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

The co-carcinogenic activity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) was evaluated in male Fischer rats by co-administering them as 5% and 0.005% of the diet, respectively, for 2 years. The effect of simultaneous administration of two urinary bladder promoting substances, sodium saccharin and L-tryptophan as 5% and 2% of the diet, respectively, was also evaluated. Five of 16 rats administered sodium saccharin plus FANFT developed bladder tumors whereas none of the rats administered FANFT, sodium saccharin, or L-tryptophan alone, sodium saccharin plus L-tryptophan, or the control diet developed bladder tumors. Possible mechanisms for the co-carcinogenic activity of sodium saccharin and FANFT are discussed.
Carcinogenesis 1983
PMID:Co-carcinogenicity of sodium saccharin and N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide for the urinary bladder. 682 91

The induction of cancer of the urinary bladder is a multi-stage process involving multiple exogenous and endogenous factors. Based on the classical initiation-promotion model, we have used N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) as initiator and sodium saccharin (SAC) or tryptophan as promoters. These latter chemicals have the properties expected of promoters: induction of hyperplasia, reversibility and nonmutagenicity. Also, tumors were induced whether the promoter was administered immediately after FANFT or beginning 6 weeks after FANFT was discontinued, but no tumors resulted if either promoter was given without initiation with FANFT. Factor(s) present in normal urine also are involved in the promotion process, in addition to the role of urine as a carrier of carcinogens. However, administration of SAC to animals with a rapidly proliferating bladder mucosa, induced by ulceration, pellet insertion, or in utero, resulted in bladder tumor induction, even without prior initiation with FANFT. To better understand the complex interaction of the multiple variables in bladder carcinogenesis, a stochastic computer model has been formulated based on long-term carcinogenicity and tissue kinetic studies in vivo. This model indicates the importance of cell proliferation and the development of hyperplasia in carcinogenesis.
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PMID:Multistage carcinogenesis in the urinary bladder. 683 93

Adult rat hepatocytes in primary culture were used to study the effect of tryptophan pyrolysis products on the transcriptional process. Hepatocytes were treated with 1, 5 and 10 micrograms/ml of 3-amino-1,4-dimethyl-5H-pyrido-[4,3-b]-indole (Trp-P-1) or 3-amino-1-methyl-5H-pyrido-[4,3-b]-indole (Trp-P-2) for 2 and 4 h. The ultrastructural study revealed the appearance of nucleolar microsegregation accompanied by a reduction in peri- and interchromatin fibrils and granules in hepatocytes exposed to 10 micrograms/ml of each pyrolysate for 1 or 2 h. Biochemical investigation showed that the incorporation of [3H]uridine into nuclear RNA of treated hepatocytes was strongly decreased. Time- and concentration-related inhibition have been established; however, the inhibitory effect of Trp-P-1 was always superior to that of Trp-P-2. The determination of Mg2+-dependent RNA polymerase activity in an in vitro system functioning with isolated rat liver nuclei incubated in the presence of Trp-P-1 or Trp-P-2 showed a 40% inhibition of this activity. After a 1-h exposure of hepatocytes to 5 and 10 micrograms/ml of Trp-P-1, the recovery of RNA synthesis capacity was complete by 2 h and that of normal ultrastructural aspect was achieved within 4 h. All these results indicated that Trp-P-1 and Try-P-2 acted at the nucleolar level by a blockade of pre-rRNA synthesis and at the extranucleolar by decreasing the ultrastructural RNP responsible for hnRNA synthesis.
Carcinogenesis 1983
PMID:Ultrastructural and biochemical alterations induced by tryptophan pyrolysis products on rat hepatocytes in primary culture. I. Action on the transcriptional process. 683 20

Multistage models of carcinogenesis proposed to account for the observed patterns of tumor development in the skin, liver, lung, bladder and other organs involve initiation of neoplastic change in a few cells by a threshold dose of carcinogen followed by conversion of these latent tumor cells into an autonomous cancer by further doses of the same and/or other carcinogens, and/or noncarcinogenic promoting agents. In the rat urinary bladder, neoplastic change can be initiated by a few weeks treatment with low doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) or N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or by a single, low dose, intravesicular instillation of N-methyl-N-nitrosourea (MNU). Very few animals treated thus will develop bladder cancer unless exposed subsequently to some further regime which will promote tumor growth from the initiated cells. Many different factors will stimulate tumor growth in the initiated rat bladder, including further low doses of complete bladder carcinogens, dietary factors such as metabolites of tryptophan or deficiency of vitamin A, the food additives saccharin and cyclamate and some alkylating agents such as cyclophosphamide and methylmethane sulfonate. New and published evidence is reviewed which supports the belief that these and other factors are promoters or later stage carcinogens in the bladder. The difficulties of defining a promoter and of identifying markers of promotion, i.e., of distinguishing the second from the later stages of carcinogenesis in the urinary bladder, are discussed with reference to the action of promoters in the mouse skin initiation/promotion model. However, in terms of their effect on an initiated population on the risk of developing cancer, it is suggested that such a distinction is largely irrelevant. Since both second and later stage carcinogens accelerate tumor development in an initiated urothelium, they both have the potential to lower the age at which bladder cancer becomes symptomatic. They are thus as important as are initiating carcinogens in determining the patterns of age-related neoplastic disease in any population.
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PMID:Effect of promoters on incidence of bladder cancer in experimental animal models. 687 29

