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PubMed1994

Measurement of BBN-induced alterations in rat urothelium by electron microscopic X-ray microanalysis.

The aim of this study was to analyse N-butyl-n-butanol-4-nitrosamine (BBN)-induced alterations of the urothelium in rats concerning its content of phosphorus, sulphur, chlorine, potassium and calcium using electron microscopic X-ray microanalysis (REM analysis). The following histopathological findings of the bladder mucosa were discovered after exposure to BBN: normal urothelium (n = 36); focal epithelial proliferations (n = 12) following 6-12 week's exposure; epithelial hyperplasia (n = 8) after urothelial carcinoma (n = 4) following 12 weeks' exposure. The observed phosphorus/sulphur and phosphorus/calcium ratios based on REM analysis did not show any statistical correlation with the morphological changes classified by light microscopy. Our data do not support the hypothesis raised by other investigators that an increase in phosphorus content or phosphorus/sulphur or phosphorus/calcium ratio could indicate early neoplastic transformations of urothelial cells as "tumor markers".

Animals↗
PubMed1995

Morphological changes of microvilli on different surfaces of epithelial cells in the rat bladder treated with N-butyl-N-(4-hydroxybutyl) nitrosamine.

This study investigates morphological changes of microvilli occurring on different surfaces of epithelial cells, including luminal surfaces, intercellular surfaces, and basal cell surfaces adjacent to the basement membrane (BM), in the rat bladder treated with N-butyl-N(4-hydroxybutyl) nitrosamine (BBN) by transmission electron microscopy (TEM). The present results showed that the microvilli were observed not only on the luminal surfaces of epithelial cells but also on the intercellular surfaces and basal cell surfaces adjacent to the BM following administration of BBN. There were a variety of morphological changes of microvilli on the luminal surfaces, intercellular surfaces and basal cell surfaces adjacent to the BM, respectively. It is suggested that the microvilli occurring on the luminal surfaces may not represent characteristics of the microvilli occurring on the intercellular surfaces and on the basal cell surfaces adjacent to the BM, and that occurrence of the microvilli on the epithelial cell surfaces may reflect a higher metabolic activity of proliferative epithelial cells and may play an important role in the processes of tumor growth during bladder carcinogenesis.

Animals↗
PubMed1997

Endoscopic observation for detection and monitoring of N-butyl-N-(4-hydroxybutyl)nitrosamine--induced bladder tumor in rats.

Recent advances in tumor carbohydrate biochemistry have demonstrated antitumor effects of locally administered GM3 ganglioside on mouse MBT-2 tumor. When intravesical therapy in N-butyl-N(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder tumor is attempted, it is essential to identify the tumor, to classify its size before therapy and to monitor the effect of the therapy. To establish a more reliable experimental therapeutic system, we assessed the development of BBN-induced rat-bladder tumor by endoscopic observation. BBN-induced bladder tumors in rats were observed serially using a 4.2-F flexible fiberscope. The endoscopic findings were compared with the histopathological findings. Intravesical tumor growth varied greatly between individual rats. The smallest change detected by endoscopy was a small edematous lesion histologically proved to be papilloma. The largest nodular lesion was determined to be a papillary, transitional cell carcinoma. This noninvasive method makes the BBN rat experimental system more reliable by allowing confirmation of tumor formation and classification of the tumor volume prior to therapy.

Animals↗
PubMed1993

Acetylsalicylic acid inhibition of n-butyl-(4-hydroxybutyl)nitrosamine-induced bladder carcinogenesis in rats.

We examined the effect of acetylsalicylic acid (ASA) on n-butyl-(4-hydroxybutyl)nitrosamine (BHBN)-induced bladder carcinogenesis in male Wistar rats. Of 29 rats that received 0.05% BHBN in their drinking water for 9 weeks, 8 developed bladder cancer. Only 1 out of 29 rats that received 0.1% ASA in their diet for 20 weeks, including the period of BHBN consumption, developed a tumor. That difference is statistically significant. Bladder weight was significantly higher in rats given BHBN than in controls and in rats given both BHBN and ASA. We conclude that ASA inhibits BHBN-induced bladder carcinogenesis.

Animals↗
PubMed1997

A histopathological mapping study of the urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in dogs.

