VCl, 2-chloroacetaldehyde (CAA), VBr, 2-bromoacetaldehyde (BAA) and EC were clearly recombinogenic in the assay. Those chemicals proven to be recombinogenic in somatic cells were investigated further in postmeiotic male germ cells, utilizing as descriptors of their genotoxicity I(CL/RL) and M(exr-)/M(exr+) indices. The I(CL/RL) index is the rate of induced chromosome loss (CL), a clastogenic event, divided by the forward mutation rate, measured as recessive lethal (RL) mutations in 700 loci of the X-chromosome. The M(exr-)/M(exr+) mutation enhancement ratio is obtained by determining RL under excision repair deficient versus repair proficient conditions. With I(CL/RL) values (2.7-6.9) similar to those obtained for cross-linking agents, vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate are all efficient clastogenic agents in Drosophila germ cells. In the absence of excision repair, however, neither CEO nor CAA gave a hypermutability response (M(exr-)/M(exr+) approximately 1). By contrast, VCl, VBr, EC and VC showed clearly enhanced M(exr-)/M(exr+) ratios, suggesting that these compounds produce some repairable DNA modification(s) that are not generated by their epoxides. This unexpected finding points to the formation of other, yet unknown, metabolites of vinyl chloride, vinyl bromide, ethyl carbamate and vinyl carbamate. Our results support the concept that the epoxides chloroethylene oxide (CEO), bromoethylene oxide (BEO) and vinyl carbamate epoxide (VCO) are the most essential mutagenic intermediates. Compared to chloroethylene oxide (CEO), 2-chloroacetaldehyde (CAA) was approximately 50 times less effective in the induction of RL, whereas BAA was inactive as a mutagen. These findings are consistent with the general view that CAA and BAA play no major role in the genotoxic action of vinyl halides.
Carcinogenesis 1996 May
PMID:Characterization by two-endpoint comparisons of the genetic toxicity profiles of vinyl chloride and related etheno-adduct forming carcinogens in Drosophila. 864 Sep 17

3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) is a mutagen/carcinogen derived from cooked foods which enhances the induction of mutations and chromosome aberrations by UV without microsomal activation. These co-mutagenic effects are considered to arise from inhibition of DNA excision repair at the incision step. However, the inhibition mechanism has not been clarified. In this study we show, using agarose gel electrophoresis, that Trp-P-1 inhibits incision by T4 endonuclease V, which cleaves DNA at the site of cyclobutane dimers. Trp-P-1 also inhibits the binding of this enzyme to UV-damaged DNA in a gel shift assay. In addition, the results of DNA unwinding assay with topoisomerase I suggest that Trp-P-1 intercalates into DNA molecules. The known intercalators ethidium bromide and acriflavine demonstrate similar effects in these experiments. However, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), which showed no co-mutagenic effects in our previous study, does not demonstrate such effects. These results suggest that Trp-P-1 changes DNA conformation by intercalation, causing inhibition of binding of repair enzymes to UV-damaged DNA, and this in turn leads to inhibition of DNA excision repair and to co-mutagenic effects.
Carcinogenesis 1996 Jun
PMID:3-Amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) inhibits the binding activity of T4 endonuclease V to UV-damaged DNA. 868 43

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

A mass spectrometric procedure is described for the structural study of the adducts formed in human hemoglobin by in vitro exposure of erythrocytes to the alkylating agent methyl bromide using different protein to reagent ratios. Peptide mapping by HPLC and tandem mass spectrometry allowed location of methylated amino acids within the protein sequence. A prominent reactivity of several nucleophilic side chains in human hemoglobin subunits was observed, which was modulated by the concentration of the alkylating agent. Cysteine residues, the main reactive sites, were fully methylated in hemoglobin exposed to a 10-fold excess of methyl bromide, differently from other residues, including histidines, showing a heterogeneous pattern of methylation that was largely directed by their environment. No evidence of methylation was found at the heme proximal histidines beta92 and alpha87. A more selective methylation was obtained when the ratio methyl bromide: hemoglobin was lowered to about 1:1. In this last case only specific residues were reactive. Among them, the N-terminal amino group of both alpha- and beta-globins, cysteine 104 in the alpha-chain and cysteine 93 (not cysteine 112) in the beta-chain, indicating a different accessibility to reaction of the sulfhydryl groups on the protein chain. Thus hemoglobin side chains are selectively modified and the degree of modification at each site is a function of the position of the single amino acid residue within the protein quaternary structure, raising the possibility that alterations of structure and functional properties of human hemoglobin following exposure to alkylating agents may be mediated through such covalent protein modifications. The results obtained demonstrate the usefulness of the analytical approach for the characterization of hemoglobin adducts with methyl bromide or similar compounds, which can constitute the basis for biomonitoring of human exposure.
Carcinogenesis 1996 Dec
PMID:Structural characterization by mass spectrometry of hemoglobin adducts formed after in vivo exposure to methyl bromide. 900 4

