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

The time of susceptibility of cells to lymphotoxin during carcinogenesis was determined. At different stages of in vitro chemical carcinogen-induced neoplastic transformation, colony formation of guinea pig cells was evaluated with lymphotoxin obtained from syngeneic nonimmune leukocytes. Cells exhibiting sequential morphological alteration, morphological transformation, and neoplastic transformation had been preserved in liquid nitrogen and, after reintroduction in culture, were analyzed simultaneously for their susceptibility to lymphotoxin. Morphologically altered and morphologically transformed cells at subcultures prior to neoplastic transformation were resistant to lymphotoxin inhibition of colony formation. Cells neoplastically transformed by N-methyl-N'-nitro-N-nitrosoguanidine in vitro or by N-methyl-N'-nitro-N-nitrosoguanidine or diethylnitrosamine with the host-mediated, in vivo-in vitro method were susceptible and exhibited a quantitatively culture-specific degree of colony inhibition. The parental noncloned and cloned neoplastically transformed cells in each series, furthermore, exhibited similar degrees of colony inhibition, which indicates that lymphotoxin susceptibility developed concomitant with, or close to, the time of neoplastic transformation and remained stable during subsequent cell generations.
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PMID:The susceptibility of guinea pig cells to the colony-inhibitory activity of lymphotoxin during carcinogenesis. 30 42

Benz[c]acridine and its 10 methyl-substituted derivatives were examined for chemical reactivity with osmium tetroxide and mutagenic activity on Salmonella typhimurium, and the results were contrasted with the electronic charge in the K region and the carcinogenic activity of benz[c]acridines. The addition of osmium tetroxide took place at the K region of benz[c]acridines. A linear relationship was established between the charge in the K region and the rate constant of the second-order reaction between osmium tetroxide and benz[c]acridines except the 5,7-dimethyl derivative whose substituent in the 5-position sterically hindered the reaction. Benz[c]acridines showed mutagenic activity in the presence of S-9 Mix, but not in the absence of S-9 Mix. There was a corresponding relationship among the K-region reactivity, mutagenic activity, and carcinogenic activity in benz[c]acridines. The only exception for this was the 7,11-dimethyl derivative in which the 11-methyl group had a steric effect on the ring-nitrogen atom. It was suggested that a common mechanism with regard to the reactivity of the K region is working in both carcinogenesis and mutagenesis. It was concluded that benz[c]acridines are activated, before they display a carcinogenic or mutagenic activity, to a proximate form such as 5,6-epoxides, through a metabolic process in which the nucleophilic property of the K region to react with electrophilic reagents plays an important role.
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PMID:Relationship of carcinogenicity, mutagenicity, and K-region reactivity in benz[c]acridines. 53 85

Fiber is not digested by endogenous enzymes but is fermented by microbes principally in the large intestine. With fermentable energy available, microbes synthesize protein by using ammonia released by their enzymes from urea and other nitrogenous substances in ingesta and intestinal secretions. Fibber fermentation also yields fatty acids that lower the concentration of free ammonia by lowering pH. Fiber increases bulk and water of intestinal contents, shortens transit time, and decreases the concentration of toxic substances in contact with the intestinal mucosa. These processes decrease duration and intensity of exposure of the intestinal mucosa to free ammonia, the form of nitrogen that is most toxic and most readily absorbed by cells. At concentrations found in the lower bowel on usual Western diets, ammonia destroys cells, alters nucleic acid synthesis, increases intestinal mucosal cell mass, increases virus infections, favors growth of cancerous cells over noncancerous cells in tissue culture, and increases virus infections. Ammonia in the bowel increases as protein intake increases. The attributes of ammonia and the epidemiological evidence comparing populations that maintain low intakes of unrefined carbohydrate with those that consume high intakes of protein, fat, and refined carbohydrates implicate ammonia in carcinogenesis and other disease processes.
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PMID:Diet and cell growth modulation by ammonia. 70 76

1. The cancerogenic pollution by non-ionizing radiations is limited to the case of solar ultraviolet, whose activity at ground level may be increased as a consequence of the stratospheric depletion of ozone, itself produced by certain chemical pollutants: nitrogen oxydes from supersonic aircrafts, freon. 2. As regards ionizing radiations, the discussion is focused on the fundamental problem of the "threshold", aand on the means by which one may obtain some quantitative data related to carcinogenesis by small radiation doses in Man. A new concept, that of a "practical threshold" is proposed. 3. One discusses a theory which links radiocancerogenesis, as well as chemical cancerogenesis, to errors produced in the repair of lesions in the DNA. 4. One presents and discusses the "rads-equivalent" project for chemical mutagens and cancerogens.
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PMID:[Carcinogenic risks associated with radiation pollution]. 79 77