Bladder tumors were induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in five Beagles and four mongrel dogs. The tumors were observed for long periods and the tumor progression was traced using histopathological mapping. The results indicated (1) that low-dose BBN over a long period induced multiple low-grade (G1-2) and low-stage (pTa-1) papillary tumors, resembling superficial bladder cancer in humans; (2) that high-dose BBN over a short period induced high-grade (G2-3) and high-stage (pT3b) nonpapillary tumors and carcinoma in situ (CIS) resembling invasive cancer and CIS in humans; (3) that beagle dogs required longer periods and higher total doses of BBN as compared with mongrel dogs; (4) that the tumors induced by low-dose BBN in beagles were observed without BBN as long as the animals lived, and neither increasing numbers of tumors nor malignant features such as deep infiltration and metastasis was observed; and (5) that low-dose BBN seems to induce mild dysplasia, which is followed by Brunn's nest-like proliferation in the lamina propria and nodular change, eventually leading to the development of papillary noninvasive transitional cell carcinoma (TCC); and that high-dose BBN seems to induce severe dysplasia which leads to CIS and nonpapillary invasive TCC. These results may contribute to clarifying the natural history of human bladder cancer.

Animals↗
PubMed1990

Nucleolar organizer regions in rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The number of nucleolar organizer regions (NORs) stained by the one-step silver colloid method was measured in preneoplastic and neoplastic bladder lesions induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. Male ACI/N rats, 6 weeks of age, were given 0.05% BBN in drinking water for 5, 8, 12, 18 and 30 weeks to induce preneoplastic and neoplastic transitional cell lesions. The mean numbers of silver-stained NORs (AgNORs) in such lesions were as follows: untreated transitional epithelium (n = 6), 1.26 +/- 0.09; transitional cell epithelium outside focal lesions (n = 10), 1.75 +/- 0.10; simple hyperplasia (n = 10), 2.01 +/- 0.15; papillary or nodular (PN) hyperplasia (n = 10), 2.15 +/- 0.19; transitional cell papilloma (n = 5), 2.37 +/- 0.12; transitional cell carcinoma (n = 5), 3.52 +/- 0.23. Thus, the mean number of AgNORs showed a step-wise increase from untreated and treated, histologically normal transitional epithelium through simple hyperplasia and PN hyperplasia to transitional cell papilloma and carcinoma. These results suggest that the mean number of AgNORs may reflect the proliferative nature of bladder lesions induced by BBN, as reported in preneoplastic and neoplastic lesions in other organs. PN hyperplasias were classified into two types based upon the mean number of AgNORs, indicating that they include reversible and irreversible changes in contrast with simple hyperplasia which is reversible change.

Animals↗
PubMed2002

Influence of pertussis toxin on superficial bladder carcinoma in rats.

The proliferation and migration of cells is a fundamental process for the metastasis of malignant tumour cells. In several in vitro studies, pertussis toxin (PTX) inhibited cell proliferation and cell motility in the human transitional cell carcinoma cell line J82. The present study investigated the effect of the intravesical application of PTX on the development of superficial bladder cancer in rats. We used the model of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN, 0.05% via drinking water x10 weeks) to induce superficial bladder carcinomas in 40 female rats. After 16 weeks the rats were treated in two groups with 0.4 ml PTX (1 microg/ml) or 0.4 ml phosphate buffered saline (PBS) by intravesical application (once a week for 10 weeks). In the 25th week urine cytology was determined and all rats were killed at week 26 followed by histological evaluation. In the control group, the urine cytology was positive for G2/G3 cells in ten of 17 rats. In the PTX group G2/G3 cells were determined in five of 20 rats ( P two tailed <0.05). Histopathologically 12 rats (71%) of the control group and 11 rats (55%) of the PTX group developed T1-T2 transitional-cell carcinomas. No local or systemic side effects were disclosed. PTX treatment reduces the development of G3 transitional cell carcinomas in rats and may represent a new approach for local therapy in superficial bladder cancer.

Animals↗
PubMed2006

Chemopreventive property of dietary ginger in rat urinary bladder chemical carcinogenesis.

The modifying potential of ginger on the development of preneoplasia and tumors in the male Wistar rat urinary bladder was investigated in a 36-week-long initiation-promotion assay for chemical carcinogenesis. Groups G1 to G3 were given 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water for 5 weeks and a 3% uracil meal for the subsequent 3 weeks. Groups G4 and G5 were treated with 3% uracil only for the same period. After these steps, groups G2, and G3 and G4 were fed for 26 weeks a ginger extract mixed at 0.5 and 1.0% in a basal diet, respectively. Thirty six weeks after the beginning of the experiment all rats were killed. The multiplicity of urothelial lesions (hyperplasia and neoplasia) was significantly lower (P = 0.013) in group G3 than in groups G1 and G2. The results suggest that 1.0% ginger meal exerts a protective effect on the post-initiation stage of rat chemically-induced urothelial carcinogenesis.

