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PubMed1991

[Inhibition by proton irradiation on the development of invasive bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in mice].

Fifty-five female C3H/He mice were given 0.05% N-bytyl-N-(4-hydroxybutyl) nitrosamine in their drinking water for 18 weeks. In week 19, eleven mice (group 3) were sacrificed to confirm that they all had bladder carcinoma. The remaining mice were divided into two groups. Group 1 received 20 Gy of proton irradiation over the whole pelvis, while group 2 received no treatment as a control. After 3 weeks all the animals were sacrificed and their bladders were resected to weigh and to examine histologically. The average weight of the bladder, as an index of the tumor volume, was 67.7 mg in group 1, 120.6 mg in group 2 and 106.5 mg in group 3. There was a significant differences (p less than 0.05) between group 1 and group 2. The incidences of superficial (pT1) and deeply invasive (pT2-3) bladder carcinomas were [10/18 (56%) and 8/18 (39%)] in group 1, [3/17 (18%) and 14/17 (82%)] in group 2 and [2/11 (18%) and 9/11 (82%)] in group 3, respectively. These rates of incidence were significantly different (p less than 0.05) between group 1 and group 2. However, there was no significant difference (p = 0.068) between group 1 and group 3. These results indicate that proton irradiation is effective for treatment of invasive bladder carcinoma in mice.

Animals↗
PubMed1992

[Inhibitory effects of IFN on N-butyl-N-(hydroxybutyl) nitrosamine induced rats bladder tumors].

Bladder tumors were induced in rats by the oral administration of 0.025% N-butyl-N-(hydroxybutyl) nitrosamine (BBN). In order to study the suppressive effects of rat interferon-alpha (IFN-alpha) on induction of carcinogenesis in vivo, rats were treated with IFN-alpha i.m. twice a week. The treatment began at 5th week of BBN administration. The bladder mucosa was observed macroscopically and microscopically, and NK activity was examined. The results were as follows. 1) There was no significant difference in the bladder to body weight ratio between the BBN + IFN-alpha and BBN groups in during stage A (10th-14th week when changes in the mucous membrane such as hypertrophy in the bladder wall or vascular formation are observed). This ratio in the BBN + IFN-alpha group was less than that in the BBN group in during stages B and C (15th-19th week and 20th-30th week respectively when tumors are visually recognizable). 2) The rate of carcinogenesis in the BBN + IFN-alpha group was less than that in the BBN group in stages A and C. 3) The pathological grade and stage of the bladder cancer in the BBN + IFN-alpha group were lower than those in the BBN group in stages B and C. 4) There was no significant difference in NK activity between the two groups in stage A, but NK activity of the BBN + IFN-alpha group was higher than that of the BBN group in stage B. 5) These findings substantiated the hypothesis that IFN-alpha can suppress tumor-growth in BBN induced bladder carcinoma.

Animals↗
PubMed1992

[Study on the effects of the hypocholesteremic agents, cholestyramine and compactin on the induction of renal tumors in rats by N-ethyl-N-hydroxyethyl nitrosamine].

