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

We studied the mouse NC tumour, a subcutaneously transplanted adenocarcinoma originally of mammary origin. Measurements per g tissue were made of 17 fatty acids (FAs), the combined amounts of n-3, n-6, saturated, unsaturated, and total FAs, and of various FA ratios in the tumour, mammary tissue, spleen, liver and plasma. Compared with mammary tissue from normal mice, tumours of vehicle-treated controls had less of seven of the FAs and more of two FAs. Mice bearing the NC tumour often had changed (usually decreased) amounts of FAs in the 'normal' spleen, liver and plasma, but not in mammary tissue. Treatment with methotrexate (MTX) was studied alone and with indomethacin which can potentiate MTX cytotoxicity. Indomethacin 1.25 mg kg-1 (INDO) increased the amounts of 3/17 tumours FAs and the unsaturated FAs, but reduced 9/17 FAs, the saturated and the unsaturated FAs in 'normal' mammary tissue, and usually had no effect on the FAs of other tissues. MTX 2 or 4 mg kg-1 (MTX 2 or 4 mg) +/- INDO in general partly restored (increased) the amounts of tumour FAs, and reduced the saturated/unsaturated FA ratio. In the 'normal' spleen and plasma also, but not in the liver, MTX 2 mg generally somewhat restored the FA composition. However, as in the liver, the spleen 20:4 and 22:6 (which form prostaglandins and lipid peroxides) did not increase in the presence of INDO. With MTX 4 mg, some of the plasma and liver FAs decreased, in contrast to the tumour. There was generally no evidence of MTX potentiation by INDO. These results are discussed in relation to carcinogenesis, cachexia, and the response to treatment.
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PMID:Changes in tissue fatty acid composition in murine malignancy and following anticancer therapy. 173 11

The effects of NaCl on lipid peroxidation levels in gastric mucosa and urine were investigated in male Wistar rats. The animals were fed NaCl-supplemented diet at concentrations of 4.0, 2.0, 1.0, 0.5, 0.25 and 0% (control) for 5 weeks. Further groups were maintained on the 4.0 or 0% NaCl diets and simultaneously administered 20 p.p.m. indomethacin dissolved in the drinking water. When the rats were killed, a dose-related increase of malondialdehyde (MDA) was found in both gastric mucosa and urine, the urinary MDA levels clearly correlating with those for stomach tissue. Cell proliferation of fundic mucosa was also significantly increased in rats fed 4.0 or 2.0% NaCl-supplemented diet. Indomethacin suppressed the 4% NaCl-associated MDA increase in both gastric mucosa and urine as well as the elevation in cell proliferation. The results clearly show that administration of NaCl, a gastric tumor promoter, is associated with enhanced lipid peroxidation in the gastric mucosa.
Carcinogenesis 1991 Dec
PMID:Enhanced lipid peroxidation in rat gastric mucosa caused by NaCl. 174 18

Prostaglandins have been implicated in the immune suppression associated with the development of some tumours. Application of the prostaglandin synthetase inhibitor indomethacin, to murine skin prior to treatment with the chemical carcinogens benzo(a)pyrene (BP) or 7,12 dimethylbenz(a)anthracene (DMBA), restored contact sensitivity responses to 2,4-dinitrofluorobenzene in BP- but not DMBA-treated mice. However, indomethacin failed to restore antibody responses in either group of mice. Prolonged treatment with BP or DMBA led to cutaneous tumour formation. Indomethacin was found to delay the onset and reduce the size of tumours in BP- but not DMBA-treated mice. It is proposed that prostaglandin-induced suppression of cellular cutaneous immunity may play a role in BP- but not DMBA-induced cutaneous carcinogenesis.
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PMID:A role for prostaglandins in the suppression of cutaneous cellular immunity and tumour development in benzo(a)pyrene- but not dimethylbenz(a)anthracene-treated mice. 190 86

The effects of the cyclooxygenase inhibitors indomethacin and carprofen on the enhancement of 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary carcinogenesis by dietary linoleate have been compared in female Sprague-Dawley rats. Indomethacin and carprofen, 0.004% and 0.02% (w/w) in the diet, respectively, were fed to rats receiving 20% fat diets containing 0.5, 4 or 12% linoleate starting 7 days after administration of 5 mg DMBA i.g. Indomethacin was shown to have a marked inhibitory effect on mammary tumorigenesis in rats fed the 4 and 12% linoleate diets, but did not alter tumorigenesis in rats fed the 0.5% linoleate diet. In contrast, carprofen was not inhibitory in any of these dietary groups, or in a separate experiment in which a 5% fat--3% linoleate diet was fed. The effect of each drug on prostaglandin E2 (PGE2) levels in normal mammary glands enriched in epithelial cells after a 3-week pretreatment with 17 beta-estradiol and progesterone was also investigated. Carprofen was shown to reduce PGE2 levels to a similar or greater extent than indomethacin at each level of linoleate in the diet. These data demonstrate that a reduction in PGE2 synthesis in the mammary epithelium does not correlate with inhibition of mammary tumorigenesis, and that other factors, including possible alterations in other products of the arachidonic acid cascade, are responsible for this inhibitory effect.
Carcinogenesis 1989 Aug
PMID:A comparison of the effects of the prostaglandin synthesis inhibitors indomethacin and carprofen on 7,12-dimethylbenz[a]anthracene-induced mammary tumorigenesis in rats fed different amounts of essential fatty acid. 250 21

