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

Ascorbic acid (vitamin C) is an important intracellular reducing agent. It also has been suggested to be (i) a protective agent against development of cancer, (ii) a therapeutic agent for malignancies and (iii) a mutagen. We have found that high concentrations of ascorbate leads to DNA damage in several in vivo and in vitro situations. Guinea-pigs receiving oral 1-methyl-1-nitrosourea (MNU) were used as a whole animal model. Administration of sodium ascorbate prior to MNU increased strand breakage in pancreatic DNA. Concentrations of ascorbate greater than 0.5 mM increased the frequency of DNA strand breaks caused by MNU in both L1210 murine leukemia cells and guinea-pig pancreatic cells in tissue culture; ascorbate alone led to DNA strand breaks in the latter cells. Investigations of the mechanism of DNA damage were carried out with purified DNA. Ascorbate produced single- and double-strand breaks in plasmid DNA. Cleavage was catalyzed by copper(II), inhibited by catalase and blocked by the presence of thiols. We conclude that superoxide and hydrogen peroxide produced during the oxidation of ascorbate leads to generation of hydroxyl free radicals that can mediate DNA strand scissions and potentiate the effects of alkylating carcinogens.
Carcinogenesis 1987 Nov
PMID:Ascorbate potentiates DNA damage by 1-methyl-1-nitrosourea in vivo and generates DNA strand breaks in vitro. 282 77

The high incidence of lung cancer in smokers is thought to be related to the direct exposure of bronchial and pulmonary cells to carcinogens in inhaled cigarette smoke. Using a 32P-postlabeling assay for chemically induced covalent DNA alterations, we found that unfractionated, relatively non-polar cigarette smoke components bound preferentially to lung and heart DNA in female ICR mice. After 6 days of topical treatment with cigarette smoke condensate (CSC) equivalent to a total of 4.5 cigarettes, covalent DNA damages was estimated to be 6.2, 5.7, 3.9 and 1.9 times higher, respectively, in lung, heart, skin and kidney than in liver, ranging from approximately 1 adduct in 5.4 +/- 0.7 X 10(6) DNA nucleotides in lung to 1 adduct in 3.3 +/- 0.6 X 10(7) DNA nucleotides in liver. Spleen DNA was virtually adduct-free. Adducts occupied two extensive zones, designated diagonal radioactive zone (DRZ) 1 and DRZ 2, on TLC fingerprints. Preference for lung and heart DNA was also observed in mice treated for 1 or 3 days. An inverse association appeared to exist between the tissue distribution of CSC-induced covalent DNA damage and the reported activity of enzymes catalyzing the metabolism of xenobiotics (cytochrome P-450 monooxygenases, phase II enzymes) and toxic oxygen species (superoxide dismutase, catalase). The results suggest that the well-known pulmonary and cardiovascular organotropism of cigarette-smoking-associated adverse health effects may, in part, have its origin in the inherent capacity of cigarette smoke components to induce lesions in lung and heart DNA in a tissue-specific manner. Possible mechanisms and health implications of the preferential binding of presumably aromatic CSC constituents to lung and heart DNA are discussed.
Carcinogenesis 1988 Jan
PMID:Tissue distribution of covalent DNA damage in mice treated dermally with cigarette 'tar': preference for lung and heart DNA. 282 34

The tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits growth and induces terminal squamous differentiation of normal human bronchial cells when added to the culture media [J. C. Willey, A. J. Saladino, C. Ozanne, J. F. Lechner, and C. C. Harris, Carcinogenesis (lond.), 5: 209-215, 1984]. We have investigated the possibility of oxygen free radicals being involved as intermediates in this process. Electron paramagnetic resonance measurements using the spin-trapping agent 5,5-dimethyl-1-pyrroline-1-oxide failed to detect oxygen free radicals in bronchial epithelial cells exposed to TPA, although oxy radicals were detected in bronchial epithelial cells after a nontoxic exposure to menadione, and in human neutrophils after exposure to TPA. Addition to the culture media of free radical scavenger, i.e., reduced glutathione, N-acetylcysteine, D-alpha-tocopherol, copper (II) (3,5-diisopropylsalicyclic acid)2, or the combination of superoxide dismutase and catalase did not affect the dose-dependent growth inhibition of TPA on the bronchial epithelial cells. Moreover, exposure of the bronchial epithelial cells to TPA did not result in increased DNA single strand breaks measured by alkaline elution, as would be expected with a free radical mediated mechanism. Thus, our results argue against the importance of oxygen free radicals in the inhibition of growth and the induction of squamous differentiation by TPA in normal human bronchial epithelial cells.
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PMID:Role of oxygen radicals in 12-O-tetradecanoylphorbol-13-acetate-induced squamous differentiation of cultured normal human bronchial epithelial cells. 282 86