Animals↗
PubMed2000

Long-term administration of galactoside-specific mistletoe lectin in an animal model: no protection against N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder carcinogenesis in rats and no induction of a relevant local cellular immune response.

Aqueous extracts from leaves of the European mistletoe (Viscum album L.) are postulated to exert an anticancer efficacy by cytotoxic and/or immunological mechanisms of action. Although popular as an unconventional therapy modality, no controlled randomized clinical trials are available, reliably documenting a clinically beneficial antineoplastic potential of the various commercial mistletoe preparations. Since previous investigations have focused on the purified galactoside-specific lectin (Viscum album L. agglutinin, VAA) as major biological response modifier in the low-dose range, the objective of the present experimental study was to examine its effect on N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced carcinogenesis in the urinary bladder of rats, a suitable animal model for human disease. The carcinogen was fed by gavage in three fractionated low doses (150 mg/kg body weight each) to obtain low-grade and low-stage transitional cell carcinomas. From the onset of the experiment VAA was injected subcutaneously twice a week (1 ng/kg body weight) continuously for either 6 or 15 months. Following an experimental period of 6 months the incidence of bladder carcinomas was 10.2% in rats given exclusively BBN and 6.7% in those additionally treated with VAA. After an experimental time of 15 months 25.8% of the rats fed BBN only and 19.7% of the animals additionally receiving VAA had developed urothelial carcinomas. The differences of the tumor incidences did not reach the level of statistical significance, neither after an experimental duration of 6 (P = 0.88) nor of 15 months (P = 0.71). A difference was found in the size of the transitional cell carcinomas. They proved to be significantly larger (P = 0.02) in the rats additionally treated with VAA for 15 months (mean maximum diameter: 3.31 mm) than in those without lectin treatment (mean maximum diameter: 1.88 mm). Quantitative immunocytochemistry analyzing a panel of immune cells yielded no evidence for the ability of the lectin to provoke a substantial, biologically relevant local cellular immune response in the wall of tumor-free and tumor-bearing bladders. From the current experiment it is obvious that galactoside-specific mistletoe lectin failed to protect against, inhibit, delay or reduce development of chemically induced urothelial carcinomas of the urinary bladder even after long-term administration in the clinically recommended schedule. It seems highly unlikely that adjuvant treatment with mistletoe extracts or VAA might favorably influence bladder cancer in patients by immunological effector mechanisms.

Animals↗
PubMed1998

Host genes affecting survival period of chemically induced bladder cancer in mice.

Treatment of C57BL/6 J (B6) and NON male mice with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) resulted in a high incidence of bladder cancer. The mean survival period, however, differed significantly by strain: 481+/-219 days in B6 (n = 31) and 203+/-119 days in NON (n = 30) (P < 0.0001). Major causes of death were renal failure due to obstruction of the urinary tract, or local invasion of tumors. The fact that the BBN-treated NON x B6 reciprocal F1 mice had survival periods as short as those of the parental NON mice suggests a genetically dominant susceptibility in NON or recessive resistance in B6. A linkage analysis of 248 back-cross mice to B6 suggested at least two quantitative trait loci determining the length of the survival period: one was mapped close to D2Mit260 (logarithm of odds, LOD, score 2.21), a microsatellite marker locus 83 cM from the centromere on chromosome 2, and another was close to D6Mit159, 7 cM from the centromere on chromosome 6 (LOD score 2.51).

Animals↗
PubMed1992

In vitro metabolism of bladder carcinogenic nitrosamines by rat liver and urothelial cells.