The mechanism of mammary carcinogenesis by N-hydroxy-2-FBS, a highly potent mammary carcinogen for the female rat by ip administration, has been investigated. Previous work in vivo indicating hydrolytic cleavage of the nitrogen-sulfur bond has been confirmed with the use of sonicates of mammary gland. One of the products of the hydrolysis was N-hydroxy-2-FA identified by its conversion to 2-FA. Since carcinogenicity tests by local application showed that N-hydroxy-2-FA was not carcinogenic for the mammary gland, desulfonylation of N-hydroxy-2-FBS by mammary gland does not account for mammary carcinogenesis. N-Hydroxy-2-FBS applied directly to the mammary gland was not carcinogenic and 2-nitrosofluorene, the product of the spontaneous decomposition of N-hydroxy-2-FBS, exhibited only weak carcinogenicity upon local application. In contrast, N-hydroxy-2-FAA, a urinary metabolite of N-hydroxy-2-FBS, was highly carcinogenic by local application and very likely mediates the action of N-hydroxy-2-FBS. A metabolic pathway for the conversion of N-hydroxy-2-FBS to N-hydroxy-2-FAA is presented. This pathway involves the intermediate formation, by mammary gland or liver, of N-hydroxy-2-FA. The site of the subsequent acetylation of the hydroxylamine is unknown at present although the mammary gland appears to be excluded.
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PMID:N-hydroxy-2-fluorenylacetamide, an active intermediate of the mammary carcinogen N-hydroxy-2-fluorenylbenzenesulfonamide. 118 17

In an effort to evaluate the possible correlation of the transforming ability of the known colon carcinogens dimethylhydrazine, 3-2'-dimethyl-4-aminobiphenyl, and methylazoxymethanolacetate to damage and repair of DNA, a series of compounds known to react with DNA-nitrogen mustard, methylmethanesulfonate, and mitomycin C--were administered to rats that had been prelabeled with 3H-thymidine. The DNA of crypt and villus of the jejunum and crypt and surface cells of the large bowel were analyzed by ultracentrifugation on an alkaline sucrose gradient. All fractions suffered degradation to such an extent that essentially no undamaged DNA was detectable. This was followed by repair and an increase in size. However, in the surface cells of the colon of animals that had received a carcinogenic insult there was far less rapid repair. Since this is the site where tumors would ultimately arise these data are supportive of the hypothesis that there is a relationship between decreased repair and carcinogenicity. In view of the age related incidence of colon cancer, repair in older animals was evaluated and was found to be less than that seen in the young. Since multiple treatment with the carcinogen dimethylhydrazine is required and there is a long latent period, the effect of this treatment on repair potential was evaluated. Similar to what was seen in the older animals, these treated rats had greatly reduced capacity to repair DNA. All these observations are consistent with the hypothesis that decreased repair of DNA alterations is a concomitant of carcinogenesis.
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PMID:In vivo repair of rat intestinal DNA damage by alkylating agents. 121 55

Alkylation of DNA by chloroethylnitrosourea (CNU) at the guanine N7 position has been shown to occur in a sequence-selective fashion. In this report we find that the depurination of these alkylated sites occurs with two distinct kinetic components--GG sequences depurinate within 30 min of exposure to CNU, while depurination at GT sequences is first observed after 1 h and continues to increase 16 h after drug exposure. These apurinic sites are converted to DNA strand breaks and constitute less than 10% of the total sites of guanine N7 alkylation. Spermidine was found to decrease alkylation in 5'-GG-3' sequences but increases alkylation at 5'-GTC-3' sequences. These findings suggest that the majority of the guanine N7 alkylations formed by CNU are stable, with a minor adduct being responsible for the slow depurination event. We propose that the rapid depurination induced by CNU occurs from an initial guanine O6 alkylation, which then depurinates via a guanine O6-N7 cyclized intermediate. We also propose that the resulting apurinic sites may lead to DNA interstrand cross-linking (ISC). In support of these hypotheses we show that (i) DNA modified with the monoalkylating agent dimethylsulfate forms DNA ISC upon depurination; (ii) ellagic acid enhances the level of guanine N7 alkylation and alters the pattern of sequence selectivity shown by three bifunctional chloroethylating agents CNU, mitozolomide and methyl 3-(2-chloroethyl)-4-oxoimidazo[5,1-d]-1,2,3,5-tetrazine-8-ca rboxylate but not with nitrogen mustard; (iii) ellagic acid has no effect upon the frequency of alkylation observed with the monofunctional alkylators N-methyl-N-nitrosourea, N-ethyl-N-nitrosourea and methylmethanesulfonate; (iv) ellagic acid increases the frequency of depurination and strand break formation induced by CNU without affecting the sequence-selective pattern of depurination.
Carcinogenesis 1992 Mar
PMID:Sequence-selective depurination, DNA interstrand cross-linking and DNA strand break formation associated with alkylated DNA. 154 33