To elucidate the association of human papillomavirus (HPV) and Epstein-Barr virus (EBV) with carcinogenesis of the esophagus, 41 surgically resected specimens and 12 cell lines of esophageal squamous cell carcinoma were examined for the presence of HPV DNA and EBV DNA by polymerase chain reaction using primers for the E6 regions of HPV-16 and -18 and for the EBNA 1 region of EBV. We designed the reaction condition to amplify HPV and EBV DNA specifically and detected by gel electrophoresis. In ethidium bromide staining, no band was detected either for the HPV E6 region of for the EBV EBNA 1 gene in any of the surgically resected specimens and the cell lines, although the HPV sequence was detectable by Southern blot hybridization, which is a more sensitive detection method than staining; three out of 41 surgically resected specimens were positive for HPV-18 by Southern blot hybridization of polymerase chain reaction products. However, the number of viral genomes has been estimated as lower than 1 x 10(-3) copies per cell based on the intensity of the hybridization signals. Moreover, the DNA samples extracted from the corresponding non-cancerous esophageal mucosa were also positive for HPV-18, and the intensities of the hybridization signals were almost the same as those of the tumors. The results of our study indicate that HPV-16, HPV-18 and EBV are not generally associated with esophageal carcinogenesis.
 ...
PMID:Absence of human papillomavirus-16 and -18 DNA and Epstein-Barr virus DNA in esophageal squamous cell carcinoma. 907 Mar 32

Colonization of Helicobacter pylori (Hp) to gastric mucosa plays an important role for the pathogenesis of gastric mucosal lesions. We previously reported the importance of monochloramine (NH2Cl), which was derived from the interaction between Hp-urease and infiltrated leukocytes, in the course of Hp-associated gastric mucosal injury. While the long-term infection of Hp in the gastric mucosa is known to be one of the virulent factors which closely link to the gastric carcinogenesis, the details of its pathogenetic mechanisms remain speculative. The present study is designed to examine whether a NH2Cl could damage the DNA of gastric cells. Rabbit gastric mucosal cells (RGMC) or KATO III cells were cultured and suspended. Cell suspensions were exposed to HOCl, NH3 or NH2Cl for 15 min to give a final concentration of 0.1 mM. The magnitude of a double strand break of DNA was quantified by measuring the remnant double strand stained by ethidium bromide (EB), and the fluorescence intensity of EB was analyzed by spectrophotometer. Separately, cell nuclei were stained by fluorescent dye (Hoechst No. 33258) in order to evaluate the levels of chromatin condensation evoked by DNA fragmentation. The number of cells with chromatin condensation was counted. During the entire experimental period, more than 85% of cells were persistently viable in all groups. NH2Cl significantly induced the DNA double strand break as well as chromatin condensation in RGMC and KATO III cells (P < 0.05). However, NH3 or HOCl did not induce the DNA double strand break as well as chromatin condensation in both cells. NH2Cl, but not its precursors (NH3 or HOCl), enhanced the levels of DNA injury, suggesting the possible involvement in the carcinogenesis of Hp-associated gastric mucosa.
 ...
PMID:Extensive DNA damage induced by monochloramine in gastric cells. 914 31

Genomic instability resulting in multiple mutations is believed to be a driving force in the carcinogenic process. In this study, the random amplified polymorphic DNA (RAPD) technique, a simple PCR-based DNA polymorphism assay system, was used for detecting genomic instability in lung cancer tissues. DNAs from 20 lung cancer (18 non-small cell lung cancers and two small cell lung cancers) and their corresponding normal tissues were amplified individually by RAPD with seven different 10-base arbitrary primers. PCR products from RAPD were electrophoretically separated in agarose gels and banding profiles were visualized by ethidium bromide staining. The ability to detect genomic instability in 20 cancer tissues by each single primer ranged from 15 to 75%. DNA changes were detected by at least one primer in 19 (95%) cancer tissues. These results seem to indicate that genomic rearrangement is associated with lung carcinogenesis and that RAPD analysis is useful for the detection of genomic instability in lung cancer tissues.
Carcinogenesis 1998 Jan
PMID:Detection of genomic instability in lung cancer tissues by random amplified polymorphic DNA analysis. 947 18