The effects of indomethacin and dexamethasone on carcinogenesis of the esophagus and forestomach were studied in male rats. The rats were treated by N-nitrososarcosine ethyl ester (NSEE) per os in a daily dose of 50 mg/kg body weight for 16 weeks. Indomethacin (25 mg per kg of the food) and dexamethasone (1 mg per kg of the food) were added to food on accomplishing the carcinogen treatment for another 16 weeks, thereafter the animals were sacrificed. NSEE induced the esophagus and forestomach tumors approximately in 90% of cases, mainly papillomas and rarely carcinomas, on the average more than 5 tumors per nat. Indomethacin and dexamethasone were shown to inhibit the development of the NSEE-induced tumors both in the esophagus and forestomach. The both drugs decreased tumor incidence approximately by 20% and tumor multiplicity more than twofold.
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PMID:[The inhibition of esophageal tumor development by the use of the nonsteroidal and steroidal anti-inflammatory preparations indomethacin and dexamethasone]. 274 48

Structural analogs of diethylstilbestrol (DES) with at least one phenolic hydroxyl group are metabolized by prostaglandin H synthase (PHS) from ram seminal vesicle microsomes (RSVM) in vitro in the presence of arachidonic acid (20:4). U.v. spectroscopy revealed the formation of p-quinoid intermediates in incubations of DES, tetrafluoro-DES and dimethylstilbestrol, and tautomerization of the quinones to the respective dien-compounds which were characterized by h.p.l.c. and GC/MS. Indomethacin inhibits the formation of these metabolites which are identical to the major metabolites formed in incubations with horseradish peroxidase/hydrogen peroxide. Covalent binding to protein was observed in incubations of PHS co-substrates. Notably, formation of reactive intermediates which bind to protein is not limited to DES-analogs which form quinone intermediates: radiolabeled hexestrol and E,E-dienestrol yield protein-bound radioactive products upon incubation with RSVM and 20:4, probably via one electron-oxidation to a phenoxy radical. PHS-catalyzed metabolism of structural analogs of DES is accompanied by a concentration-dependent increase in cyclo-oxygenase activity. The measurement of the 20:4-dependent oxygen uptake rates in vitro can serve as a convenient assay for estrogenic compounds which undergo co-oxidation. At high concentrations, however, DES structural analogs can inhibit rather than stimulate PHS. The PHS-catalyzed formation of reactive intermediates from DES structural analogs and their effect on PHS may be of importance for their biological activity in estrogen target tissues with low mono-oxygenase activity.
Carcinogenesis 1986 Jan
PMID:Co-oxidation of diethylstilbestrol and structural analogs by prostaglandin synthase. 308 Feb 50

Inflammation and the release of potentially damaging substances, such as reactive oxygen intermediates (ROI) and lipid oxidation products from inflammatory cells, have been linked to the potentiation of carcinogenesis. Murine macrophages when stimulated with phorbol esters induce 5,6 ring saturated thymine residues (T'), a lesion of known oxidative origin, in co-cultivated mammalian cells. Induction of this damage was inhibited by catalase and induced in target cells by reagent H2O2 alone. In the present studies, we used defined populations of macrophages with high, low and intermediate capacities for the release of H2O2 or metabolites of arachidonic acid (AA) to assess the relative contribution of these classes of compounds to the induction of saturated thymines. Macrophages activated with Bacillus Calmette-Guerin (BCG), which have the highest capacity for the release of H2O2 and the lowest for the release of metabolites of AA, induced the lowest levels of saturated thymines. Resident macrophages from the unmanipulated peritoneum, which have the lowest capacity for the production of H2O2 and the highest capacity for release of AA metabolites, induced more saturated thymines than did the BCG macrophages. Inflammatory macrophages elicited by casein, which have an intermediate capacity for release of H2O2 and AA metabolites, induced the highest level of saturated thymines. Zymosan, which induced more release of AA metabolites than release of H2O2, was a better stimulant for the induction of T' than TPA, which is a better stimulant for secretion of H2O2. Nordihydroguaiaretic acid (NDGA), an inhibitor of the lipoxygenase and cyclooxygenase pathways for metabolism of AA, inhibited the induction of T' by resident macrophages. Indomethacin, an inhibitor of the cyclo-oxygenase path, enhanced induction of T'. Taken together, the data suggest that while H2O2 has the capacity to induce T' in 3T3 cells, it may not be the only mediator of DNA damage and that lipoxygenase generated metabolites of AA may (alone or in concert with ROI) play an important role in the induction of oxidative DNA damage by macrophages.
Carcinogenesis 1986 May
PMID:The effect of macrophage development on the release of reactive oxygen intermediates and lipid oxidation products, and their ability to induce oxidative DNA damage in mammalian cells. 308 20

