Induction Of Urinary Bladder Tumors Research Articles

Selective inhibition of integrin αvβ6 leads to rapid induction of urinary bladder tumors in cynomolgus macaques.

Administration of a novel and selective small molecule integrin αvβ6 inhibitor, MORF-627, to young cynomolgus monkeys for 28 days resulted in the rapid induction of epithelial proliferative changes in the urinary bladder of 2 animals, in the absence of test agent genotoxicity. Microscopic findings included suburothelial infiltration by irregular nests and/or trabeculae of epithelial cells, variable cytologic atypia, and high mitotic rate, without invasion into the tunica muscularis. Morphologic features and patterns of tumor growth were consistent with a diagnosis of early-stage invasive urothelial carcinoma. Ki67 immunohistochemistry demonstrated diffusely increased epithelial proliferation in the urinary bladder of several monkeys, including those with tumors, and αvβ6 was expressed in some epithelial tissues, including urinary bladder, in monkeys and humans. Spontaneous urothelial carcinomas are extremely unusual in young healthy monkeys, suggesting a direct link of the finding to the test agent. Inhibition of integrin αvβ6 is intended to locally and selectively block transforming growth factor beta (TGF-β) signaling, which is implicated in epithelial proliferative disorders. Subsequent in vitro studies using a panel of integrin αvβ6 inhibitors in human bladder epithelial cells replicated the increased urothelial proliferation observed in monkeys and was reversed through exogenous application of TGF-β. Moreover, analysis of in vivo models of liver and lung fibrosis revealed evidence of epithelial hyperplasia and cell cycle dysregulation in mice treated with integrin αvβ6 or TGF-β receptor I inhibitors. The cumulative evidence suggests a direct link between integrin αvβ6 inhibition and decreased TGF-β signaling in the local bladder environment, with implications for epithelial proliferation and carcinogenesis.

Enhancement of Urinary Bladder Carcinogenesis by the Role of Chronic Bacterial Infection-induced Inflammation (Imunnohistochemical and Biochemical studies)

Background: Bacterial infections traditionally have not been considered major causes of cancer. Recently, however, bacteria have been linked to cancer by two mechanisms: induction of chronic inflammation and production of carcinogenic bacterial metabolites. The most specific example of the inflammatory mechanism of carcinogenesis is Escherichia coliinfection. E. coli has been epidemiologically linked to urothelial carcinoma of the urinary bladder by its propensity to cause lifelong inflammation. This inflammation is in turn thought to cause cancer by inducing cell proliferation and production of mutagenic free radicals and N-nitroso compounds. Material and methods: After each 3, 6 and 9 months of daily oral administration ofdibutyl amine (DBA) plus sodium nitrate (nitrosamine precursors) in drinking water, curcuma in grinding diet and bladder injection with E. coli, rats were sacrificed. The excited bladder were dissected, processed and stained with H&E and anti-Ki67 immunohistochemical stains. This was followed by Elisa for caspse-3 and statistical analysis. Results: The current results indicated that E. coli infection in the bladder tissues increases the carcinogenic ability of nitrosamine precursors through caused marked alteration in the form hyperplastic, dysplastic and metaplastic urothelium. Also, there was a statistically significant increase in ki67 immunoreactivity in urothelium. However, a statistically significant decrease in the concentration of caspase-3 in bladder tissue consequently caused the process of carcinogenesis. All these changes were less marked after curcuma treatment when compared with the group that not treated with curcuma. Conclusion: Bacterial infection of the urinary bladder may play a major additive and possible role in bladder carcinogenesis. Rhizome of curcuma may have a protective action during induction of urinary bladder tumors.

Lack of Enhanced Epithelial Cell Proliferation in the Urinary Bladder of Heterozygous p53 Knockout Mice Given Sodium Ortho-phenylphenate or Uracil

In the present study, we investigated epithelial cell proliferation in heterozygous p53 knockout (p53+/-) mice after administration of two urinary bladder non-genotoxic carcinogens, in comparison with that in wild-type littermates (p53+/+). Mice at 10-weeks of age were given 2% sodium ortho-phenylphenate (Na-OPP) or 2.5% uracil in the basal diet for 4 weeks. Uracil evoked a marked elevation of epithelial cell proliferation and development of papillary or diffuse epithelial hyperplasia associated with calculus formation in p53+/- as well as p53+/+ mice. Administration of Na-OPP caused alkalization of the urine in both. Neither Na-OPP nor uracil induced a higher epithelial cell proliferative response in p53+/- mice as compared with p53+/+ mice. While we previously reported p53+/- mice to be highly sensitive to a genotoxic urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine, the present results suggest that p53+/- mice may not have a high susceptibility to induction of urinary bladder tumors by non-genotoxic carcinogens.

ChemInform Abstract: Structure and Metabolic Fate of N‐Nitrosodialkylamines in Relation to Their Organotropic Carcinogenicity with Special Reference to Induction of Urinary Bladder Tumors

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Structure and metabolic fate of N-nitrosodialkylamines in relation to their organotropic carcinogenicity with special reference to induction of urinary bladder tumors

The metabolic fates of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and N,N-dibutylnitrosamine (DBN) were investigated in the rat and other animal species, to elucidate a possible relationship between metabolism and organotropic carcinogenicity to the urinary bladder of these N-nitrosamines. The principal urinary metabolite of BBN as well as of DBN in the rat was N-butyl-N-(3-carboxypropyl)nitrosamine (BCPN), which was demonstrated to be the active form of these compounds as bladder carcinogen. The species difference in response to BBN or DBN is discussed on the basis of the urinary excretion rate of BCPN. Metabolism in vivo and carcinogenicity of a number of BBN analogues were investigated in the rat and a general scheme for biotransformation of N-alkyl-N-(omega-hydroxyalkyl)nitrosamines is given. A possible correlation of structure and metabolism with organotropic carcinogenicity of BBN analogues is discussed, with special reference to selective induction of urinary bladder tumors.