Aromatic amines, including 2-naphthylamine, 4-aminobiphenyl and benzidine, are known urinary bladder carcinogens in man and other species, but in rodents, aromatic amines and amides have usually induced liver tumors, occasionally also with tumors of the bladder and other tissues. Variations in organ specificity are related to differences in metabolism; for the production of bladder tumors, the rates of acetylation and deacetylation appear to be critical. Bladder specific carcinogens in rodents and other species have subsequently been identified, including N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) administered in the drinking water, N-[(4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) in the diet and N-methyl-N-nitrosourea (MNU) instilled intravesically. When low doses of several bladder carcinogens (BBN, FANFT, 2-acetylaminofluorene, and 3,3'-dichlorobenzidine) are administered to rats, either simultaneously or sequentially, a synergistic effect is observed with respect to bladder carcinogenesis. In addition, a multistage carcinogenesis process has been demonstrated for the rat bladder using MNU or FANFT as initiators, and dietary sodium saccharin, sodium cyclamate, or tryptophan as promoters. Calculi (or pellets) appear to enhance the promotion process but are not necessary for it to occur. Recent studies also indicate that urine has a role in the promoting process. The urothelium normally has a very low mitotic rate. If mucosal proliferation is increased, such as during fetal development or during regeneration and repair of an ulcer, the bladder appears to be considerably more sensitive to the effects of promoting substances. For example, if sodium saccharin is administered to rats after ulceration of the bladder, even without prior administration of an initiator, bladder carcinoma develops. Under these conditions, the substance appears as a carcinogen. Human populations with increased bladder epithelial proliferation, such as fetus, infants, patients with bacterial cystitis or men with partially obstructive prostatism, may have increased susceptibility to the action of carcinogenic or promoting stimuli.
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PMID:Promotion in urinary bladder carcinogenesis. 687 31

It has been shown that the occurrence of the preneoplastic lesion, papillary or nodular hyperplasia (PN hyperplasia) in rat urinary bladder induced by carcinogens is correlated with that of cancer. Therefore, the promoting effects of chemicals in two-stage bladder carcinogenesis were judged by measuring their ability to induce PN hyperplasia in rats. Male rats were given N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then one of 16 test chemicals for 32 to 34 weeks. Saccharin, ascorbate, DL-tryptophan, allopurinol, and diphenyl promoted development of PN hyperplasia. The dose-response of the promoters were examined in both sexes of rats by administration of saccharin at doses of 0.04, 0.2, 1.0 and 5.0% for 32 weeks after BBN treatment. The occurrence of PN hyperplasia was significantly increased in the group given 5% saccharin. Dose-response curves showed enhanced hyperplastic responses in both sexes given 0.2 to 5% saccharin. The organ specificities of promoters were studied in rats initiated with BBN or 2-acetylamino-fluorene (2-AAF) followed by phenobarbital or saccharin for 32 weeks. Phenobarbital greatly enhanced hepatocarcinogenesis. Saccharin significantly enhanced the occurrence of both BBN-induced and 2-AAF-induced PN hyperplasia. However, there was no effect of phenobarbital on the urinary bladder or of saccharin on the liver. The rats showed a strain difference in susceptibility of the urinary bladder to saccharin; ACI rats were most susceptible and Sprague Dawley rats were most resistant to saccharin. The membrane potential of superficial epithelial cells in the urinary bladder of rats treated with saccharin was measured with an intracellular microelectrode and found to be higher than that of controls.
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PMID:Effects of promoters on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in the rat. 687 32

