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PubMed1977

Induction of tumours by administration of N-dibutylnitrosamine and derivatives to infant mice.

Pulse doses of N-dibutylnitrosamine(DBN), N-butyl-N-(4-hydroxybutyl)nitrosamine(BBN) and N-butyl-N-(3carboxypropyl)nitrosamine(BCPN) suspended in 1% gelatin, were administered s.c. to infant CDF1 mice, and the experiment terminated at one year of age. Tumours were induced in lungs and liver. The incidences of lung adenomas were 73-95% in all treated mice, with no sex differences. Hepatocellular adenomas and a carcinoma were found with an incidence of 81% (21/26) in DBN, 59% (13/22) in BBN, and 32% (9/28) in BCPN-treated males and the incidence was 23% (5/22) in DBN-treated females. Only one papilloma of the fore-stomach was induced in mice treated with DBN. These results indicated that the s.c. administration of DBN, BBN, and BCPN induced tumours of the lung and liver, but no tumours of the urinary bladder, under these experimental conditions. The carcinogenic effect on mice at the treated dose level was DBN greater than BBN greater than BCPN.

Adenoma↗
PubMed1980

Effect of Schistosoma haematobium and N-butyl-N-(4-hydroxybutyl)nitrosamine on the development of urothelial neoplasia in the baboon.

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.

Animals↗
PubMed2005

Tumour-suppression activity of the proapoptotic regulator Par4.

The proapoptotic protein encoded by Par4 (prostate apoptosis response 4) has been implicated in tumour suppression, particularly in the prostate. We report here that Par4-null mice are prone to develop tumours, both spontaneously and on carcinogenic treatment. The endometrium and prostate of Par4-null mice were particularly sensitive to the development of proliferative lesions. Most (80%) Par4-null females presented endometrial hyperplasia by 9 months of age, and a significant proportion (36%) developed endometrial adenocarcinomas after 1 year of age. Similarly, Par4-null males showed a high incidence of prostate hyperplasia and prostatic intraepithelial neoplasias, and were extraordinarily sensitive to testosterone-induced prostate hyperplasia. Finally, the uterus and prostate of young Par4-null mice have increased levels of the apoptosis inhibitor XIAP (X-chromosome-linked inhibitor of apoptosis), supporting the previously proposed function of Par4 as an inhibitor of the (zeta)PKC (atypical protein kinase)-NF-(kappa)B (nuclear factor-(kappa)B)-XIAP pathway. These data show that Par4 has an important role in tumour suppression, with a particular relevance in the endometrium and prostate.

Age Factors↗
PubMed1999

Inhibition of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rats by green tea.

BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied in sites other than the urinary tract. The present study examined the inhibition by green tea of vesical tumors induced in rats by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). METHODS: In the first series of experiments, 0.05% BBN was added to the drinking water of rats and remained present for 5 weeks. In one experiment, six groups of animals received either tap water, green tea, matcha, hojicha, oolong tea or black tea from week 6. In a second experiment, three groups of rats received either tap water, green tea extract or powdered green tea mixed into a pellet diet from week 6. In a third experiment, five groups of rats were fed a pellet diet with addition of either 0, 0.15, 1.5 or 3.0% powdered green tea from week 6. All rats were killed and examined at 40 weeks. RESULTS: Green tea, particularly green tea leaves, dose-dependently inhibited the growth of BBN-induced urinary bladder tumors when given after the carcinogen. CONCLUSIONS: Green tea may inhibit bladder tumor growth.

Animals↗
PubMed2002

Promoting the effects of intravesical instillation of saline on bladder lesion development in rats pre-treated with BBN.

BACKGROUND: At present, immunotherapeutic agents such as bacillus Calmette-Guerin (BCG) and anti-tumor chemotherapeutic agents in saline are used intravesically in patients with bladder carcinoma. However, of greater significance is the possibility that the saline vehicle may itself promote carcinoma development in the bladder. METHODS: The potential promoting effects of intravesical instillation of saline were assessed in female F344 rats. The animals were divided into 3 groups, all of which received 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for the first 10 weeks. They were then maintained without further treatment (group 1) or received intravesical instillations of 0.3 mL of saline or distilled water once a week for 6 weeks, 15 weeks after the end of the BBN treatment (groups 2 and 3). At 32 weeks, all the animals were killed and examined immunohistochemically with proliferating cell nuclear antigen (PCNA) antibody, as well as by routine histopathologic examination. RESULTS: Both the incidence and the number of bladder carcinomas were higher in the animals that received instillations of saline than in those who did not receive the instillations. Significant increases in tumor size were also noted for the saline-treated groups, although this was not linked with the PCNA labeling index. CONCLUSIONS: The results indicate that saline is a promoter of urinary bladder carcinogenesis either because of the catheterization or the fluid itself.