Male Wistar rats were administered with 0.1% N-ethyl-N-hydroxyethyl nitrosamine (EHEN)-containing diet for 2 weeks, and were then Rept for further 23 weeks on basal diet. At 25 weeks, the rats were divided into three groups. Group I was fed on basal diet to 40 weeks. Group II was fed on 2% cholestyramine-containing diet to 40 weeks. Group III was fed on 0.02% compactin-containing diet to 40 weeks. At 40 weeks after the start of experiment, the rats were sacrificed and examined histologically for the incidence of renal cell tumors (RCT) and dysplastic foci (DF) of the kidney. The serum levels of total cholesterol at 40 weeks were 108.9 +/- 23.4, 78.8 +/- 12.5, 95.6 +/- 43.4 mg/dl in Groups I, II and III, respectively. The levels were significantly lower in Groups II and III (p less than 0.01, 0.05, respectively, Wilcoxon test) than Group I. The average numbers of DF were 4.5 +/- 4.1, 1.3 +/- 0.3, 2.3 +/- 2.0 per cm2 of kidney slices in Groups I, II and III, respectively. DF were significantly less in Group II than Group I (p less than 0.025, Wilcoxon test), and less in Group III than Group I (not statistically significant). There was no statistical difference between Groups II and III. RCT were observed in 9 of 34 kidneys (26%), 2 of 18 (11%), 1 of 20 (5%) in Groups, I, II and III, respectively. The ratios of kidneys with RCT were lower in Group II than Group I (not statistically significant), and lower in Group III than Group I (p less than 0.05, qui-square test). There was no statistical difference between Groups II and III. RCT were classified into gross and microscopic lesions. Four gross RCT were found in 4 rats of Group I; no gross RCT was in Groups II and III. There were 5 microscopic RCT in 5 rats, 3 in 2, 1 in 1 in Groups I, II and III, respectively. In Group I, serum levels of total cholesterol were compared between the following subgroups; the rats with RCT and/or with more than 10 DF per kidney, and the rats without RCT and with less than 10 DF per kidney. The mean level was 120.8 +/- 21.8 mg/dl in the former subgroup, which was significantly higher than that (94.1 +/- 19.6 mg/dl) in the latter subgroup (p less than 0.025, Wilcoxon test). The serum cholesterol was suggested to act as a promoter in the development of DF and RCT.

Animals↗
PubMed1993

[Early changes of sugar chains in bladder luminal cell membrane of rat treated with N-butyl-N-(4-hydroxybutyl) nitrosamine detected by immunohistochemical transmission electron microscopy].

Early changes of sugar chain detected by binding with lectins on luminal cell membrane of rat bladder epithelium treated with N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) were immunohistochemically examined with a transmission electron microscopy using ferritin-labeling lectins. BBN was given to male Wistar rats at the concentration of 0.05 W/V% in drinking water, and the rats were sacrificed at 4, 8, 16, 20 weeks, respectively, after the beginning of the BBN treatment. The bladder was treated with Half Karnovsky's solution via intra aortic cannulation for 20 minutes, and then removed. A part of bladder was examined grossly and by a light microscopy. The other part was cut into 3 x 3 mm squares and fixed with 2.5% glutaraldehyde solution and washed with 0.1 M cacogyl buffer with 10% sucrose. The tissue was sectioned and then incubated with ferritin-labeling lectins; concanavalin A (Con A), ulex europeaus agglutinin (UEA-1), peanut agglutinin (PNA) and dolichos biflorus agglutinin (OBA), respectively. These specimens were examined under a transmission electron microscopy. In cell membrane of the normal bladder, binding of Con A was found occasionally and binding of PNA was found focally, but binding of UEA-1 and DBA occurred incompletely on the cell membrane. The plaque and ridge on cell surface of bladder epithelium found to be obscured at 8 weeks after the treatment with BBN, and microvilli were barely observed under an electron microscope, but they increased gradually and could be seen by the microscope at the time of 16 weeks after the BBN treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

[Effect of intravesical bacillus Calmette-Guérin on N-butyl-N-(4-hydroxybutyl)-nitrosamine induced urinary bladder carcinogenesis in rats].

The effect of intravesical Bacillus Calmette-Guérin (BCG) on N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) induced urinary bladder carcinogenesis was pathologically evaluated. As a suppressive study of BCG on initiation, F344 female rats given 0.05% BBN orally for 6 weeks had intravesical instillation of either BCG or saline 3 times during BBN administration (Group A). As an inhibitory study of BCG on promotion, F344 female rats given the same strength BBN for 10 weeks had intravesical instillation of either BCG or saline 4 times starting at 7th week of BBN administration (Group B). The bladders were extirpated at 18th or 36th week after BBN administration in Group A and at 10th or 18th week in Group B. The lesions in the bladder were classified into 4 pathological findings; simple hyperplasia, papillary or nodular hyperplasia, papilloma and transitional cell carcinoma. The incidence of the lesions and the number of the lesions per 10 cm basement membrane were observed. BCG did not inhibit the growth of transitional cell carcinoma in Group A nor in Group B, rather partly promoted carcinogenesis. These results indicate that BCG have no inhibitory effect on carcinogenesis. We concluded that prophylactic effect of intravesical BCG is not due to inhibition of carcinogenesis but elimination of residual tumors by strong antitumor effect of BCG.