The capacity of in vitro bioassays to detect the potential carcinogenicity of metal compounds is reviewed. The in vitro bioassays discussed include: bacterial reversion analysis to determine the capacity of metal salts to revert Salmonella typhimurium histidine auxotrophs or to revert Escherichia coli WP 2 tryp- to tryptophan prototrophy; examination of the ability of metal salts to preferentially inhibit cell growth in Bacillus subtilis cells deficient in DNA repair pathways; determination of the ability of metal salts to induce resistance to base analogs in mammalian cells; the capacity of metal salts to enhance viral transformation of mammalian cells or to transform cells in the absence of virus; and the ability of metal salts to induce chromosomal aberrations in mammalian cells. Using each of these in vitro bioassays, diverse metal compounds have been identified as potential carcinogens. Furthermore, the use of different compounds of a specific metal may allow a determination of the valence which may be required for carcinogenesis.
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PMID:Effects of metals in in vitro bioassays. 702 30

The effects of amino acids on the enhanced agglutinability of bladder cells with concanavalin A induced by subcarcinogenic treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine were examined. The amino acids examined were L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamic acid, L-glutamine, L-glycine, DL- and L-histidine, L-hydroxyproline, L-isoleucine, D- and L-leucine, L-lysine, L-methionine, DL- and L-phenylalanine, L-proline, L-serine, L-threonine, DL-, D- and L-tryptophan, L-tyrosine and D- and L-valine. They were added to powdered diet at a concentration of 2.0%. L-Leucine, L-isoleucine, L-valine, DL- and D-tryptophan prolonged the period during which the bladder cells showed enhanced agglutinability with concanavalin A. Leupeptin, a protease inhibitor, and L-leucyl-L-leucine were also examined at a concentration of 0.1% because of their similar chemical structures, and were found to have the same effect. The tumor-promoting effects of DL-tryptophan and leupeptin have already been established by in vivo carcinogenesis experiments. The effects of L-leucine, L-isoleucine, L-valine, D-tryptophan and L-leucyl-L-leucine, detected by this short term assay, suggest that these compounds may also be promoters of bladder cancer in rats.
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PMID:Detection of amino acids as possible promoters of bladder cancer in rats by measuring their enhancement of agglutination of bladder cells by concanavalin A. 716 May 80

The effect of sodium saccharin (SAC) or L-tryptophan (LT) on urinary bladder carcinogenesis initiated by feeding N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) for 4 weeks as 0.2% of the diet to male F344 weanling rats was evaluated. SAC was fed as 5% of the diet, and LT was 2% of the diet. FANFT fed for 4 weeks followed by 100 weeks of control diet did not produce any carcinomas; one of 25 rats developed a bladder papilloma. Of 26 rats fed SAC for 100 weeks after FANFT, two developed papillomas, and five developed carcinomas (p less than 0.03). Of 26 rats fed LT for 100 weeks after FANFT, three developed papillomas, and two developed carcinomas (p greater than 0.1) Eight rats fed FANFT for 72 weeks all developed bladder carcinomas, but rats fed control diet alone, control diet with SAC, or control diet with LT did not develop any bladder tumors. Scanning electron microscopic examination of Week 104 of the experiment showed the presence of pleomorphic microvilli on the bladder surface of some rats fed SAC of LT whether following 4 weeks of control diet alone or 4 weeks of FANFT. Four weeks of FANFT feeding, a lower dose than used previously in our studies, appears to be a subcarcinogenic level. Under these experimental conditions, the promoting activity of SAC is demonstrated with statistical significance. The results with LT were not statistically significant.
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PMID:Effect of L-tryptophan and sodium saccharin on urinary tract carcinogenesis initiated by N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide. 724 68

Aromatic amines have been implicated in the etiology of bladder cancer in humans since Rehn observed the disease in 3 workers in the German aniline dye industry in 1895. 2-Naphthylamine was identified 40 years later as one of the carcinogens in tests involving the feeding of the chemical to dogs. The discovery of N-2-fluorenylacetamide as a carcinogen in rodents inducing tumors of the bladder and other organs provided a more inexpensive and rapid model for the study of bladder carcinogenesis. The metabolic activation pathways of aromatic amine and amide compounds has been extensively examined. In the 1960's, organ-specific rodent models were discovered with the use of N-butyl-N-(4-hydroxybutyl) nitrosamine, N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, or N-methyl-N-nitrosourea. Recent experiments have demonstrated that bladder carcinogenesis can be divided into two stages similar to the initiation-promotion model in mouse skin. Possible promoters have included sodium saccharin, sodium cyclamate, and tryptophan. Certain metabolites of the latter compound are also N-substituted aryl compounds. Lastly, recent studies of the relationship of urine to the carcinogenic process in the bladder indicate that it can act as a promoting agent as well as a carrier of carcinogenic substances.
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PMID:Urinary bladder carcinogenesis with N-substituted aryl compounds: initiation and promotion. 734 85


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