UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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Promoting effects of Na or K phosphate salts on rat two-stage bladder carcinogenesis were compared. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and thereafter received 1.4% Na3PO4, 2.0% NaH2PO4, 1.0% K3PO4, or 2.5% KH2PO4, these dietary concentrations being selected because they result in approximately equal levels of Na+ and K+ in the urine, equivalent to moderate natriuresis or kaluresis in comparison with our previous data. Treatment with Na3PO4 or K3PO4 induced significant increase in urinary pH compared with control values, whereas urinary pH in the NaH2PO4 and KH2PO4 groups was comparable to control values. With regard to preneoplastic lesion development, both incidences and multiplicity were significantly increased in the groups given Na3PO4 or K3PO4 compared with both controls and NaH2PO4 or KH2PO4 groups, respectively. Furthermore, treatment with Na3PO4 significantly increased multiplicity of papillomas, accompanied by a tendency to increased incidence. No statistically significant difference in promoting potential between Na3PO4 and K3PO4 groups was evident. The present results thus suggest that tumor promotion under conditions of moderate natriuresis or kaluresis depends primarily on high urinary pH.
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PMID:Comparative promoting activities of phosphate salts on rat two-stage bladder carcinogenesis under conditions of equivalent urinary Na+ or K+ levels. 168 39

Quinone metabolites of catechol estrogens have been postulated to mediate estradiol-induced carcinogenesis. In this study, this postulate was examined by investigating the effect of modulators of quinone metabolism on estradiol-induced tumor incidence in male Syrian hamsters. 2(3)-t-Butyl-4-hydroxyanisol (BHA) and dicumarol which are known to stimulate or inhibit respectively, the activity of quinone reductase, lowered tumor incidence by 33 and 42% respectively (3/9 and 5/12 tumor-free animals/total respectively), from 100% (13/13) observed with 17 beta-estradiol (E2) treatment only. Ebselen, a substance with glutathione peroxidase-like activity, and sodium 2-mercaptoethanesulfonate (Mesna), a cytoprotective thiol-containing agent, were only marginally effective in decreasing the estradiol-induced kidney tumor incidence (3/11 and 4/19 tumor-free animals/total respectively). The lowering of tumor incidence by BHA and dicumarol correlated well with a 40-45% decrease in renal peroxidatic activity of cytochrome P450 in hamsters treated with these substances plus estradiol for 1 month. In addition, these compounds also inhibited the oxidation of diethylstilbestrol to its corresponding quinone in vitro. An influence on quinone reductase or other detoxifying enzymes in chronically treated male Syrian hamsters could not be detected. These data support a mediation of estradiol-induced carcinogenesis by quinones formed by metabolic oxidation of catechol estrogens.
Carcinogenesis 1990 Apr
PMID:Inhibition of estrogen-induced kidney carcinogenesis in Syrian hamsters by modulators of estrogen metabolism. 169 Oct 52

Ion transport across premalignant large bowel mucosa in CF1 mice was evaluated by measuring sodium and chloride fluxes across voltage-clamped colonic segments obtained from control animals and animals treated for 4 wk with the procarcinogen 1,2-dimethylhydrazine, which induces tumor development principally in the distal colon. In control CF1 mouse colon, the net flux of sodium was 5.1 +/- 0.7 and 4.6 +/- 0.7 microEq.cm-2.h-1 and the net flux of chloride was 6.1 +/- 1.3 and 0.8 +/- 1.2 microEq.cm-2.h-1 in the distal and proximal colon, respectively. Removal of bicarbonate decreased the net flux of sodium 1.5 +/- 0.5 and 1.9 +/- 0.7 microEq.cm-2.h-1 in the distal and proximal colon, respectively, while the net flux of chloride was decreased to 1.7 +/- 1.8 microEq.cm-2.h-1 in the distal colon but was unaltered (0.8 +/- 0.1 microEq.cm-2.h-1) in the proximal colon. Addition of 25 mM bicarbonate stimulated the net flux of sodium and chloride absorption in the distal colon but increased net flux of sodium absorption alone in the proximal colon and stimulated net flux of chloride secretion. Removal of chloride decreased net flux of sodium to 3.4 +/- 1.4 and 1.8 +/- 0.8 microEq.cm-2.h-1 in the distal and proximal colon, respectively. Addition of 20 mM Cl stimulated net flux of sodium in the distal but not the proximal colon. These data suggest that sodium absorption is mediated by an electroneutral Cl-dependent, HCO3-dependent process (i.e., Na-H Cl-HCO3 dual exchange) in control distal colon and by an electroneutral HCO3-dependent process in control proximal colon. Following 1,2-dimethylhydrazine treatment, net flux of sodium in the distal colon was not stimulated by the addition of Cl or HCO3, and transport in the proximal colon was similar to that in control animals. However, 1,2-dimethylhydrazine treatment appears to uncouple Na-H Cl-HCO3 exchange in the distal colon early in the process of large bowel carcinogenesis.
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PMID:Uncoupling of sodium chloride transport in premalignant mouse colon. 169 47