Evidence has been obtained that implicates the generation of reactive oxygen species as an early and critical event in the promotion of neoplastic transformation in mouse JB6 cells. The time courses for specific inhibition by CuZn-superoxide dismutase (CuZn-SOD) of the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced promotion of neoplastic transformation in JB6 cells and for changes in antioxidant enzyme activities associated with TPA-exposure were examined. The antipromoting effect of CuZn-SOD was found to be critically dependent on the time of addition of CuZn-SOD relative to the start of a 14-day exposure of cells to TPA. Treatment of JB6 P+ Clone 22 and Clone 41 cells with CuZn-SOD for 18 h before, simultaneously with or up to 1 h after exposure to TPA, all inhibited promotion of transformation maximally. Delay of addition of CuZn-SOD by 2 h or more after the start of TPA treatment resulted in a marked decrease in the promotion inhibitory effect. CuZn-SOD added 24 or 48 h after TPA had no effect on promotion of transformation. Exposure of JB6 cells to 0.2- (superoxide anion radical) generated exogenously by the aerobic xanthine oxidase reaction resulted in promotion of neoplastic transformation that was prevented by concurrent addition of CuZn-SOD. Taken together these studies provide evidence that increased superoxide anion generation within the first 2 h following TPA exposure is an essential event in promotion of transformation in JB6 cells. Upon TPA exposure, JB6 Clone 41 cells exhibited time-specific activity changes in the cellular SOD, glutathione peroxidase (GSH-Px), and catalase. SOD and GSH-Px activities were reduced to 54% and 26% respectively of basal levels within 2 h of TPA treatment. GSH-Px activity recovered to basal levels within 4 h and CuZn-SOD within 48 h. Catalase activity was maximally reduced to 50% of basal within 1 h after TPA treatment and rebounded to greater than basal levels within 4 h. It is postulated that a c-kinase-dependent event induces rapid elevation of superoxide anion following TPA exposure and that this leads to reduced activity of antioxidant enzymes. Since antipromotion by exogenous CuZn-SOD is effective only during the first 2 h following TPA exposure, this suggests that the promotion-relevant 0.2- elevation is transient.
Carcinogenesis 1988 Feb
PMID:Early superoxide dismutase-sensitive event promotes neoplastic transformation in mouse epidermal JB6 cells. 282 3

We have measured the capacity of highly-purified, paraffin oil-elicited neutrophils to induce DNA single-strand breaks in a newly established plasmacytoma cell line, RIMPC 2304, which was induced by a retrovirus containing the c-myc and V-Ha-ras oncogenes. This cell line effectively repairs DNA damage induced by gamma-irradiation. DNA damage induced by neutrophils was correlated with the oxidative burst of the neutrophils. The levels of superoxide anion, H2O2, and HOCl produced after stimulation of the neutrophils (6 X 10(5)/cm3) with the tumor promoter phorbol myristate acetate (100 nM) were 33.8 microM, 12.8 microM and 1.7 microM respectively in 15 min, and 98 microM, 20 microM and 8.7 microM respectively in 90 min. The results of alkaline elution experiments revealed that when the same concentration of neutrophils was co-incubated for 15 min in serum-free medium with an equal number of radioactively labeled RIMPC 2304 cells, the latter incurred a level of damage that approximated that caused by 300 rad equivalents of gamma-irradiation or by a 1-min treatment with 20 microM H2O2 at 37 degrees C. Damage from neutrophils was coincident with the oxidative burst; it was induced rapidly (within 5 min) but remained high for more than 90 min. The level of damage achieved was dependent upon the ratio of neutrophils: target cells and was clearly detectable at ratios as low as 0.25:1. Induction of single-strand breaks was completely inhibited by catalase and partially inhibited by superoxide dismutase, mannitol, and reduced glutathione but not by Na azide. Addition of the non-steroidal anti-inflammatory drug indomethacin either enhanced (at 50 microM) or had no effect (at 2 microM) on the damage detected. Finally, repair of strand breaks induced by neutrophils was significantly slower (half-time approximately 10 min) than that observed for repair of similar levels of damage induced by H2O2 or gamma-irradiation (half-times approximately 3 min, each). The results indicate that neutrophils cause prolonged DNA damage in neighboring cells. Moreover, they indicate that although H2O2 produced in the oxidative burst is an essential mediator of the damage observed, additional reactive oxygen intermediates including the superoxide anion are also implicated. The data are discussed in relation to the possible role of neutrophils in chronic inflammation and in pristane-induced plasmacytoma formation in mice.
Carcinogenesis 1988 Dec
PMID:Activated neutrophils induce prolonged DNA damage in neighboring cells. 284 79

