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

The generation of superoxide and related free radicals and the mobilization of catalytic iron due to ethanol metabolism have been suggested as mechanisms of alcohol-induced liver injury as well as of the increased risk of cancer observed in alcoholics. Cleavage of double stranded DNA is produced by both free radicals as well as by catalytic iron. The effects of ethanol metabolism on DNA cleavage were therefore studied in vitro as well as in vivo in isolated hepatocytes. Intactness of double stranded DNA was studied by measuring ethidium bromide fluorescence after DNA electrophoresis. In vitro, the metabolism of acetaldehyde by aldehyde oxidase caused cleavage of Lambda phage DNA. Cleavage was inhibited by both superoxide dismutase and desferrioxamine indicating the role of superoxide radicals and catalytic iron respectively. Studies with HIND III digests of the Lambda phage indicate a lack of specificity in the breaks with respect to nucleotide sequences. Addition of EDTA greatly enhanced cleavage. In vivo, ethanol metabolism caused minimal breakage in hepatocyte DNA and addition of acetaldehyde (100 microM) markedly enhanced cleavage; all cleavage was inhibited by desferrioxamine. The metabolism of ethanol to acetaldehyde and the further metabolism of acetaldehyde by aldehyde oxidase generates free radicals and mobilizes iron; these may contribute to alcohol-induced injury and carcinogenesis.
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PMID:DNA cleavage during ethanol metabolism: role of superoxide radicals and catalytic iron. 217 Jul 94

This hypothesis paper reviews diverse evidence suggesting that intracolonic production of oxygen radicals may play a role in carcinogenesis. The hypothesis began to evolve when the author made the chance discovery that 1/10,000 dilutions of feces generated detectable quantities of highly reactive hydroxyl radicals (HO.). The rate of HO. formation, detected using DMSO as a molecular probe, was quite remarkable, corresponding to that which would be produced by over 10,000 rads of gamma irradiation per day, absorbed in the periphery of the fecal mass adjacent to the mucosa. The relatively high concentrations of iron in feces, together with the ability of bile pigments to act as iron chelators that support Fenton chemistry, may very well permit efficient HO. generation from superoxide and hydrogen peroxide produced by bacterial metabolism. Such free radical generation in feces could provide a missing link in our understanding of the etiology of colon cancer: the oxidation of procarcinogens either by fecal HO., or by secondary peroxyl radicals (ROO.) to form active carcinogens or mitogenic tumor promotors. Intracolonic free radical formation may explain the high incidence of cancer in the colon and rectum, compared to other regions of the GI tract, as well as the observed correlations of a higher incidence of colon cancer with red meat in the diet, which increases stool iron, and with excessive fat in the diet, which may increase the fecal content of procarcinogens and bile pigments.
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PMID:Free radicals and the etiology of colon cancer. 218 44

The results of long-term studies of factors of gastric carcinogenesis in steel workers are presented. Relationships between tumor incidence and effects of iron dust, oil aerosols containing heavy hydrocarbons, high temperature and nitrogenous gases were established. Chronic gastric diseases aggravated by highly-hazardous industrial environmental factors increase the risk of carcinogenesis. Measures aimed at preventing primary gastric tumor development in steel workers should include dust and oil aerosol control and timely identification and treatment of chronic gastric lesions.
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PMID:[Malignant neoplasms of the stomach in metallurgy workers]. 234 98

The modifying effects of sinigrin (Sin) and indole-3-carbinol (I3C) on the hepatocarcinogenesis induced by diethylnitrosamine (DEN) were investigated in male ACI/N rats. Rats were divided into six groups: group 1 was given DEN (40 p.p.m.) in the drinking water for 5 weeks, starting at 7 weeks of age; group 2 was treated with DEN and diet containing 1200 p.p.m. Sin; group 3 received DEN and diet containing 1000 p.p.m. I3C; group 4 was given Sin diet alone; group 5 was given I3C diet alone; and group 6 served as controls. The diet containing Sin or I3C was fed to the rats starting at 6 weeks of age until 1 week after the carcinogen exposure. At termination of the experiment (week 29), the incidences of iron-excluding altered foci (11.22 +/- 3.22/cm2) and liver cell tumors (6/12, 50%) and the tumor multiplicity (0.9/rat) in rats of group 2 were significantly smaller than those of group 1 (foci incidence, 48.33 +/- 6.34/cm2, tumor incidence, 10/10, 100%; multiplicity, 9.5/rat) (P less than 0.02). Similarly, the incidence of iron-excluding hepatocellular foci (17.65 +/- 4.67/cm2) and tumor multiplicity (2.4/rat) with a slight reduction of tumor incidence (9/12, 75%) in rats of group 3 were significantly lower than those of group 1 (P less than 0.001). There were no liver cell neoplasms in rats of groups 4, 5 and 6. Thus, Sin and I3C inhibited the hepatocarcinogenesis induced by DEN when they were administered concurrently with the carcinogen.
Carcinogenesis 1990 Aug
PMID:Inhibitory effect of sinigrin and indole-3-carbinol on diethylnitrosamine-induced hepatocarcinogenesis in male ACI/N rats. 238 27