Administration, Intravesical↗
PubMed1997

[Changes in tissue and blood polyamines during N-butyl-N-(4-hydroxybutyl) nitrosamine-induced bladder carcinogenesis in rats].

BACKGROUND: Polyamine are recognized as cell growth factors. We studied in order to determine whether alterations in the levels of tissue and blood polyamines were useful biochemical markers for bladder tumor. METHODS: The concentrations of three polyamines, diamine, spermidine and spermine, in urinary bladder and blood were determined during N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis in male F344 rats. At 5 weeks of age, rats were given 0.05% BBN in the drinking water for 20 weeks. RESULTS: BBN induced bladder hyperplasia in 4 of 5 rats at 8 weeks, papillomas in 2 of 5 rats at 12 weeks, and transitional cell carcinoma in all the rats by 20 weeks. The levels of total polyamine in both bladder and blood of the rats during 12-20 weeks were significantly higher than those of the control animals given water alone. The elevation of total polyamine was mainly due to the increase of spermidine of the three polyamines, which was coincident with the incidence of bladder tumors. CONCLUSION: The results indicated that the polyamines are excellent biochemical markers for bladder tumors.

Animals↗
PubMed1999

[Effect of liarozole on the cell proliferation activity in the rat urinary bladder epithelium induced by N-butyl-N-(4-hydroxybutyl) nitrosamine].

INTRODUCTION AND OBJECTIVES: Recently, the chemopreventive effects of various drugs on N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced rat urinary bladder carcinogenesis have been reported. The aim of this study was to evaluate the effect of liarozole, an antitumor agent that inhibits the metabolism of retinoids, on the initial stage of BBN induced rat urinary bladder carcinogenesis. MATERIALS AND METHODS: Seven-week-old, male Wistar rats were used. The rats were divided into four groups. All groups except control were allowed free access to the drinking water containing 0.05% BBN. Groups Lz40 (n = 5) and Lz80 (n = 5) were administered the liarozole solution, twice daily by gavage (40 mg/kg/day and 80 mg/kg/day, respectively). Group BBN (n = 5) was given no liarozole. The control group (n = 4) received no carcinogen. At 9 weeks after the start of the experiment, all rats were killed by ether anesthesia and their urinary bladders were taken for evaluation. The urinary bladders were fixed in 10% buffered formalin, embedded in paraffin, sectioned, and immunohistochemical staining using anti-proliferative cell nuclear antigen (PCNA) antibody was performed by the avidin-biotin-peroxidase complex (ABC) method. We calculated the PCNA positive rate and compared among the four groups. RESULTS: The PCNA positive rate of group BBN was 23.5 +/- 3.7%. Compared with group BBN, the PCNA positive rate of groups Lz40 and Lz80 were statistically less (16.4 +/- 4.3% and 9.8 +/- 2.6%, respectively). Furthermore, the PCNA positive rate of group Lz80 was statistically less than that of group Lz40. CONCLUSION: The results indicate that liarozole may inhibit the activity of cell proliferation in the initial stage of BBN-induced rat urinary bladder carcinogenesis and may be dose-dependent.

Animals↗
PubMed2000

Transgenic rats carrying copies of the human c-Ha-ras proto-oncogene exhibit enhanced susceptibility to N-butyl-N-(4-hydroxybutyl)nitrosamine bladder carcinogenesis.

