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Cancer Prevention Research... Nov 2009Nonsteroidal anti-inflammatory drugs (NSAID) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically, and also in clinical trials...
Nonsteroidal anti-inflammatory drugs (NSAID) have been highly effective in preventing colon, urinary bladder, and skin cancer preclinically, and also in clinical trials of colon adenoma formation. However, certain NSAIDs cause gastrointestinal ulceration and may increase cardiovascular events. Naproxen seems to cause the lowest cardiovascular events of the common NSAIDs other than aspirin. Nitric oxide (NO)-naproxen was tested based on the finding that adding a NO group to NSAIDs may help alleviate GI toxicity. In the azoxymethane-induced rat colon aberrant crypt foci (ACF) model, naproxen administered at 200 and 400 ppm in the diet reduced mean ACFs in the colon by about 45% to 60%, respectively. NO-naproxen was likewise administered in the diet at roughly equimolar doses (300 and 600 ppm) and reduced total ACF by 20% to 40%, respectively. In the hydroxybutyl (butyl) nitrosamine rat urinary bladder cancer model, NO-naproxen was given at 183 or 550 ppm in the diet, and naproxen at 128 ppm. The NO-naproxen groups had 77% and 73% decreases, respectively, in the development of large urinary bladder tumors, whereas the 128 ppm naproxen group also showed a strong decrease (69%). If treatments were started 3 months after hydroxybutyl (butyl) nitrosamine, NO-naproxen (550 ppm) and naproxen (400 ppm) were also highly effective (86-94% decreases). In the methylnitrosourea-induced mammary cancer model in rats, NO-naproxen and naproxen showed nonsignificant inhibitions (12% and 24%) at 550 and 400 ppm, respectively. These data show that both naproxen and NO-naproxen are effective agents against urinary bladder and colon, but not mammary, carcinogenesis.
Topics: Alkylating Agents; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azoxymethane; Butylhydroxybutylnitrosamine; Carcinogens; Colonic Neoplasms; Diet; Female; Male; Mammary Neoplasms, Experimental; Methylnitrosourea; Naproxen; Nitric Oxide Donors; Precancerous Conditions; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Urinary Bladder Neoplasms
PubMed: 19892664
DOI: 10.1158/1940-6207.CAPR-09-0080 -
Japanese Journal of Cancer Research :... Dec 2001We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in...
p53 and H-ras mutations and microsatellite instability in renal pelvic carcinomas of NON / Shi mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine: different genetic alteration from urinary bladder carcinoma.
We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in urinary bladder carcinomas (UBCs) and their metastatic foci in the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse urothelial carcinogenesis model. In the present study, an analysis of p53 and H-ras mutations as well as MSI was performed on 12 renal pelvic carcinomas (RPCs) and 8 metastatic or invading foci produced by the same experimental procedure. Histologically, 10 of the RPCs were transitional cell carcinomas and the remaining 2 were squamous cell carcinomas. p53 mutations were infrequent and only found in one primary RPC (8%), its metastatic foci and an invading lesion in another animal (in a total 2 of 12; 17%). H-ras mutations were slightly more frequent (found in 3 of 12 animals; 25%), 4 of 5 involving codon 44, GTG to GCG, not a hot-spot reported for human cancers. In two cases, H-ras mutations were confined to lung metastasis and not detectable in their primary RPCs. MSI analysis was available for 6 pairs of primary RPCs and their metastatic foci, and 4 animals (67%) had MSI at one or more microsatellite loci. Overall, the distribution of genetic alterations differed from that in UBCs produced by the same experimental protocol. The results thus suggest that different genetic pathways may participate in carcinogenesis of the upper and lower urinary tract due to BBN.
Topics: Animals; Butylhydroxybutylnitrosamine; DNA Mutational Analysis; Genes, p53; Genes, ras; Kidney Neoplasms; Mice; Microsatellite Repeats; Mutagenesis; Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Urinary Bladder Neoplasms
PubMed: 11749692
DOI: 10.1111/j.1349-7006.2001.tb02150.x -
Neoplasia (New York, N.Y.) Aug 2008Cancer of the urinary bladder is often a result of exposure to chemical carcinogens. Models of this disease have been developed by exposing rodents to...