Indomethacin, a nonsteroidal antiinflammatory agent which inhibits prostaglandin biosynthesis, is an effective inhibitor of mammary carcinogenesis in rats. However, the activity of indomethacin as a chemopreventive agent is limited by toxicity. The present studies were conducted to determine if the toxic and anticarcinogenic effects of indomethacin can be modified by the phenolic antioxidant, butylated hydroxytoluene (BHT). Simultaneous administration of BHT resulted in a dose-related inhibition of indomethacin toxicity in female Sprague-Dawley rats, and increased the tolerable indomethacin dose from 50 to 150 mg/kg diet. When BHT (5000 mg/kg diet) and indomethacin (50 mg/kg diet) were administered in combination, no increased inhibition of 7,12-dimethylbenz(a)anthracene-induced mammary carcinogenesis was observed above that attained by administration of BHT alone or indomethacin alone at those doses. However, when the indomethacin dose was increased to 100 mg/kg diet, an enhanced inhibition of carcinogenesis was attained when BHT and indomethacin were administered from 2 weeks prior to until 1 week after 7,12-dimethylbenz(a)anthracene administration. These data indicate that "combination chemoprevention" regimens can be utilized to reduce the toxicity of anticarcinogenic drugs. However, the BHT-indomethacin interaction appears to involve a functional or dispositional antagonism which limits the anticarcinogenic efficacy of increasing indomethacin dose level.
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PMID:Combination chemoprevention of rat mammary carcinogenesis by indomethacin and butylated hydroxytoluene. 308 82

NMRI and SENCAR, two stocks of mice commonly used in multistage skin carcinogenesis studies, were compared with respect to the effects of inhibitors of arachidonic acid metabolism for the following 12-O-tetra-decanoylphorbol-13-acetate (TPA)-elicited events: tumor promotion, DNA synthesis in vivo and in vitro, ornithine decarboxylase induction, and prostaglandin (PG) E2 synthesis. Previous work had shown that the cyclooxygenase inhibitor indomethacin enhanced TPA promotion in SENCAR mice. We report here that over the same dose range (50 to 200 micrograms) indomethacin caused a dose-dependent inhibition of promotion in NMRI mice. Significant reversal of this inhibition was achieved with concomitant application of 10 micrograms PGF2 alpha but not PGE2. DNA synthesis studies showed that low doses of indomethacin and flurbiprofen increased TPA-stimulated DNA synthesis in primary cultures from SENCAR mice; indomethacin suppressed this response in NMRI cultures. In vivo DNA synthesis studies showed the same pattern: indomethacin enhanced TPA-stimulated DNA synthesis in SENCAR mice but inhibited in NMRI mice. Other classes of inhibitors of arachidonate metabolism (i.e., the cyclooxygenase-lipoxygenase inhibitors 5,8,11,14-eicosatetraynoic acid and phenidone and the phospholipase A2 inhibitor dibromoacetophenone) had inhibitory activity in vitro and in vivo in both stocks of mice. Indomethacin was found to inhibit TPA-induced ornithine decarboxylase activity to the same extent in both mice. Indomethacin was also very effective in inhibiting TPA-induced PGE2 synthesis in both stocks of mice. 5,8,11,14-Eicosatetraynoic acid and phenidone were likewise suppressive in both stocks of mice. It is concluded that the NMRI and SENCAR mice respond similarly to TPA with respect to promotion, DNA synthesis, ornithine decarboxylase induction, and PG synthesis. The difference appears to be in the degree of involvement of the lipoxygenase pathway.
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PMID:Events associated with mouse skin tumor promotion with respect to arachidonic acid metabolism: a comparison between SENCAR and NMRI mice. 310 6

The mechanism of the anti-promoting effect of the prostaglandin (PG) synthesis inhibitor indomethacin in colon carcinogenesis was investigated. Male Sprague-Dawley rats received 0.002% water solution of indomethacin as drinking water freely for 3 days, then a subcutaneous injection of various doses of PGE2 and/or an intrarectal instillation of 12 mumol of sodium deoxycholate as a colon tumor promoter. Ornithine decarboxylase (ODC), a marker of tumor promotion, in the distal colonic mucosa was assayed at 4 hr after deoxycholate instillation. Indomethacin significantly suppressed the deoxycholate-augmented increase of ODC activity, while exogenous PGE2 restored or further increased the augmented ODC activity. The amount of PGE2 and the level of ODC activity were well correlated. However, PGE2 alone without deoxycholate did not increase the activity. Deoxycholate markedly increased colonic mucosal PGE2 at 1 hr after the instillation, and indomethacin decreased it. The results indicate that PGE2, the production of which is stimulated in the colonic mucosa by deoxycholate, is involved in the induction of colonic mucosal ODC. This is probably why PG synthesis inhibitors may inhibit the tumor promotion and prevent cancer development in the colon.
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PMID:Involvement of prostaglandin E2 in bile acid-caused promotion of colon carcinogenesis and anti-promotion by the cyclooxygenase inhibitor indomethacin. 311 24


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