Malondialdehyde (MDA) is a product of free-radical reaction with lipids and has been implicated in a variety of pathological processes including inflammation and carcinogenesis. In order to document the toxic reactions related to the pathogenic mechanisms of mineral fibers, asbestos and other mineral dusts were examined for their potency to produce lipid peroxidation using the thiobarbital method for MDA measurement. Human peripheral blood-derived neutrophils (PMN), guinea pig peritoneal macrophages, and guinea pig alveolar lavage cells produced MDA when treated with crocidolite asbestos. Of the various mineral dusts tested, only crocidolite showed a significant increase of MDA production. The amount of MDA produced by PMN treated with crocidolite increased with milling the fiber and with the incubation time. Both superoxide dismutase (SOD) and catalase were examined for their ability to inhibit MDA formation. At concentrations of up to 50 micrograms/10(6) cells, SOD did not inhibit the MDA formation in macrophages. However, catalase at the same concentration inhibited MDA formation in macrophages completely. A possible mechanism of MDA formation and its relationship with superoxide production are discussed.
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PMID:Mineral fiber-induced malondialdehyde formation and effects of oxidant scavengers in phagocytic cells. 284 74

Male F-344 rats were fed a diet containing 2% di-(2-ethylhexyl)phthalate (DEHP) for 95 weeks. Liver nodules and/or hepatocellular carcinomas (HCC) developed in 6/10 rats fed DEHP and none were found in controls (P less than 0.005 by chi 2 test). All the nodules and HCC were negative for gamma-glutamyl transpeptidase. In the non-tumorous portions of liver, the hepatocytes contained an increased number of peroxisomes and extensive accumulation of lipofuscin. By immunocytochemical analysis, the liver peroxisomes in rats treated chronically with DEHP had visually detectable decrease in the H2O2-degrading catalase and increase in H2O2-producing fatty acyl-CoA oxidase. These results show that higher dietary level of DEHP, which causes substantially greater degree of peroxisome proliferation than the 1.2% dietary level used in the National Toxicology Program bioassay (1982, Publication no. NTP-80-37, Tech. Report Series No. 217), can induce liver tumors in male rats.
Carcinogenesis 1987 Sep
PMID:Absence of gamma-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. 288 2