In order to establish the importance of the target organ in the activation of bladder carcinogens, we compared rat liver and urothelial cell alpha-hydroxylation activities using as substrates N-nitrosobutyl(4-hydroxybutyl)amine and its metabolite N-nitrosobutyl(3-carboxypropyl)amine, two potent urinary bladder carcinogens in animals. Previous studies have shown that the production of molecular nitrogen can serve as an indicator of nitrosamine alpha-hydroxylation. The use of doubly 15N-labelled nitrosamines and the gas chromatography-mass spectrometric detection of 15N2 formed gives a measurement of the extent of this metabolic step. Various amounts of 15N-labelled substrates were incubated for 60 min at 37 degrees C with rat liver S9 preparations or urothelial cell homogenates in the presence of a NADPH generating system. Both enzyme sources metabolized 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine and N-nitrosobutyl(3-carboxypropyl)amine through the alpha-hydroxylation pathway. Using hepatic S9 fractions, 15N2 production from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine increased from 1.69 +/- 0.02 nmol/h per mg protein (mean +/- S.E.) to 5.78 +/- 0.5 with substrate concentrations ranging between 0.55 and 5.55 mM. 15N2 produced by urothelial cell homogenates was about 40-50% that of the liver S9. 15N-labelled N-nitrosobutyl(3-carboxypropyl)amine was also metabolized through the alpha-hydroxylation pathway both by hepatic S9 and urothelial cell homogenates, though to a lesser extent. 15N2 production was about 10-times less than from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine, but again urothelial cell 15N2 production was about 40-50% that of the liver. Treatment with phenobarbital resulted in a 2.7-fold increase in the 15N2 produced from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine by hepatic S9. No effect was observed with urothelial cell homogenates. Acetone treatment had no effect on 15N2 production from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine by hepatic S9, but raised 15N2 production by urothelial cell homogenates 1.8 times. Although the liver has a greater capacity than the bladder for activating the 15N-labelled nitrosamines studied, the target organ can metabolize bladder carcinogens, thus increasing the possibility of a local toxic effect. Moreover, the distribution of P-450 isozymes might be different in the bladder and this could affect the metabolism of nitrosamines reportedly formed in the human bladder in some pathological conditions.

Acetone↗
PubMed1989

Effects of sodium salts of phenobarbital and barbital on development of bladder tumors in male F344/NCr rats pretreated with either N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide or N-nitrosobutyl-4-hydroxybutylamine.

Promoting effects of sodium salts of phenobarbital (NaPB) and barbital (NaBB) on the development of bladder tumors were investigated in F344 male rats initiated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) or N-nitrosobutyl-4-hydroxybutylamine (BBN). To initiate with FANFT, rats were fed 0.2% FANFT mixed in diet for either 2 or 6 weeks and 2 weeks later were offered diet containing 1000 ppm of NaPB or NaBB. Rats were killed either at 52 or 68 weeks of age. To initiate with BBN, rats were given 0.05% BBN in drinking water for 4 weeks and beginning 1 day later were fed NaBB mixed in diet at 1000 ppm for up to 52 weeks. NaBB promoted bladder carcinogenesis initiated by either FANFT or BBN; the incidence and average number of simple or preneoplastic nodular (PN) hyperplasias, papillomas, and carcinomas per 10 cm of urothelium were significantly increased in the groups receiving NaBB following exposure to FANFT for 6 weeks (p less than 0.05) or BBN for 4 weeks (p less than 0.01). No such effect was seen in rats fed FANFT for only 2 weeks. NaPB also significantly increased (p less than 0.05) the frequency of preneoplastic PN hyperplasias but not the average number of papillomas and carcinomas per 10 cm of urothelium in rats fed FANFT for 6 weeks. NaBB was an effective promoter of bladder carcinogenesis under these experimental conditions, as expected from its known promoting effect on transitional epithelium of the renal pelvis, but NaPB in contrast did not affect the incidence or multiplicity of bladder papillomas or carcinomas under these conditions. NaPB could be considered a promoter for bladder urothelium only by the less rigorous criterion that it increased the frequency of preneoplastic PN hyperplasia.

Animals↗
PubMed1994

Subcellular localization and characterization of interleukin-1 alpha produced by rat bladder cancer cells.

A rat bladder cancer cell line BC31ad, previously reported to constitutively release tumor necrosis factor alpha (TNF alpha), was found to produce an interleukin (IL)-1-like factor inducing proliferation of murine thymocytes in a standard costimulation assay (LAF activity). IL-1-like factor was partially purified by DEAE-Sephacel, Sephacryl S-200 and MonoQ-FPLC chromatographies from the serum-free conditioned medium of a BC31 adderived clone, C19, to the specific activity of 3.2 x 10(6) U/mg and characterized as a protein of molecular weight 17 kDa with isoelectric point 5.2. LAF activity of IL-1-like factor was specifically neutralized with anti-rat IL-1 alpha but not with anti-rat IL-1 beta. These findings show that the IL-1-like factor is rat IL-1 alpha, although the precise molecular relationship with monocyte IL-1 alpha is unclear. Furthermore, IL-1 alpha was shown to be primarily located in the cytosol and plasma membrane without spontaneous release. A kinetics study indicated that it was leaked into the medium late in culture resulting from cell destruction, in contrast to TNF alpha which was released as the cell number was increased. We discussed the possible role of IL-1 alpha as an autocrine or paracrine growth regulator.