Twenty rats were randomized into a vesicosigmoidostomy and an unoperated control group. In both groups the 24 hour excretion of secondary amines, nitrate, nitrite and nitrosamines was measured before and after gavage of proline and nitrate, piperazine and nitrate, N-nitrosoproline, mono-N-nitrosopiperazine. The urinary nitrosamine concentrations were not significantly different between both groups neither before nor after application of the several substances. Thirty rats were randomized into two vesicosigmoidostomy groups with and without antibiotic coverage and an unoperated control group. After ligation of distal rectum and mesosigmoid the rectosigmoids were removed. No significant concentrations of volatile nitrosamines could be measured in the rectosigmoid contents of the three groups. One hundred and twenty rats randomized into three groups following vesicosigmoidostomy received the potential nitrosamine antidotes sodium-2-mercaptoethane sulfonate or sodiumpentosan-polysulfate or acted as controls. 12/118 (10.2%) developed adenomas and 25/118 (21.2%) adenocarcinomas at the vesico-colonic anastomosis with no significant differences between the three groups concerning tumor incidence or mortality. The results show that colon carcinomas occur in a rat model for ureterosigmoidostomy without evidence for thus induced nitrosamine formation. This and the missing effect of nitrosamine antidotes suggest that other factors than nitrosation must be responsible for colon carcinogenesis following urinary diversion via intestine.
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PMID:Tumor induction in a rat model for ureterosigmoidostomy without evidence of nitrosamine formation. 171 71

Calcium valproate is an anticonvulsant agent with pharmacokinetic properties similar to sodium valproate and valproic acid. Potential carcinogenesis of calcium valproate was evaluated in B6C3F1 mice and Wistar rats given 125, 250 and 500 mg/kg in the diet for 104 weeks. Survival in treated rats increased in a dose-related pattern despite a tumorigenic response in females. Adenocarcinomas of the uterus and cervix were increased in treated rats when compared to controls. The incidence of uterine neoplasia was 8, 20, 14 and 32% in the control, 125, 250 and 500 mg/kg groups, respectively. Neoplasia in treated rats were detected against a higher than expected background of adenocarcinomas in concurrent controls, since 8% incidence in controls was substantially above the laboratory historical database value of 0.6%. Tumors varied from epithelial masses confined to the endometrium, to transmural, highly desmoplastic neoplasms that invaded the serosa lining and the peritoneal cavity. These tumors metastasized in treated rats but not in controls. The statistically significant (P less than 0.01) increase in uterine adenocarcinomas found in females given 500 mg/kg of calcium valproate contrasts the absence of this tumor type in a previous rat carcinogenicity bioassay with valproic acid. Subcutaneous fibrosarcomas were significantly increased in valproic acid-treated males, but no uterine tumors were reported in females. It is puzzling that a true carcinogenic potential would be expressed by markedly different target organs as obtained with the acid and calcium salt of this moiety.
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PMID:Calcium valproate-induced uterine adenocarcinomas in Wistar rats. 172 66

Chlorophyllin (CHL), a sodium/copper salt of chlorophyll used in the treatment of geriatric patients, exhibits potent antimutagenic activity in a range of assays in vitro and in vivo. The protective effects of CHL were studied in Sprague-Dawley rats using inhibition of carcinogen-DNA binding as an end-point. Animals were administered CHL (150 mg/kg body wt) and [2-14C]2-amino-3-methylimidazo[4,5-f]quinoline (IQ, 50 mg/kg body wt) by single oral gavage. Covalent IQ-DNA binding in liver was determined 8, 24 and 48 h after dosing; CHL inhibited binding at these times by 58, 56 and 46% respectively, compared with rats given IQ alone. The total liver burden of IQ-derived radioactivity was reduced in CHL-treated rats, as was the total amount of radiolabel eliminated in the urine and bile. However, elimination via the feces was increased in rats given CHL, both in terms of total radiolabel eliminated and amount of unmetabolized IQ in dichloromethane extracts of feces. Finally, pretreatment with CHL in the drinking water, or injection of CHL into isolated loops of intestine in situ, reduced the absorption of IQ from the gut. Collectively, these findings indicate that, when administered simultaneously with the carcinogen, CHL attenuates IQ-DNA binding in rat liver by interacting with IQ in the gut and reducing carcinogen uptake, distribution and metabolism. The results suggest that further studies should be conducted with respect to the protective mechanisms and possible anti-carcinogenic properties of CHL.
Carcinogenesis 1992 Jan
PMID:Protection by chlorophyllin against the covalent binding of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) to rat liver DNA. 173 63