Cancer of the urinary bladder is often a result of exposure to chemical carcinogens. Models of this disease have been developed by exposing rodents to N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN). The resultant tumors are histologically similar to human disease, but little is known about genetic similarities to the latter. Such knowledge would help identify or corroborate genes found important in human bladder cancer and suggest biologically appropriate mechanistic studies. We address this need by comparing gene expression profiles associated with urothelial carcinoma for three different species: mouse, rat, and human. We find that many human genes homologous to those differentially expressed in carcinogen-induced rodent tumors are also differentially expressed in human disease and are preferentially associated with progression from non-muscle-invasive to muscle-invasive disease. We also find that overall gene expression profiles of rodent tumors correspond more closely with those of invasive human tumors rather than non-muscle-invasive tumors. Finally, we provide a list of genes that are likely candidates for driving this disease process by virtue of their concordant regulation in tumors of all three species.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Disease Models, Animal; Disease Progression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Invasiveness; Oligonucleotide Array Sequence Analysis; Rats; Urinary Bladder Neoplasms
PubMed: 18670642
DOI: 10.1593/neo.08432 -
International Journal of Molecular... 2012To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male...
To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) CONTROL: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti-inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN-treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti-proliferative and anti-inflammatory properties.
Topics: Animals; Anti-Inflammatory Agents; Anticarcinogenic Agents; Antioxidants; Atorvastatin; Biomarkers, Tumor; Butylhydroxybutylnitrosamine; Cell Proliferation; Drug Evaluation, Preclinical; Heptanoic Acids; Male; Oxidative Stress; Pyrroles; Rats, Wistar; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 22942715
DOI: 10.3390/ijms13078482 -
Acta Cirurgica Brasileira Aug 2012To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN).
PURPOSE
To determine the effects of water-soluble derivative of green propolis in bladder cancer angiogenesis in rats given N-butyl-(-4-hydroxybutyl) nitrosamine (BBN).
METHODS
Nine groups were established, where six of them (Groups 1 to 6), the animals received 0.05% BBN in their drinking water for 14 weeks. From the 32nd to the 40th week, Groups 1, 2, 3 and 4 were treated respectively with water, L-lysine (300 mg/kg/day), celecoxib (30 mg/kg/day) and propolis (300 mg/kg/day). Groups 5 and 6 were given propolis and L-lysine from the 1st to the 40th week (150 mg/kg/day). Microvascular density was determined by histological sections stained for the marker CD-31 and analyzed with specific software.
RESULTS
The microvascular density in bladder carcinomas was lower (p<0.01) in rats receiving propolis than in controls given carcinogen only. On the other hand, the microvascular density of tumors in rats receiving carcinogen and L-lysine for 40 weeks from the beginning of carcinogen treatment was significantly higher (p<0.01) than in the corresponding controls.
CONCLUSION
Water-soluble derivative of propolis inhibits angiogenesis in BBN-induced rat bladder cancer, while L-lysine treatment stimulates angiogenesis if initiated concurrently with BBN.
Topics: Angiogenesis Inhibitors; Animals; Butylhydroxybutylnitrosamine; Carcinoma; Disease Models, Animal; Female; Lysine; Neovascularization, Pathologic; Plant Extracts; Propolis; Rats; Rats, Wistar; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms; Water
PubMed: 22850703
DOI: 10.1590/s0102-86502012000800003 -
Hinyokika Kiyo. Acta Urologica Japonica Sep 1995The effect of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) on the small intestine in rat, in which augmentation cystoplasty was performed, was examined. Seventeen rats... (Review)
Review
The effect of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) on the small intestine in rat, in which augmentation cystoplasty was performed, was examined. Seventeen rats were divided into 3 groups: 1) jejunum-transplanted group (5 cases), 2) ileum-transplanted group (6 cases) and 3) control group without operation (6 cases). A part of the small intestine was transplanted to the urinary bladder, then 0.05% BBN was given for 12 weeks. The rats were killed 30 weeks after the beginning of the administration for histopathological evaluation. Bladder tumors in various grades were confirmed in all the cases. In two cases in the jejunum-transplanted group, transitional cell carcinoma was found in the urinary bladder, one of which had an invasion to the adjacent part of the jejunum to the bladder mucosa. These findings suggest that the metabolic products of carcinogens, excreted into urine, had no effect on the transplanted small intestine.