Animals↗
PubMed1984

Inhibition of tumor development in the regenerating rat urinary bladder stimulated to proliferate by cyclophosphamide.

The present study deals with the effect of stimulation of urothelial proliferation on experimental bladder carcinogenesis. To induce proliferative activity of the bladder mucosa cyclophosphamide (cp) was intraperitoneally administered to rats in a single dose (100 mg/kg). N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was used as carcinogen and administered by gavage in 3 fractionated doses when proliferation of the urothelium was highest at 28 and 40 hr as well as 7 days following the injection of cp. Contrary to our original working hypothesis, tumor development proved to be inhibited in the bladder following initial stimulation of urothelial proliferation by cp. After administration of a low total dose of BBN (300 mg/kg) and an experimental period of 6 and 12 months none of the rats pretreated with cp developed a tumor in the regenerating bladder, whereas solitary transitional cell papillomas were observed in 6.7% of the control animals with a quiescent bladder. Following administration of BBN at a high total dose (1.300 mg/kg) and an induction time of 4, 6 and 12 months papillomas and non-invasive papillary transitional cell carcinomas occurred in only 21.6% of the rats initially receiving cp but in 48.1% of the control animals without stimulation of urothelial proliferation by cp. After treatment with BBN alone there was a far larger number of rats with multiple tumors in the quiescent bladder. The reduction in the incidence of tumors following administration of cp is not attributable to a prolongation of the latency period or induction time. It is an open question which mechanisms are responsible for the observed inhibition of experimental bladder carcinogenesis. An increased DNA repair induced synchronously with the stimulated replicative de-novo DNA synthesis or a decreased activity of urothelial enzymes metabolizing BBN to its ultimate carcinogen are proposed as the most likely explanations.

Animals↗
PubMed1983

Promoting effects of various chemicals in rat urinary bladder carcinogenesis initiated by N-nitroso-n-butyl-(4-hydroxybutyl)amine.

We studied the capacity of various chemicals to promote urinary bladder cancer in male F344 rats after initiation by N-nitroso-n-butyl-(4-hydroxybutyl)amine (BBN). The rats were given initially 0.01% BBN in the drinking-water for 4 wk and then the test compound in the diet for 34 wk. Effects were judged by measuring the formation of preneoplastic lesions papillary or nodular hyperplasia (PN hyperplasia) of the urinary bladder. Administration of 5%, but not 0.5% (w/w) sodium saccharin in the diet significantly increased the incidence and extent of PN hyperplasia. This finding could be related to the induction of cancers in the rat urinary bladder by high levels of saccharin. Sodium ascorbate (5%). DL-tryptophan (5%) and allopurinol (0.02%) also significantly increased the extent of PN hyperplasia in the affected animals, but other test chemicals, such as acetazolamide (0.35%) and quercetin (5%) did not. The results with sodium saccharin and DL-tryptophan were consistent with previous findings and suggest that sodium ascorbate and allopurinol have promoting activities in urinary bladder carcinogenesis in rats. No correlation was found between the extent of crystalluria and promotion of preneoplastic lesions.

Acetazolamide↗
PubMed1984

Principal components analysis of haematological data from F344 rats with bladder cancer fed N-(ethyl)-all-trans-retinamide.

Several multivariate statistical methods are available which can alleviate the problems of analysing the large volumes of data generated from toxicological experiments. One such technique, principal components analysis, provides a method for exploring the relationships between a number of variables (such as blood parameters) and for eliminating redundant data if strong correlations exist between the characters. It also provides a method for clustering individuals, which may reveal similarities between animals in a treatment group or highlight individual 'outliers'. The application of principal components analysis to a set of haematological data from a trial evaluating the efficacy of a synthetic retinoid against carcinogen-induced bladder cancer in the rat has clearly shown, in two bivariate plots, that while some animals in the carcinogen-treated groups were normal, others were anaemic and that animals fed the synthetic retinoid and killed at 1 year had a microcytic anaemia. A full exploration of the data using conventional univariate statistical analysis would have involved at least 28 graphic representations of the data, as well as the interpretation of more than 130 means and SDs. Principal components analysis provides a valuable additional tool for the statistical analysis and exploration of toxicological data, but it must be used in conjunction with univariate or other multivariate methods if hypothesis testing is required. The use of multivariate techniques in toxicology may best be assessed by their practical application to toxicological data, and this paper presents such an evaluation with the aim of encouraging further exploration of the usefulness of principal components analysis. The raw data on which most analyses have been carried out are given.

Analysis of Variance↗