Photolysis of arylazides with long-wavelength UV light in an aqueous medium produces short-lived reactive species that bind to DNA and induce mutations in Salmonella typhimurium TA98. Nitrenes are known reactive products of azide photolysis, so that the DNA-binding and mutagenic species is either a nitrene or nitrene derivative. In the present study we presupposed that the nitrenium ion is the key intermediate. The electronic properties of 19 nitrenium ions with different chemical structures were calculated by the semi-empirical method AM1 and the resulting values plotted against the logarithm of the mutagenicity (log MUT) by means of linear regression analysis. Log MUT correlates with the stability of the nitrenium ion, the energy level of the LUMO and the charges on the exocyclic nitrogen with r = -0.804, 0.865 and -0.874 respectively. Thus, the mutagenicity of the azides is directly proportional to the stability of the nitrenium ions and inversely proportional to the electrophilicity of the exocyclic nitrogen. Furthermore, the mutagenicity of the azides correlates with the mutagenicity of the corresponding arylamines with r = 0.91 (n = 13). These correlations support the key role of the nitrenium ions and demonstrate the value of their electronic structure for the prediction of the mutagenicity of arylazides and arylamines.
Carcinogenesis 1992 Apr
PMID:Quantitative structure-activity relationships of mutagenic aromatic and heteroaromatic azides and amines. 157 21

The DNA base adduct, 8-hydroxyguanine (8-OHGua), has been reported to be a key biomarker relevant to carcinogenesis and cellular oxidative stress important in tumor promotion. Although investigators often report artificially high levels of 8-OHGua in DNA samples that have been exposed to phenol solutions and/or air during processing, few quantitative results are available. We show that routine phenol-based DNA purification procedures can increase 8-hydroxydeoxyguanosine (8-OHdG) levels 20-fold in samples that are exposed to air after the phenol is removed from the solutions. Surprisingly, air exposure alone accounts for a significant portion of this increase (4-fold) when compared to dG or DNA samples that have been solubilized in buffers purged with nitrogen. Most importantly, phenol treatments of DNA are shown to sensitize DNA to 8-OHdG formation by subsequent exposures to air. The sensitization of DNA occurs even though extensive dialysis is used between phenol treatment and enzymatic DNA digestion. Alternate procedures, including chloroform:isoamyl-alcohol extractions, also yield air-sensitive DNA samples. Other artifacts of organic extraction prior to air exposure include alterations in DNA base ratios after nuclease digestions. Overall, these results strongly suggest that studies of 8-OHdG in carcinogenesis should avoid dry conditions, such as lyophilization followed by exposure to air, and that all four of the bases should be monitored before 8-OHdG concentrations are normalized by undamaged deoxynucleoside concentrations. Failure to heed these precautions can lead to 2- to 20-fold overestimates of 8-OHdG in target tissues or in vitro models.
Carcinogenesis 1992 Jul
PMID:Phenol sensitization of DNA to subsequent oxidative damage in 8-hydroxyguanine assays. 163 1

A three-dimensional molecular template has been generated for substrates of human debrisoquine 4-hydroxylase cytochrome P450 (CYP2D6). This template defines the stereochemical requirements for CYP2D6 substrates in terms of the volume occupied and positions of key atoms. The modelling was based on the X-ray crystallographic coordinates of the location of the attacked C5 atom of camphor in relation to the haem in cytochrome P450 cam. Interactive molecular graphics combined with energy calculations were used to identify allowed conformers to superpose known CYP2D6 substrates to yield a molecular template. This model takes into account the site of attack of the known substrates and the requirement for a protonated nitrogen atom to interact with an anion site of the protein. A nitrogen-anion distance of between 2.5 and 4.5 A was allowed for the interaction. The substrates modelled were cardiovascular drugs (debrisoquine, sparteine, guanoxan and perhexiline), beta-adrenergic blocking agents (bufuralol and propranolol), tricyclic anti-depressants (desipramine, amitriptyline and nortriptyline) and other miscellaneous compounds (phenformin, methoxy-amphetamine, codeine and dextromethorphan). The template generated in this manner was then used to determine the likelihood that certain other compounds were substrates for CYP2D6. A carcinogenic protein pyrolysate product, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), did not fit the template and is therefore unlikely to be activated by this enzyme. A potent carcinogen in tobacco smoke, 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), fitted the template but could not be modelled to form a favourable nitrogen-anion interaction. Experimental substrate competition studies also showed that NNK is unlikely to be a CYP2D6 substrate. It was also shown that the widely used drug for treatment of breast cancer, trans-1-(4-beta-dimethylaminoethoxyphenyl)-,2-diphenyl-1-ene (tamoxifen), did not fit the molecular template and is unlikely to be metabolized by CYP2D6. Coordinates of the template are available.
Carcinogenesis 1991 Dec
PMID:A three-dimensional molecular template for substrates of human cytochrome P450 involved in debrisoquine 4-hydroxylation. 174 20


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