To determine if ovarian cancer patients would be suitable for MAGE-peptide vaccine-based immunotherapy, the frequency of expression of the MAGE-1-4 genes in ovarian tumours was assessed using reverse transcription polymerase chain reaction (RT-PCR) and product verification with digoxigenin-labelled oligonucleotide probes specific for each MAGE gene. In addition, the frequency of expression of more recently discovered tumour antigens (BAGE, GAGE -1, -2 and GAGE -3, -6) was established using RT-PCR and ethidium bromide staining. In this study 1/16 normal ovarian tissue specimens and 11/25 benign lesions expressed MAGE-1. In non-malignant tissue there was preferential expression of MAGE-1 in premenopausal women. A total of 15/27 malignant specimens expressed MAGE-1, including 10/14 serous cystadenocarcinomas. Expression of other tumour antigens was infrequent. The finding of MAGE-1 expression in both benign and malignant tissue questions previous assumptions regarding the role of MAGE genes in carcinogenesis. In addition, preferential MAGE-1 gene expression in non-malignant premenopausal tissue suggests that the MAGE genes may be involved in cellular proliferation as opposed to carcinogenesis or possibly that MAGE gene expression is under cyclical hormonal control. Finally, this study indicates that serous cystadenocarcinomas may be suitable tumours for MAGE-1 peptide immunotherapy.
 ...
PMID:MAGE, BAGE and GAGE: tumour antigen expression in benign and malignant ovarian tissue. 974 7

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is a synthetic dithiolethione with chemopreventive activity against carcinogen-induced neoplasia of liver, lung, and colon in several animal model systems. Protection from tumor formation is associated with elevation of Phase II enzymes, including glutathione (GSH) transferase and NAD(P)H:quinone oxidoreductase (DT-diaphorase) in experimental carcinogenesis models in vivo. To investigate the time and dose relationships of the pharmacological action of oltipraz and to develop a model for its investigation, a human colon adenocarcinoma HT29 cell line was primarily used. In this cell line, oltipraz resulted in increased activity of both GSH transferase and DT-diaphorase. At the maximum effective concentration (100 microM), the elevation of GSH transferase was 3-fold and that of DT-diaphorase was 2-fold. The optimal duration of oltipraz exposure to HT29 cells was 24 h, following which the peak in enzyme activity was observed at 24 h after removal of the drug, and activity had almost returned to control levels after 72 h in drug-free media. Steady-state mRNA levels for DT-diaphorase were observed to increase during the period of drug exposure and remained elevated, even as catalytic activities declined to control levels, suggesting additional mechanisms for control of the activity of this enzyme. More prolonged drug exposure was associated with less induction of the detoxication enzymes, prompting an investigation of the possible toxicity of oltipraz to these cells. Although the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed inhibition of proliferation (IC50, 100 microM oltipraz), a clonogenic assay demonstrated no loss of clonogenicity. Oltipraz is known to be extensively metabolized in many species; two major metabolites include a 3-ketone (metabolite 2, M2) and a molecular rearrangement to a pyrrolopyrazine derivative (metabolite 3, M3), numerous conjugates of which are formed in vivo. To investigate the potential cause of the lag in response, we synthesized two major oltipraz metabolites (M2 and M3) and tested their efficacy in enzyme induction. The activity of DT-diaphorase was induced similarly by both oltipraz and M2 (2.6- versus 2.8-fold baseline) at 100 microM, whereas M3 was inactive at all concentrations. M2 also resulted in a 5.8-fold elevation of steady-state DT-diaphorase mRNA levels. Both enzyme activity and steady-state mRNA peaked at 24 h as with the parent compound. Thus, the oxidative desulfuration of oltipraz results in the formation of an active metabolite, but this process is not rate limiting for the induction of detoxicating enzymes. These data support the use of intermittent schedules in oltipraz in clinical trials of chemoprevention because of evidence of attenuation of response. The metabolite M2, but not M3, is as active as the parent compound and may be considered for clinical development in its own right.
 ...
PMID:Cellular kinetics of induction by oltipraz and its keto derivative of detoxication enzymes in human colon adenocarcinoma cells. 981 50

Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) has been used to rapidly profile the protein content of human cell lysates from MCF-10 cell and variant lines. The method was used to study the protein profiles of these cells as they progressed from normal breast epithelium to fully malignant cells. Distinct differences in the protein profiles were observed with progression, and specific proteins associated with carcinogenesis (p53, c-myc, and c-erbB-2) were heavily expressed in these cells as detected by MALDI-TOFMS. These proteins were also isolated using non-porous reversed-phase high performance liquid chromatography (NP-RP-HPLC) and mass analyzed by MALDI-TOFMS to provide molecular weight information without interference from other proteins in the whole cell lysates, and to avoid suppression effects in mixtures of proteins detected by MALDI-TOFMS. In order to confirm the identity of these oncoproteins, the cell lysates were subjected to one-dimensional (1-D) gel separation and subsequently electroblotted onto a poly(vinylidene difluoride) (PVDF) membrane for further analysis. Trypsin and cyanogen bromide digestions were performed on these proteins eluted from excised PVDF bands which were then analyzed by MALDI-TOFMS. The identity of these proteins was confirmed by database matching procedures.
 ...
PMID:Protein profiles and identification of high performance liquid chromatography isolated proteins of cancer cell lines using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. 1003 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>