Bleomycin-induced, unscheduled DNA synthesis (UDS) in Triton X-100-permeabilized mouse ascites sarcoma cells was enhanced 2- to 5-fold by addition of ribonucleoside triphosphates at 0.2-2.0 mM and 1.5- to 3-fold by addition of ferrous ions at 10 microM. Sensitivity to deferoxamine, a specific iron chelator, suggested that iron was essential to nucleotide-enhanced, bleomycin-induced UDS. Enhancement by nucleotides was not attributed to iron impurities in the nucleotide preparations, because ferrous ions did not substitute for nucleotides, but nucleotides further enhanced bleomycin-induced UDS which was maximally stimulated by the optimal concentration of ferrous ions. The effects of nucleotides and ferrous ions on bleomycin-induced UDS were thought to be due to increased bleomycin-induced DNA damage rather than enhanced DNA synthesis. The results suggest that pharmacological action of bleomycin is affected by the concentrations of nucleotides as well as ferrous ions.
Carcinogenesis 1985 Jun
PMID:Effects of nucleoside triphosphates and ferrous ions on bleomycin-induced unscheduled DNA synthesis. 240 74

We evaluated certain histochemical tests for their ability to detect premalignant mucosa in the dimethylhydrazine model of colonic carcinogenesis. Biweekly colonoscopic biopsies of the descending colon were performed for 29 wk in control and dimethylhydrazine-treated rats. Biopsy specimens of the splenic flexure, rectum, and any visualized tumors were taken. The specimens were stained with periodic acid-Schiff to detect neutral mucins, high-iron diamine alcian blue to detect sialylated and sulfated mucins, fluoresceinated peanut agglutinin, and fluoresceinated Ulex europeus agglutinin. None of the first three tests consistently detected premalignant mucosa. However, Ulex europeus agglutinin, which bound to only 3% of control biopsy specimens throughout the course of the study, bound to increasing numbers of biopsy specimens in the dimethylhydrazine-treated animals, reaching a maximum of 90% positivity by 13-16 wk. Moreover, Ulex europeus agglutinin bound strongly to all biopsy specimens from tissues adjacent to tumors and to 93% of tumors. Mucosal atrophy and focal dysplasia were present more frequently in specimens taken from the rectum (but not the splenic flexure) of dimethylhydrazine-treated animals than of control animals, but there was no correlation between the histochemical markers and either atrophy or dysplasia. We conclude that Ulex europeus agglutinin binding is a consistent feature of premalignant colonic mucosa in dimethylhydrazine-treated rats.
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PMID:Serial observations of colonic carcinogenesis in the rat. Premalignant mucosa binds Ulex europeus agglutinin. 243 Aug 52

Oxygen radical-induced genetic damage may be mediated by products of lipid peroxidation, in particular, arachidonic acid. Hydroxy- and hydroperoxyeicosatetraenoic acids (HETEs and HPETEs) are intermediates in the metabolism of arachidonic acid to the leukotrienes. Several isomeric hydroxy- and hydroperoxy-6,8,11,14-eicosatetraenoic acids were evaluated for their ability to cause DNA single-strand breaks in human lymphocytes. Both HETEs and HPETEs induced strand breaks in a dose-dependent fashion at concentrations of 5, 10 and 20 microM. At each concentration, HETEs were more effective in producing breakage than the corresponding HPETEs. Each of the isomeric forms used were equally effective in producing strand breaks. Antioxidants (superoxide dismutase, catalase and mannitol) were protective. Iron chelation by desferrioxamine suppressed strand breakage by 45% and an additional 33% inhibition was observed upon the addition of the calcium chelator EGTA.
Carcinogenesis 1989 Jun
PMID:Hydroxy- and hydroperoxy-6,8,11,14-eicosatetraenoic acids induce DNA strand breaks in human lymphocytes. 249 98

