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

The genotoxic activity of benzidine was studied in two cell lines derived from rat (H4) and human (HepG2) hepatomas which have been shown to be capable of activating certain promutagens. The responses were compared to results in two lung-derived fibroblast lines (IMR-90 and V79) which appear to have little or no metabolizing capability. Benzidine was found to induce sister chromatid exchanges in the two liver-derived cell lines in a dose-dependent fashion but failed to induce sister chromatid exchanges in the fibroblast lines. Since one proposed pathway for benzidine activation involves prostaglandin-mediated metabolism, we tested the effect of pretreatment with indomethacin, an inhibitor of this metabolic pathway. Indomethacin was highly effective in inhibiting benzidine-induced sister chromatid exchanges in both H4 and HepG2 cells. These results suggest that some DNA damage may occur in the livers of fast acetylating species such as the rat without prior N-acetylation and that some amount of DNA damage may occur in the livers of slow acetylating species, even when the liver is not the target organ for carcinogenesis.
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PMID:Induction of sister chromatid exchanges by benzidine in rat and human hepatoma cell lines and inhibition by indomethacin. 326 48

Indomethacin, a nonsteroidal antiinflammatory agent which inhibits prostaglandin biosynthesis, has significant activity in inhibiting the growth and/or inducing the regression of transplantable tumors. The present study was designed to determine if, in addition to its chemotherapeutic effects, indomethacin also acts as a cancer chemopreventive agent. Fifty-day-old virgin female Sprague-Dawley rats were given a single intragastric dose of either 8 or 16 mg of 7,12-dimethylbenz(a)anthracene (time 0). Basal diet was supplemented with 25 or 50 mg of indomethacin per kg of diet by the following protocol: (a) -2 to +1 week; (b) +1 week to end; or (c) none. Administration of indomethacin by both protocols resulted in an inhibition of mammary tumorigenesis; however, the effect of -2 to +1 week indomethacin exposure was primarily on the induction of benign mammary tumors, while +1 week to end indomethacin administration inhibited the induction of both benign mammary tumors and mammary cancers. These data indicate that indomethacin has significant protective activity when administered either during the "early" stage (comprising the carcinogen-target cell interaction) or the "late" stage (postcarcinogen tumor development) of mammary carcinogenesis in rats. Possible mechanisms of indomethacin action include both local and systemic effects.
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PMID:Modulation of rat mammary carcinogenesis by indomethacin. 391 46

The mechanism whereby bile acids promote colon tumor development was studied. Bile acids increase intestinal ornithine decarboxylase (ODC), an effect that is suppressed by indomethacin, an inhibitor of prostaglandin (PG) synthesis. Male Sprague-Dawley rats were pretreated with 0.002% indomethacin solution in drinking water for 3 days, then given a single intrarectal instillation of 20 mg of deoxycholate and/or 1 mg of PGE2. Four hours later, the rats were killed, and the ODC activity was measured in the mucosa of the distal large bowel. ODC was significantly lower in rats given indomethacin plus deoxycholate than in those given deoxycholate alone, but it was significantly higher in rats treated with indomethacin and PGE2 plus deoxycholate. Without deoxycholate, indomethacin plus PGE2 did not elevate ODC compared with indomethacin alone or no treatment. Indomethacin reduced the colonic mucosal PG level. Thus, PGE2 mediates the deoxycholate-induced colonic mucosal ODC activity, and overcomes the inhibition of this enzyme activity by indomethacin. It is concluded that the anti-promoting effect of indomethacin in colon carcinogenesis, previously demonstrated, may result from the indomethacin inhibition of PG synthesis.
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PMID:Prostaglandin E2 counteracts the inhibition by indomethacin of rat colon ornithine decarboxylase induction by deoxycholic acid. 392 7

Indomethacin was not observed to produce any significant effect upon hamster buccal pouch carcinogenesis. No statistically significant difference in delayed hypersensitivity response to dinitrochlorobenzene was found between indomethacin-treated, tumor-bearing and control groups.
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PMID:Indomethacin and 7,12-dimethylbenz(a)anthracene-induced carcinogenesis in the hamster buccal pouch. 392 5