A quantitative in vitro transformation assay has been developed for the first time using primary rat kidney epithelial (RKE) cells. RKE cells were grown in a 50:50 mixture of 3T3 conditioned medium and DF8 medium composed of Ham's F-12/DMEM supplemented with ferrous sulfate, vasopressin, transferrin, sodium selenite and 10% fetal bovine serum. Colony forming efficiency of cells plated in this medium was high, ranging from 2.4 to 16%. Normal RKE cells treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) became transformed to a preneoplastic state of enhanced in vitro growth potential and formed large colonies of morphologically altered cells, whereas RKE cells treated with vehicle alone ceased proliferating and/or sloughed off the dish within 4-6 weeks. Relative survival and percent transformation frequency (Tf) of RKE cells exposed to MNNG were inversely proportional and both were dose dependent. MNNG concentration of 0.5, 1.0 and 2.0 micrograms/ml resulted in transformation frequencies of 0.13, 0.37 and 1.1% respectively (n = 4). Morphologically transformed colonies gave rise to cell lines with indefinite growth capacity and neoplastic potential. One of six transformed RKE cell (TRKE) lines injected into nude mice produced adenocarcinomas. This assay represents the first in vitro model for studying mechanisms of chemical transformation of normal kidney epithelial cells and may also be useful as a screen for identifying potential renal carcinogens.
Carcinogenesis 1992 Jan
PMID:Development of a quantitative in vitro transformation assay for kidney epithelial cells. 173 69

Five non-genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36-week in vivo assays for carcinogenesis were reevaluated in a 20-week experiment in order to assess the summation influence of dietary uracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L-ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the 11th to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of PN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group. The results confirm that uracil given in the middle of the post-initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.
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PMID:Summation effects of uracil and other promoters on epithelial lesion development in the F344 rat urinary bladder initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine. 175 81

The therapeutic history of sodium diethyldithiocarbamate (dithiocarb) is briefly reviewed. Dithiocarb was discovered serendipitously in our laboratory 35 years ago for the specific treatment of nickel carbonyl poisoning. Since that time, the therapeutic efficacy of dithiocarb has been reported for many disorders, including: nickel, cadmium, thallium, copper, and mercury poisonings, experimental nickel carcinogenesis, protection against radiation damage to bone marrow, treatment of candidiasis in experimental animals, hepatolenticular degeneration (Wilson's disease), systemic lupus erythematosis, and human immunodeficiency virus infection (HIV). It has been used as an antagonist to cisplatin and cyclophosphamide toxicities, and as an antidote to hepatotoxicity induced by chloroform, carbon tetrachloride, and halothane. Most recently, it has been observed that the progression of HIV-1 infection is inhibited by dithiocarb administered intravenously or orally to patients with acquired immunodeficiency syndrome (AIDS). Attention is directed to the interactions of divalent cations to viral infections and to metal chelators (e.g., dithiocarb) as potential antiviral agents.
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PMID:Therapeutic properties of sodium diethyldithiocarbamate: its role as an inhibitor in the progression of AIDS. 184 85

The concentrations of nitrite, thermo- and acetic acid-labile TEA-responsive compounds (TACs) and N-nitroso compounds (NOCs) as a group were measured in human gastric juice collected just before and 1, 2 and 4 h after oral ingestion of 1 g ascorbic acid (AA) or 200 mg sodium nitrate, separately or in combination. Individual responses of gastric [nitrite] following ingestion of AA alone varied widely, with both decreases and increases being observed, and showed no correlation with gastric pH. While a mixed response was also noted for [NOC] and [TAC], substantial decreases were observed in 5/6 individuals with initial [NOC] greater than 0.2 microM and 3/3 individuals with initial [TAC] greater than 0.2 microM, implying that (i) AA effectively inhibited gastric nitrosation and (ii) a basal amount of NOCs and TACs was present in gastric juice which could not be lowered by AA ingestion. Statistical analysis indicated that global mean values of gastric [NOC] were significantly reduced (P less than 0.02) 1-4 h after ingestion of AA. Ingestion of 200 mg sodium nitrate alone resulted in increases in gastric [NOC], which in some cases were very substantial. While nitrosation appeared lower following ingestion of the same dose of nitrate in combination with 1 g AA, the difference from the effects of nitrate alone was not statistically significant. In aqueous buffer, pH 2.5, and in the presence of 1 mM AA, 50 microM nitrite was consumed with a t1/2 of 50 min only if molecular oxygen had first been removed from the system. In the presence of oxygen, no consumption of nitrite could be detected in 50 min, reflecting nitrite recycling (oxidation of nitric oxide to higher oxides of nitrogen and hydrolysis back to nitrite). It is likely that nitrite recycling occurring after collection of gastric juice accounted for the inconsistent responses of gastric nitrite following ingestion of AA. Incubation of human gastric juice, pH 2.5, in vitro in the presence of 50 microM sodium nitrite for 60 min resulted in an increase of [NOC] and [TAC] from 0.10 to 0.70 and 1.10 microM respectively. Nitrosation was efficiently inhibited by AA, 2.27 mM AA resulting in 87 and 100% inhibition respectively. Removal of oxygen from the reaction mixture did not have any significant effect on the extent of nitrosation in the presence or absence of AA.
Carcinogenesis 1991 Aug
PMID:Studies in gastric carcinogenesis. V. The effects of ascorbic acid on N-nitroso compound formation in human gastric juice in vivo and in vitro. 186 Jan 56

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