The author reviews the problem of the pattern of lipid peroxidation in cancer cells with special reference to a comparison between normal liver cells and hepatomas both transplanted and induced by diethylnitrosamine. It is stated that the loss of lipid peroxidation is proportional to the degree of de-differentiation of hepatoma cells. During carcinogenesis, however, the loss is already evident at the stage of preneoplastic nodules. A common feature of all tumors, independently of the extent of the loss of peroxidation in basal conditions, is the lack of further stimulation by ADP/iron or by ascorbate/iron. As regards the reasons for the decline in lipid peroxidation, they are certainly not unique. An important cause is the low activity of the enzymes of the monooxygenase microsomal chain. Another very important one is the change in lipid composition of membranes, with a marked decrease in polyunsaturated fatty acids, which are the main substrate for lipid peroxidation. It has been shown that enrichment of membranes of hepatomas with arachidonic acid results in restoration of stimulation of peroxidation by ascorbate/iron, but not with ADP/iron. The last type of stimulation mostly reflects the behaviour of the monooxygenase chain, whereas ascorbate/iron-induced stimulation does not require the presence of an efficient cytochrome P450-chain. Another cause for decreased lipid peroxidation in tumors is the increased rigidity of membranes, due to the large increase in cholesterol content: this prevents to some extent the influx of oxygen inside the membranes. Yet another cause is the presence of increased amounts of antioxidants in both cytosol and membranes. The main toxic product of lipid peroxidation, 4-hydroxynonenal, has been found to elicit several actions at extremely low concentrations. In fact, 4-hydroxynonenal stimulates chemotaxis of polymorphonuclear leukocytes, stimulates plasma membrane adenylate cyclase, stimulates plasma membrane guanylate cyclase, and stimulates phospholipase C. The last three enzymes involve the action of G-proteins. The effect of the aldehyde is present at less than micromolar concentrations, which may occur inside the cells in certain conditions. Moreover, at concentrations from 10(-6) to 10(-7) M, the aldehyde is able to block oncogene c-myc expression in the human erythroleukemic K562 cell line, which at the same time becomes able to express the gamma-globin gene. These facts are discussed with reference to a possible biological meaning of the loss of lipid peroxidation in tumors.
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PMID:Lipid peroxidation and cancer: a critical reconsideration. 251 Mar 83

Leukocyte-induced DNA damage may partially account for the known association between chronic inflammation and malignancy. Since elucidation of the chemical nature of leukocyte-induced DNA damage may enhance our understanding of the mechanisms underlying leukocyte-induced DNA damage and the carcinogenesis associated with inflammation, the present study was undertaken to characterize the chemical modifications that occur in DNA exposed to stimulated human neutrophils. Calf thymus DNA was exposed to phorbol myristate acetate (PMA)-stimulated neutrophils in the presence or absence of exogenously added iron ions. DNA samples were subsequently hydrolyzed, derivatized and analyzed by gas chromatography-mass spectrometry with selected-ion monitoring. A variety of base modifications including cytosine glycol, thymine glycol, 4,6-diamino-5-formamidopyrimidine, 8-hydroxyadenine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine, and 8-hydroxyguanine were identified. The yield of these various base products was increased by the addition of iron ions. Specifically, in the presence of physiologic quantities of iron ions, approximately 7 of every 1,000 DNA bases were modified. Addition of the superoxide anion scavenger, superoxide dismutase, the hydrogen peroxide scavenger, catalase, the hydroxyl scavenger, dimethylsulfoxide, or the iron chelator, deferoxamine, to DNA mixtures containing PMA, neutrophils, and iron ions, greatly decreased the yield of the damaged DNA base products. Our results indicate that stimulated human neutrophils can damage each of the four bases in DNA. It is likely that hydroxyl radical, generated via an iron catalyzed Haber-Weiss reaction, mediates neutrophil-induced DNA base damage, since: (a) the chemical structure of neutrophil-induced DNA base damage is consistent with a hydroxyl radical-mediated mechanism, (b) hydroxyl radical generated via ionizing radiation in aqueous solution produces DNA base modifications that are identical to neutrophil-induced DNA base modifications, (c) iron ions increase neutrophil-induced DNA base damage, and (d) iron chelators or scavengers of superoxide anion, hydrogen peroxide or hydroxyl radical decrease neutrophil-induced DNA base damage.
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PMID:Damage to the bases in DNA induced by stimulated human neutrophils. 255 79

The effect of parenteral and oral iron was examined in the rat 1,2 dimethylhydrazine (DMH) colorectal carcinogenesis model in a series of experiments. Parenteral supplementation of iron was found to augment tumor yield (p = 0.012) and oral iron was found to augment tumor incidence (p = 0.03, when control groups were combined). In addition, phytic acid, a significant component of dietary fiber was found to reverse the augmenting effect of oral iron on tumor yield and incidence (p = 0.09 for both). Furthermore, in a short term DMH nuclear toxicity assay, analysis of the karyorrhectic index (KI), there was no difference in the KI between oral iron and phytate dietary groups (p = 0.53 for the left colon and p = 0.2 for the right colon), implying that iron's effect on colorectal tumor induction takes place during the promotional phase of carcinogenesis and not during initiation. These experiments support the epidemiologic observation that dietary iron may augment colorectal cancer risk and that the mechanism by which dietary fiber diminishes colorectal cancer risk may be the chelation of dietary iron by the phytic acid component of dietary fiber.
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PMID:The effect of iron on experimental colorectal carcinogenesis. 256 Jun 18


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