We have established a transgenic rat line carrying three copies of the human c-Ha-ras proto-oncogene with its own original promoter region, Jcl/SD-TgN(HrasGen)128Ncc (Hras128) rat. c-Ha-ras protein from expression of transduced and endogenous c-Ha-ras genes could be detected in the bladder epithelium of untreated transgenic rats. To examine their susceptibility to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced urinary bladder carcinogenesis, male transgenic and wild-type littermates were treated with 0.05% BBN in their drinking water for 10 weeks and then killed at week 20. The numbers and volumes of total macroscopic bladder tumors including both transitional cell papillomas and carcinomas (TCC) per rat were much greater in Hras128 rats than in their wild-type counterparts. The numbers of carcinomas per rat were also significantly greater in Hras128 rats. Two cases of TCC exhibiting invasion of the bladder muscle layer, which is extremely rare in the wild-type animals under the experimental conditions used, were also observed in Hras128 rats. The GGC-->GAC mutations at codon 12 of the transgene were observed in only two TCC out of 21 bladder tumors (9.5%), assessed by RFLP analysis and direct sequencing. SSCP analysis did not show any endogenous c-Ha-ras gene mutations. One of 25 tumors (4.0%) in wild-type rats had an endogenous c-Ha-ras gene mutation at codon 12 that was detected (GGA-->GAA) by single-strand conformation polymorphism and direct sequencing. These results indicate that the Hras128 rat is highly susceptible to BBN carcinogenesis and may be utilized as a rat model for analysis of bladder tumor development. The mutation findings indicate that the enhanced tumor development is not primarily due to mutations occurring in the transgene.

Animals↗
PubMed2000

Celecoxib inhibits N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced urinary bladder cancers in male B6D2F1 mice and female Fischer-344 rats.

Epidemiological studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a role in the prevention of human cancers. A number of preclinical studies have also suggested that inhibition of cyclooxygenase (COX) with NSAIDs has an anticancer effect in animal models of colon, urinary bladder, skin, and breast. In these studies, we evaluated the COX-2 inhibitor celecoxib in two rodent models of urinary bladder cancer. Male B6D2F1 mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN) developed transitional and squamous cell urinary bladder cancers, many of which grew rapidly and caused substantial morbidity that required sacrifice of the mice. Groups of mice received various daily doses of celecoxib in the diet (1250, 500, or 200 mg/kg of diet) beginning 7 days before the initiation of 12 weekly doses of OH-BBN. Mice were checked weekly for the presence of palpable urinary bladder masses. The study was terminated at 8 months following the initial treatment with OH-BBN. The percentage of mice with large palpable bladder lesions, which necessitated sacrifice of the mice, was 40% in the OH-BBN control group. In contrast, only 10% of all celecoxib-treated mice required sacrifice before the scheduled termination of the experiment, implying that all three doses of celecoxib inhibited the formation of large palpable lesions. Celecoxib did not significantly alter the incidence of preneoplastic bladder lesions, but did dose-dependently decrease the total number of urinary bladder cancers/mouse, palpable plus microscopic, by 77, 57, and 43% at dosages of 1250, 500, and 200 mg of celecoxib/kg of diet, respectively. In the second model, female Fischer-344 rats were administered OH-BBN twice/week for a period of 8 weeks. After 8 months, all rats developed preneoplastic lesions, whereas roughly 60% of the rats developed relatively small urinary bladder cancers. Rats were treated continually with celecoxib in the diet (500 or 1000 mg/kg of diet) beginning either 1 week prior to the initial OH-BBN treatment or beginning 1 week following the last OH-BBN treatment. Neither celecoxib treatment regimen significantly altered the number of preneoplastic lesions. Whereas celecoxib treatment initiated prior to OH-BBN administration decreased cancer incidence roughly 65%, celecoxib treatment initiated beginning 1 week after the last dose of OH-BBN profoundly decreased cancer incidence (>95%). Celecoxib did not alter the body weights of the mice or rats, or cause other signs of toxicity at any of the doses studied. Taken together these results demonstrate that: (a) celecoxib effectively inhibits tumor growth and enhances survival in the mouse model of urinary bladder cancer; and (b) celecoxib profoundly inhibits development of urinary bladder cancers in the rat model even when administered following the last dose of OH-BBN. Clinical trials will be necessary to determine whether COX-2 inhibitors will provide a clinical benefit in human bladder cancer.