Activation of benzo[a]pyrene to bind to proteins by co-oxidation with prostaglandin synthesis was studied in rat liver and lung microsomes and cytosols. The kinetics of this activation showed a two-phase reaction; a rapid initial reaction for 2-4 min after addition of arachidonic acid and then a slow reaction or a plateau state. The reaction was linear only with low contents of the enzyme proteins, and was slower with more than 1 mg of enzyme per ml of incubation mixture. Other unsaturated fatty acids were also effective in activating benzo[a]pyrene with both microsomes and cytosols. With microsomal proteins linoleic acid was more effective than arachidonic acid, whereas with cytosolic proteins arachidonic acid was the best cofactor. Linolenic acid could also activate benzo[a]pyrene, though less efficiently, but oleic acid had no influence on the binding. Indomethacin did not inhibit the activation, but nordihydroguaiaretic acid and quercetin significantly reduced the binding. Addition of hematin significantly increased the binding. The NADPH-dependent bindings of benzo[a]pyrene to proteins with liver and lung microsomes were one-third and one-twelfth the values after incubation with arachidonic acid. Addition of glutathione or Ca2+ ion reduced the binding significantly. The present results suggest the importance of co-oxidation with lipoxygenase for activation of benzo[a]pyrene and the possible role of both the arachidonic acid cascade system and the NADPH-dependent cytochrome P-450 system in metabolic activation of chemical carcinogens.
Carcinogenesis 1984 Jul
PMID:Arachidonic acid-dependent activation of benzo[a]pyrene to bind to proteins with cytosolic and microsomal fractions from rat liver and lung. 632 41

The conversion of 2-amino-6-methyldipyrido[1,2-a:3' ,2' -d]-imidazole (Glu-P-1), a highly mutagenic principle in a pyrolysate of glutamic acid, to protein-bound metabolites in vitro was examined with microsomes from various tissues of female F344 rats. Addition of NADPH to the incubation mixture containing microsomes and [14C]Glu-P-1 increased the binding of its metabolites to microsomal proteins linearly with time for up to 30 min, while on addition of arachidonic acid the binding increased linearly only for the first 2-4 min of incubation and then levelled off. However, due to the initial rapid binding, addition of arachidonic acid resulted in 6-fold greater binding of metabolites to small intestinal microsomes than addition of NADPH on incubation for 4 min, and with microsomes from liver and colon, arachidonic acid was found to be a better cofactor than NADPH for activation of Glu-P-1. Indomethacin significantly inhibited the increase in binding by arachidonic acid. Additions of linoleic and linolenic acids also increased the binding, but addition of oleic acid had no influence. With hepatic microsomes from 3-methylcholanthrene-treated rats, binding within 4 min after addition of arachidonic acid was greater than that after addition of NADPH and the reverse on further incubation. These findings suggest that prostaglandin synthetase may serve as an alternative enzyme to cytochrome P-450 monooxygenases for conversion of Glu-P-1 to active intermediates in all the rat tissues investigated.
Carcinogenesis 1984 May
PMID:Activation of 2-amino-6-methyldipyrido[1,2-a:3' ,2' -d]imidazole, a mutagenic pyrolysis product of glutamic acid, to bind to microsomal protein by NADPH-dependent and -independent enzyme systems. 642 9

Indomethacin treatment to rats bearing dimethylhydrazine-induced colonic cancer resulted in increased mortality (p less than 0.01) and a greater incidence of metastases compared to untreated animals with the same stage of disease. It is postulated that indomethacin might have a promotional effect on the spread of autochthonous experimental colon cancer.
Carcinogenesis 1984 Feb
PMID:Enhancement of colonic cancer by indomethacin treatment in dimethylhydrazine pretreated rats. 669 45