Carcinogenicity and modification of the carcinogenic response by BHA, BHT, and other antioxidants.

Carcinogenicity tests showed that addition of the antioxidant BHA to the diet of F344 rats induced high incidences of papilloma and squamous cell carcinoma of the forestomach of both sexes. Male hamsters given BHA for 24 weeks also developed papilloma showing downward growth into the submucosa of the forestomach. These results indicate that BHA should be classified in the category of "sufficient evidence of carcinogenicity" as judged by IARC criteria. The 3-tert isomer of BHA seemed to be responsible for the carcinogenicity of crude BHA in the forestomach of rats. BHT was not found to be carcinogenic in rats or mice. In two-stage carcinogenesis in rats after appropriate initiation, BHA enhanced carcinogenesis in the forestomach and urinary bladder of rats, but inhibited carcinogenesis in the liver. BHT enhanced the induction of urinary bladder tumors and inhibited that of liver tumors, but had no effect on carcinogenesis in the forestomach. BHT could be a promoter of thyroid carcinogenesis. Sodium L-ascorbate enhanced forestomach and urinary bladder carcinogenesis. Ethoxyquin enhanced kidney and urinary bladder carcinogenesis, but inhibited liver carcinogenesis. Thus, these antioxidants modify two-stage chemical carcinogenesis in the forestomach, liver, kidney, urinary bladder, and thyroid, but show organ-specific differences in effects.

Fluoro-substituted N-nitrosamines. 8. N-Nitrosodibutylamine and omega-fluorinated analogues: in vivo metabolism in relation to the induction of urinary bladder cancer in the rat.

Urinary excretion of N-nitrosodibutylamine (NDBA) and of two omega-fluorinated analogues [N-nitroso-4,4,4-trifluorobutyl-butylamine, NDBA-F3; N-nitroso-bis(4,4,4-trifluorobutyl)-amine, NDBA-F6] was studied in male Sprague-Dawley (SD) rats. After oral application of equimolar doses (0.44 and 1.32 mmol/kg body wt.) urines were collected (48 h) and analyzed for parent compounds, and for nitrosamine metabolites by gas chromatography/Thermal Energy Analyzer (GC/TEA) and gas chromatography/mass spectrometry (GC/MS). After administration of NDBA the known major metabolites N-nitroso-3- hydroxybutylbutylamine (3-OH-NDBA) and N-nitroso-3-carboxypropylbutylamine (BCPN) were excreted in urine. After application of the omega-fluorinated analogue NDBA-F6, however, urinary and biliary nitrosamine metabolites were detected only in trace amounts. This finding demonstrates a strong inhibitory effect of fluorine substitution on oxidations at omega, (omega-1) and beta-positions. Confirmation of this inhibitory effect of omega-fluorine substitution is given from the excretion profiles of NDBA-F3 which shows metabolic oxidations only at the nonfluorinated chain: N-nitroso-3-hydroxybutyl-4,4,4-trifluorobutylamine (3-OH-NDBA-F3) and N-nitroso-3-carboxypropyl-4,4,4-trifluorobutylamine (BCPN-F3) were excreted as main metabolites. Our results on metabolism together with the available data on carcinogenicity of the compounds in the rat strongly support the hypothesis that omega-oxidation of one butyl-chain is a prerequisite for the induction of urinary bladder tumors with NDBA. For the induction of liver tumors, alpha-C-hydroxylation appears to be the crucial event.

Further studies on the effect of leupeptin, a protease inhibitor, on induction of bladder tumors in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effect of a microbial protease inhibitor, leupeptin, on the induction of urinary bladder tumors in W rats by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Three groups of animals were given 0.01% BBN in their drinking water for 12 weeks. A basal powder diet supplemented with 0.1% leupeptin was given to group A throughout the experiment and to group B when BBN administration was stopped. Group C was given the basal diet without leupeptin throughout the study. The total preservation period was 40 weeks. Results clearly showed that when leupeptin was given during the promotion step of bladder carcinogenesis (as in group B), it increased the size of tumors and the incidences of cancer and invasion. When leupeptin was given throughout the experiments, its effect was counteracted (as in group A).

3080. Bladder tumours from nitrosomethyldodecylamine: Lijinsky W. & Taylor H.W. (1975). Induction of urinary bladder tumors in rats by administration of nitrosomethyldodecylamine. Cancer Res.35, 958

3080. Bladder tumours from nitrosomethyldodecylamine: Lijinsky W. & Taylor H.W. (1975). Induction of urinary bladder tumors in rats by administration of nitrosomethyldodecylamine. Cancer Res.35, 958

Effect of various factors on induction of urinary bladder tumors in animals by N-butyl-n-(4-hydroxybutyl)nitrosoamine.

Effect of various factors on induction of urinary bladder tumors in animals by N-butyl-n-(4-hydroxybutyl)nitrosoamine.

Induction of urinary bladder tumors in ACI-N rats by butyl(3-carboxypropyl)nitrosoamine, a major urinary metabolite of butyl-(4-hydroxybutyl)nitrosoamine.

Induction of urinary bladder tumors in ACI-N rats by butyl(3-carboxypropyl)nitrosoamine, a major urinary metabolite of butyl-(4-hydroxybutyl)nitrosoamine.