Animals↗
PubMed2001

Alterations of beta- and gamma-catenin in N-butyl-N-(-4-hydroxybutyl)nitrosamine-induced murine bladder cancer.

Abnormal degradation of beta-catenin caused by alteration of the glycogen synthase kinase-3beta (GSK-3beta) consensus motif is an important step for carcinogenesis. We hypothesize that beta- and gamma-catenin may play an important role in the pathogenesis of bladder cancer. We tested this hypothesis through analysis of beta- and gamma-catenin in both murine and human bladder cancers. A murine bladder cancer model was prepared by use of N-butyl-N-(-4-hydroxybutyl)nitrosamine (BBN) in 6-week-old male B6D2F1 mice. After 4, 8, 12, 16, 20, 24, and 28 weeks of BBN treatment, bladder specimens were harvested and analyzed for both protein and gene expression for beta- and gamma-catenin. Mutational analysis of the NH(2)-terminal regulatory domains of beta- and gamma-catenin was performed in each specimen by PCR-single-strand conformational polymorphism (SSCP) analysis. Mutations were further confirmed by direct DNA sequencing with a dye terminator method. Human bladder cancer specimens with normal tissues, dysplasia, carcinoma in situ, and carcinoma of grades, 1, 2, and 3 were also analyzed for beta- and gamma-catenin expression. beta- and gamma-catenin were analyzed for mutations by SSCP and direct DNA sequencing. Intracellular accumulation of beta- and gamma-catenin was observed in 6 of 20 invasive carcinoma specimens. There was no intracellular accumulation of beta- and gamma-catenin in mucosal dysplasia, papillary or nodular dysplasia, and carcinoma in situ specimens. On an SSCP analysis for beta-catenin, abnormal bandshifts were detected in two invasive carcinomas with intracellular beta-catenin accumulation. Further sequencing revealed two mutations [AGT(S) to ATT(I) and TCT(S) to CCT(P)] within the consensus motif for GSK-3beta phosphorylation. On the other hand, SSCP analysis for gamma-catenin followed by sequencing revealed three mutations in two invasive carcinomas with intracellular accumulation of gamma-catenin. These three alterations affected the 3' downstream region outside the GSK-3beta phosphorylation site [ACC(T) to GCC(A), CTC(L) to ATC(I), and CTC(L) to ATG(M)]. In human bladder cancer, beta- and gamma-catenin expression was significantly weaker than in normal bladder. On SSCP analysis one abnormal bandshift was observed in high-grade human bladder cancer with intracellular beta-catenin accumulation. DNA sequencing revealed mutation TCT(S) to TGT(C). In summary, alterations in beta- and gamma-catenin are late events favoring tumor progression in mouse BBN-induced bladder cancer. Changes affecting the GSK-3beta phosphorylation site appear to be associated with activation of beta-catenin, but not with activation of gamma-catenin. In human blabber cancer, beta- and gamma-catenin expression is similar to the expression in the mouse model. The present study demonstrates that beta- and gamma-catenin may play an important role in bladder cancer progression.

Aged↗
PubMed1992

[The lithium carbonate promotion of urothelial tumors in rats induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine].

The effect of lithium carbonate on promotion of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced bladder tumors in rats was studied. Lithium carbonate acted as promoter in bladder carcinogenesis resulting in a 6-fold increase in the tumor occurrence as compared to controls. The experiments with sequential injection of the agent showed its promoting effect to be most apparent within 3-6 months following exposure to the carcinogen.

Animals↗
PubMed1992

The diverse modification of N-butyl-N-(4-hydroxybutyl) nitrosamine induced carcinogenesis in urinary bladder by dibromodulcitol and dianhydrodulcitol.