Aspirin and indomethacin, administered systemically by oral route, were found to delay the development of hamster buccal pouch epidermoid carcinomas induced by thrice weekly topical applications of a 0.5 percent solution of 7,12-dimethylbenz(a)anthracene (DMBA) in mineral oil. Forty male and female Syrian hamsters (Mesocricetus auratus) were divided into four equal groups. In Group 1 animals the left buccal pouch was painted thrice weekly with DMBA. Group 2 animals were painted thrice weekly with DMBA and received 12 mg. aspirin daily by oral route. Group 3 animals were painted thrice weekly with DMBA and received 1 mg. indomethacin daily by oral route. Group 4 animals were maintained as untreated controls. Two animals in each of the four groups were killed with ether at 8, 10, 12, 13, and 14 weeks after the start of the experiment. At the time of sacrifice the buccal pouches were photographed and the average number of tumors and the average size of tumors in each group were noted. The left and right buccal pouches were dissected, fixed in 10 percent formalin, sectioned in paraffin, and stained with hematoxylin and eosin. Autopsies were also performed on each animal. Both left and right buccal pouches and major organs were studied histologically. Both aspirin and indomethacin in the dosages used were found to delay DMBA buccal pouch carcinogenesis. A suggested mechanism of action is the inhibition of prostaglandin synthesis by the role of both aspirin and indomethacin as inhibitors of prostaglandin synthetase. Indomethacin appeared to exert a greater tumor-inhibiting effect than aspirin in the dosages used.
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PMID:Delay in hamster buccal pouch carcinogenesis by aspirin and indomethacin. 679 84

Modulation of ultraviolet-B (UVB) skin carcinogenesis by topical treatment with two antiinflammatory drugs expected to have different mechanisms of action has been studied in the hairless mouse. Indomethacin is a nonsteroidal antiinflammatory agent which may act by inhibiting prostaglandin biosynthesis. Triamcinolone acetonide is a steroidal antiinflammatory agent. Both of these drugs inhibited the induction of epidermal ornithine decarboxylase by UVB when applied topically in a acetone vehicle. A UVB skin tumor study was designed. Groups of mice were irradiated daily with UVB for 20 days, each mouse receiving a total of 17.1 kJ UVB per sq m. Group 1 was treated with acetone immediately after each irradiation; Group 2 received 700 nmol indomethacin in acetone immediately after each irradiation; Group 3 received 14.4 nmol triamcinolone acetonide in acetone immediately after each irradiation. Mice were killed after 52 weeks, and the tumors were excised and examined histologically. Both topical indomethacin and topical triamcinolone acetonide were effective in reducing the incidence and size of the skin tumors induced by UVB. This evidence supports the hypothesis that the induction of ornithine decarboxylase may be a critical component of UVB skin carcinogenesis and that inhibition of ornithine decarboxylase induction can be used as a screen for agents which will inhibit UVB skin carcinogenesis.
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PMID:Inhibition of ultraviolet-B epidermal ornithine decarboxylase induction and skin carcinogenesis in hairless mice by topical indomethacin and triamcinolone acetonide. 710 93

The effects of indomethacin on the urinary bladder and renal pelvis in rats treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) were studied. Two hundred female Sprague-Dawley rats were divided into four groups. Group 1 received control diet without added chemicals. Group 2 was treated with indomethacin (1 mg/kg per day) in the drinking water throughout the experiment. Groups 3 and 4 received 0.2% FANFT in the diet for seven weeks followed by control diet. In addition to FANFT, Group 4 received indomethacin, 1 mg/kg per day, for the entire experiment. The rats were sacrificed after 92 weeks. There were no urothelial tumors in the control group, one renal pelvic tumor in the indomethacin group, 4 tumors in the FANFT group and 10 urothelial tumors in the FANFT + indomethacin group. The difference between Groups 3 and 4 was statistically significant (P < 0.05). Moderate and severe hyperplasia of the renal pelvic and papillary epithelium was found in 15 of 48 rats in Group 2 (indomethacin only) as compared with 6 of 49 control rats (P < 0.05). Moderate and severe hyperplasia was equally frequent in Groups 3 and 4 (14 and 17 animals in each group, respectively). Twenty-four rats in Group 2 had mammary tumors as compared to 12 animals in Group 1 (P < 0.01). Five of the tumors in Group 2 were adenocarcinomas. There was no difference between the number of mammary tumors in Groups 3 and 4 (36 and 32 animals in each group, respectively). The results suggest that indomethacin enhances FANFT-induced urinary tract carcinogenesis. Indomethacin also seems to exert some tumorigenic activity in the mammary gland.
Carcinogenesis 1995 Jul
PMID:Effect of indomethacin on N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced urinary tract carcinogenesis. 761 82


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