Topics: Animals; Butylhydroxybutylnitrosamine; Carcinogens; Carcinoma, Transitional Cell; Female; Intestine, Small; Rats; Rats, Wistar; Transplantation, Heterotopic; Urinary Bladder; Urinary Bladder Neoplasms; Urinary Diversion
PubMed: 7484529
DOI: No ID Found -
Japanese Journal of Cancer Research :... Oct 1992We examined the activity of spermidine/spermine N1-acetyltransferase (SAT), a rate-limiting enzyme of the biodegradation of polyamines, in... (Comparative Study)
Comparative Study
We examined the activity of spermidine/spermine N1-acetyltransferase (SAT), a rate-limiting enzyme of the biodegradation of polyamines, in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced transitional cell carcinoma (TCC) and melamine-induced papillomatosis of rat bladder, and compared the activity to that of ornithine decarboxylase (ODC). Both activities were higher in both lesions than in control rats. The difference between SAT and ODC activities in cancerous tissue and papillomatosis was not significant. Cells stained for proliferating cell nuclear antigen (PCNA) were abundant in papillomatosis. TCC had areas with much PCNA. The results indicated that an elevation of SAT activity occurs in both reversible and irreversible proliferation of bladder epithelium and could be important in bladder carcinogenesis.
Topics: Acetyltransferases; Animals; Biomarkers, Tumor; Butylhydroxybutylnitrosamine; Carcinoma, Transitional Cell; Cell Division; Epithelium; G1 Phase; Hyperplasia; Male; Nuclear Proteins; Ornithine Decarboxylase; Papilloma; Polyamines; Proliferating Cell Nuclear Antigen; Rats; Rats, Inbred F344; S Phase; Triazines; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 1360468
DOI: 10.1111/j.1349-7006.1992.tb02718.x -
Carcinogenesis Mar 2019Amylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease...
Amylo-α-1,6-glucosidase,4-α-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Germline mutations lead to glycogen storage disease type III (GSDIII). We recently found AGL to be a tumor suppressor in xenograft models of human bladder cancer (BC) and low levels of AGL expression in BC are associated with poor patient prognosis. However, the impact of low AGL expression on the susceptibility of normal bladder to carcinogenesis is unknown. We address this gap by developing a germline Agl knockout (Agl-/-) mouse that recapitulates biochemical and histological features of GSDIII. Agl-/- mice exposed to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had a higher BC incidence compared with wild-type mice (Agl+/+). To determine if the increased BC incidence observed was due to decreased Agl expression in the urothelium specifically, we developed a urothelium-specific conditional Agl knockout (Aglcko) mouse using a Uroplakin II-Cre allele. BBN-induced carcinogenesis experiments repeated in Aglcko mice revealed that Aglcko mice had a higher BC incidence than control (Aglfl/fl) mice. RNA sequencing revealed that tumors from Agl-/- mice had 19 differentially expressed genes compared with control mice. An 'Agl Loss' gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL loss in promoting carcinogenesis and provide a rationale for evaluating Agl expression levels, or Agl Loss gene signature scores, in normal urothelium of populations at risk of BC development such as older male smokers.
Topics: Animals; Butylhydroxybutylnitrosamine; Genetic Engineering; Glycogen Debranching Enzyme System; Mice; Mice, Inbred C57BL; Mice, Knockout; Sequence Analysis, RNA; Urinary Bladder Neoplasms
PubMed: 30403777
DOI: 10.1093/carcin/bgy139 -
Aging induces changes in cancer formation and microbial content in a murine model of bladder cancer.GeroScience Jun 2024Bladder cancer (BCa) incidence is tightly linked to aging. Older patients with BCa present with higher grade tumors and have worse outcomes on Bacillus-Calmette-Guerin...