The effects of intravesical therapy with adriamycin, 1.6-dibromo-1.6-dideoxydulcitol (DBD) or with 1.6-dianhydrodulcitol (DAD) on bladder carcinogenesis were investigated in rats. To induce premalignant lesions in the urinary bladder female Sprague-Dawley rats received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 4 weeks and then post-treated intravesically with one of the antitumor drugs and examined once a week for 3 months. These antitumor drugs in healthy rats (i.e. without the pre-administration of BBN) did not cause any significant morphological changes in the urinary bladder after intravesical application once a week for 3 months. In the applied dose BBN alone induced only premalignant lesions in the urinary bladder. However, neoplastic lesions occurred in the groups treated with BBN and adriamycin (9 papillomas and 3 carcinomas in 14 animals). Similarly intravesical application of DBD after BBN administration resulted 5 carcinomas among the 11 animals. On the contrary no urinary bladder tumor was found in the animals treated with BBN and DAD. As DAD is one of the conversion products of DBD it is conceivable that the difference between DBD and DAD action may be due to the formation of other solvolytic product from DBD than DAD.

Administration, Intravesical↗
PubMed1992

In vitro stimulation of microsomal diethyl nitrosamine deethylase activity by vitamin K3 (menadione).

Vitamin K3 (menadione) has been found to stimulate diethyl nitrosamine (DEN)-deethylase activity in rat liver microsomes. The vitamin also takes care of the inhibitory effect of the anaerobic conditions as well as those of cytochrome poisons like sodium azide and sodium cyanide, possibly through production of active oxygen species. The enzyme was also stimulated by H2O2 and SOD and inhibited by catalase, thereby suggesting that H2O2 or some derivatives of it may be the active oxygen species involved in the reaction.

Animals↗
PubMedDate not supplied

Lack of preventive efficacy of FK228, a histone deacetylase inhibitor, against N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder carcinogenesis in p53+/- and p53+/+ mice.

BACKGROUND: The efficacy of FK228, a histone deacetylase inhibitor that is currently under early clinical trials for cancer therapy, against N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN) -induced mouse urinary bladder carcinogenesis was examined. MATERIALS AND METHODS: Heterozygous p53-deficient (p53+/-) and wild-type (p53+/+) mice were given FK228 (0, 0.01 and 0.1 mg/kg i.p., 3 times/week, respectively) after 10 weeks of 0.05% BBN treatment, and were sacrificed at 22 and 24 weeks after the start, respectively. RESULTS: There was no significant difference in the incidence of urinary bladder tumors among groups in the p53+/- or p53+/+ mice, although the high dose of FK228 increased the p21WAF1 mRNA expression in urinary bladder cancers in animals of both genotypes. CONCLUSION: The present data indicate a lack of any inhibitory effects of FK228 on BBN-induced mouse urinary bladder carcinogenesis under the present conditions.

Animals↗
PubMed1992

[Inhibitory effect of vitamin E on rats with bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine].

The anticancer activity of vitamin E may involve its functions as an antioxidant free radical scavenger, and immunomodulater. We studied the effect of vitamin E on rats with bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Three-week-old male Wistar rats were given a diet containing 0 (A), 2 mg (B:control), 40 mg (C), and 60 mg (D) of vitamin E per 100 g of food, respectively, until they were 30 weeks old. The carcinogen, 0.05% BBN was given in drinking water to the rats for 8 weeks from the 9th week of age, and all rats were killed at 30 weeks old. The number and the size of the tumors, the thickness of epithelial cell layers in hyperplasia, the diameter of papillary tumor, and the cellular atypia were assessed by using a point method according to U-test. As assessment of immune response, the lymphocyte count in blood, the degree of lymphocyte infiltration in tissue, and CD4 (helper/inducer-T cell)/CD8 (suppressor/cytotoxic-T cell) ratio in blood by flow cytometry using monoclonal antibodies were evaluated according to the t-test. Moreover, the correlation between CD4/CD8, cellular atypia, and serum level of vitamin E were evaluated by coefficient of correlation. There were no differences between any two groups in the number or the size of the tumors. The cellularity in group A was significantly higher than that in group D (p less than 0.05). The point of the cellular atypia tended to decrease, with increasing dose of vitamin E, but not significantly, whereas the CD4/CD8 tended to increase by increasing the dose of vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMedDate not supplied

DNA content analysis, expression of Ki-67 and p53 in rat urothelial lesions induced by N-butyl-N-(4-hydroxybutyl) nitrosamine and treated with mitomycin C and bacillus Calmette-Guérin.