Hepatic metabolism of long-chain fatty acids was studied in male rats fed a defined choline-deficient (CD) diet with and without choline and after methotrexate (MTX) administration. Peroxisomal beta-oxidation was increased approximately 4-fold in the peroxisome-enriched fraction of CD-fed animals, whereas the catalase activity was increased 1.3-fold. The urate oxidase activity was marginally affected. The CD-fed rats also revealed elevated capacity for hydrolysis of palmitoyl-CoA in the cytosolic fraction (2.0-fold), whereas the microsomal palmitoyl-CoA hydrolase activity was decreased. Notably, the increased peroxisomal beta-oxidation, the catalase activity and palmitoyl-CoA hydrolase activities (the membrane-bounded and cytosolic) were almost fully prevented by adding choline to the CD-diet. Thus, the change in these enzyme activities appears to be a consequence of a choline-deficiency provoked by the CD diet. MTX administration of normal fed rats (ND diet) had no effects on the peroxisomal beta-oxidation, catalase activity and urate oxidase activity. MTX treatment of the ND-fed animals, however, increased the mitochondrial palmitoyl-CoA hydrolase activity and decreased the microsomal enzyme activity. As choline-deficiency and MTX increased the hepatic lipid level, the overall results suggest that fat accumulation is not an 'induction signal' for increased peroxisomal beta-oxidation. The CD diet alone increased the reduced glutathione content in liver, whereas MTX did not significantly change this level. Whether the changes of H2O2-generating peroxisomal oxidation of long-chain fatty acids may be an important step in a chain of events, which eventually results in tumour formation by choline-deficiency, should be considered.
Carcinogenesis 1988 Apr
PMID:Effect of choline-deficiency and methotrexate administration on peroxisomal beta-oxidation, palmitoyl-CoA hydrolase activity and the glutathione content in rat liver. 289 92

Reduced glutathione (GSH) is mutagenic in Salmonella in the presence of gamma-glutamyltranspeptidase (GGT), with the highest response obtained in strain TA102. Reduced cysteinylglycine, one of the products of GGT metabolism of GSH, is mutagenic in the absence of GGT. In strain TA102, GSH mutagenesis was dependent on molecular oxygen, enhanced by iron, inhibited by EDTA, desferrioxamine mesylate, mannitol, butylated hydroxyanisole, peroxidase and catalase, but not by superoxide dismutase. Binding of GSH or its GGT-dependent metabolites to DNA in vitro was not detected. This is consistent with a model of an indirect mechanism of mutagenesis, i.e. cleavage of GSH by GGT, followed by facile auto-oxidation of the resulting cysteinylglycine, with the production of free radicals which lead to the (pen)ultimate mutagen, H2O2.
Carcinogenesis 1988 May
PMID:Glutathione mutagenesis in Salmonella typhimurium is a gamma-glutamyltranspeptidase-enhanced process involving active oxygen species. 289 53

Previous studies from our laboratories have shown that carcinogenic peroxisome proliferators significantly increase the mRNA levels of peroxisomal beta-oxidation genes in the rat liver by enhancing the transcriptional activity. Because of a good correlation between the inducibility of peroxisome proliferation and carcinogenicity of this class of xenobiotics, we proposed that sustained induction of peroxisomal beta-oxidation system and the resultant oxidative stress form the basis for carcinogenesis. Since this concept implies that tumors should develop only in tissues which display maximal peroxisome proliferation, we have now assessed the degree to which catalase and the three beta-oxidation genes are expressed in liver and 12 extrahepatic tissues of adult rats fed for 2 weeks a diet containing 0.025% ciprofibrate (w/w), a peroxisome proliferator. In the ciprofibrate-treated rats, the levels of catalase mRNA increased to less than 2-fold in liver, kidney, intestine, and heart, but no change was detected in other tissues. The mRNA levels of the three genes of beta-oxidation system in the liver of adult rats treated with ciprofibrate increased greater than 20-fold. In contrast, in the kidney, small intestine, and heart the increases in the mRNA levels of all three beta-oxidation genes were small and varied from 2- to 4-fold following ciprofibrate treatment. Ciprofibrate did not significantly increase the levels of these mRNAs in the other nine tissues. These results correlated well with the levels of peroxisomal beta-oxidation activity, peroxisome volume density, and the immunologically quantified proteins in various tissues. These results provide evidence for the presence of beta-oxidation enzymes in peroxisomes of many tissues of rat and for tissue (cell)-specific differences in the inducibility of mRNAs of these beta-oxidation genes. The marked inducibility of beta-oxidation genes in liver and subsequent development of liver tumors support the hypothesis that tumors develop in tissues that show inducibility of peroxisome proliferation vis a vis beta-oxidation system following exposure to peroxisome proliferators.
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PMID:Comparison of constitutive and inducible levels of expression of peroxisomal beta-oxidation and catalase genes in liver and extrahepatic tissues of rat. 290 Jun 80


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