Bladder cancer (BCa) incidence is tightly linked to aging. Older patients with BCa present with higher grade tumors and have worse outcomes on Bacillus-Calmette-Guerin (BCG) immunotherapy. Aging is also known to result in changes in the gut microbiome over mammalian lifespan, with recent studies linking alterations in the gut microbiome to changes in tumor immunity. There is limited information on the microbiome in BCa models though, despite known links to aging and immunotherapy. The purpose of this study was to evaluate how aging impacts tumor formation, inflammation, and the microbiome of mice given the model BCa carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We hypothesized old animals would have larger, more inflamed tumors and a shift in their fecal microbiome compared to their younger counterparts. Young (~8-week-old) or old (~78-week-old) C57Bl/6J animals were administered 0.05% BBN in drinking water for 16 weeks and then euthanized or allowed to progress for an additional 4 weeks. After 16 weeks of BBN, old mice had higher bladder to body weight ratio than young mice, and also muscle invasive tumors, which were not seen in their young counterparts. Old animals also had increased innate immune recruitment, but CD4/CD8 T cell recruitment did not appear different. BBN dramatically altered the microbiome in both sets of animals as measured by ß-diversity, including changes in multiple genera of bacteria. These data suggest old mice have a differential response to BBN-induced BCa. Given the median age of patients with BCa, understanding how the aged phenotype interacts with BCa is imperative.
Topics: Humans; Mice; Animals; Aged; Disease Models, Animal; Butylhydroxybutylnitrosamine; Urinary Bladder Neoplasms; Carcinogens; Aging; Mammals
PubMed: 38270807
DOI: 10.1007/s11357-024-01064-9 -
British Journal of Cancer Nov 1980Experiments were conducted to determine whether bladder cancer would develop in primates (Papio sp.) infected with S. haematobium and concurrently exposed to low...
Experiments were conducted to determine whether bladder cancer would develop in primates (Papio sp.) infected with S. haematobium and concurrently exposed to low initiating doses of the bladder carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). To control for the systemic effects of schistosomiasis, 5 baboons were infected with S. mansoni, which does not lay its eggs in the bladder wall; to control for the effect of the carcinogen alone, 5 others were treated with BBN alone at the rate of 5 or 50 mg/kg per week for the duration of the experiment. Five animals were infected with S. haematobium and had no further treatment, and the main experimental group of 10 baboons was infected with S. haematobium and also treated weekly with 5 mg/kg BBN for up to 2½ years. Four of the 10 animals in the last group, but none in the three control groups developed neoplastic disease of the urothelium. Four animals with S. haematobium plus BBN treatment developed in situ carcinoma in the bladder (3 latent adenomatous lesions and 1 more advanced papillary tumour) and 2 of these animals plus 1 other had slightly dysplastic urothelial endophytic papillary growths of the ureter which penetrated the muscle layer. By contrast, none of the control animals developed urothelial carcinomas, though 4/5 of those with S. haematobium infection alone had inflamed bladders with polypoid lesions, and one individual had endophytic papillary hyperplasia of the ureter. The animals were killed after 2½ years while still relatively immature or adolescent, and it is possible that had they been allowed to survive longer some of the BBN-only group would have developed bladder cancer, and more of the latent lesions seen in the BBN + schistosomiasis group would have progressed to invasive carcinoma. It is postulated that, in this model for human bilharzial bladder cancer, schistosomiasis supplies the proliferative stimulus necessary to accelerate cancer growth from latent tumour foci produced by exposure to low doses of the bladder carcinogen. In areas of endemic schistosomiasis, carcinogenesis might be initiated, for example, by low doses of nitrosamines produced in the urinary tract during bouts of bacteriuria.
Topics: Animals; Body Weight; Butylhydroxybutylnitrosamine; Hematocrit; Male; Neoplasms, Experimental; Nitrosamines; Papio; Schistosoma haematobium; Schistosomiasis; Ureter; Urinary Bladder; Urinary Bladder Neoplasms
PubMed: 7459210
DOI: 10.1038/bjc.1980.308