N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-induced urothelial carcinogenesis is a useful model for studying urothelial carcinogenesis. Here, the DNA content and the expression of Ki-67 and p53 in urothelial lesions induced by BBN and treated with mitomycin C (MMC) and Bacillus Calmette-Guérin (BCG) were investigated. Female Fisher 344 rats were distributed into five groups treated with 0.05% BBN in their drinking water for 20 weeks. Ten animals were used as negative control. Intravesical instillations were performed with MMC, BCG and physiological saline solution (PSS), once per week, for 6 weeks. The animals were sacrificed 1 week after the last intravesical instillation. DNA ploidy analysis was carried out by static cytometry. Ki-67 and p53 were analysed immunohistochemically in paraffin-embedded tissue. The incidence of lesions developed in rats with PSS was greater than in rats instilled with MMC and BCG. The incidence of aneuploidy was lower in tumours treated with MMC and BCG. Low- and high-grade papillary carcinoma treated with MMC and BCG showed a decrease in labelling index and an increase of apoptotic index. The proliferative index was correlated with the apoptotic index (r=0.438, p<0.01). Significant correlations were also found between the proliferative index and lesion, and the apoptotic index and lesion (r=0.425, p<0.01 and r=0.275, p<0.01), respectively. A significant correlation was found between ploidy and the apoptotic index (r=0.245, p<0.05). Our results provide information on the biological behaviour of chemically-induced bladder tumours treated with MMC and BCG.

Aneuploidy↗
PubMed2007

Dietary beta-cryptoxanthin inhibits N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice.

Recent epidemiological studies have indicated that high dietary consumption of fruit and vegetables results in lower risk of bladder cancer. To confirm these findings, we investigated in the current study the effects of dietary administration with beta-cryptoxanthin extracted from Citras unshiu oranges on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis in mice. Male ICR mice were divided into 6 experimental and control groups. Groups 1 through 4 were given OH-BBN (500 ppm) in drinking water for 6 weeks to induced urinary bladder neoplasms. Mice in groups 2, 3 and 4 were fed the diets mixed with 1, 5 and 25 ppm of beta-cryptoxanthin, respectively, starting 1 week after the cessation of OH-BBN exposure, and kept on these diets for 24 weeks until the termination of the study. Group 5 was treated with the diet containing the test compound (25 ppm) alone, and group 6 served as an untreated control. All animals were sacrificed at week 32 for histopathology and immunohistochemistry (cyclin D1). Feeding with beta-cryptoxanthin decreased the incidence and multiplicity of preneoplastic and neoplastic lesions of urinary bladder. Notably, the highest dose (25 ppm) of the test chemical significantly lowered the occurrence of bladder carcinoma, in conjunction with reducing the cyclin D1-positive cell ratio. These findings suggest that beta-cryptoxanthin is able to prevent OH-BBN-induced bladder carcinogenesis in mice.

Animals↗
PubMed1991

Promutagenic lesions persist in the DNA of target cells for nitrosamine-induced carcinogenesis.

Immunohistochemical procedures for the location of O6-methylguanine (O6-meGua) permit detection of cells proficient for the metabolism of N-nitrosodimethylamine (NDMA) and deficient for the repair of this DNA lesion. Such cells are potentially at high risk for cancer induction and are present in various tissues. In animals maintained on a protein-deficient diet, the distribution and intensity of alkylation of individual cells is altered, particularly in liver where fewer cells apparently retain the capacity to metabolize the nitrosamine, thereby permitting increased levels of alkylation in other tissues. In the renal cortex, specific, O6-meGua-positive target cells for renal cancer induced by a single dose of NDMA in weanling rats persist at least up to the appearance of early lesions. Persistence of alkylated cells in several tissues indicates prospects for the detection of environmental exposure.

Alkylation↗