Administration, Intravesical↗
PubMed2003

Inhibitory effect of clotrimazole on angiogenesis associated with bladder epithelium proliferation in rats.

BACKGROUND: Up-regulation of epithelial vascular endothelial growth factor (VEGF) expression was recently reported at an early stage of bladder carcinogenesis in rats. Subsequently, clotrimazole (CLT) was reported to exert an inhibitory effect on the in vitro proliferation of vascular endothelial cells stimulated by VEGF. The present study was performed to evaluate the effect of CLT on the initial stage of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced carcinogenesis of the urinary bladder in rats. METHODS: Seven-week-old-female Wistar rats were divided into both a control group and the other four groups that were allowed free access to drinking water containing 0.05%BBN. Two groups of rats (10-CLT and 20-CLT) received CLT (100 mg/kg per day) once daily by gavage for 10 and 20 weeks, respectively. The other two groups of rats (10-BBN and 20-BBN) were maintained on the same BBN-containing drinking water for 10 and 20 weeks, respectively, without receiving CLT. After removing the urinary bladder of each rat, expression of VEGF and VEGF receptor FLT1, and new capillaries were examined by immunohistochemical staining. VEGF mRNA was detected by the reverse transcription polymerase chain reaction. RESULTS: The ratio of VEGF-positive cells and the expression of VEGF mRNA were lower in the 20-CLT group than in the 10-BBN group. Newly formed capillaries in the 20-CLT group were significantly decreased compared with those in the 10-BBN group. CONCLUSION: These quantitative data suggested that CLT can inhibit VEGF expression in vivo and hence inhibit angiogenesis in the early stages of bladder carcinoma.

Animals↗
PubMed2003

Preventive effects of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine in rat by green tea leaves.

BACKGROUND: Recently, the anticarcinogenic effects of green tea have been studied in sites other than the urinary tract. Although the incidence of bladder cancer has increased, responses to therapy have been limited. The present work examined the preventive effects of green tea against bladder tumors induced in rats by the carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine(BBN). METHODS: From week 5 to week 9, all the groups were exposed to 0.05% BBN in the drinking water for 5 weeks. Rats were divided into four groups. Group 1 was fed a CE-2 diet and tap water for the entire experimental period and served as the control group. Group 2 was fed the green tea leaves after carcinogen exposure. Groups 3 and 4 received green tea leaves before carcinogen exposure. All rats were killed and examined at 44 weeks. RESULTS: Green tea leaves prevented the growth of BBN-induced urinary bladder tumors when given before the carcinogen. CONCLUSION: Green tea may inhibit tumor initiation in the bladder.

Animals↗
PubMed1997

Morphological changes in the basement membrane during progression from non-invasive to invasive rat bladder cancer induced by N-butyl-N-(4-hydoxybutyl) nitrosamine.

OBJECTIVE: To investigate the ultrastructural changes in the basement membrane (BM) in the rat model of bladder cancer when progressing from non-invasive to invasive disease. MATERIALS AND METHODS: N-butyl-N-(4-hydoxybutyl) nitrosamine (BBN) was administered to 50 rats (7 weeks old) in their drinking water (0.05% BBN) for 28 weeks. At between 20 and 28 weeks, 10 rats were killed every 2 weeks and morphological changes of the BM were investigated by transmission electron microscopy and histological changes by light microscopy. RESULTS: At between 20 and 28 weeks, the transitional cell carcinoma (TCC) of the rat bladder induced by BBN progressed from non-invasive (stage Ta) to invasive (stage T1-2) disease. Focal thinning and discontinuity of the BM occurred in five of 26 rats with non-invasive TCC and in all 24 rats with invasive TCC. CONCLUSIONS: Stage Ta bladder cancer in the rat model may be associated with degradative changes in the BM and can be divided into two types, Ta1 where there is no degradation of the BM and Ta2, where the BM is degraded.

Animals↗
PubMed1999

Antitumour effects of the angiogenesis inhibitor AGM-1470 on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

OBJECTIVE: To examine the antitumour effects of the angiogenesis inhibitor AGM-1470 (TNP-470) on rat urinary bladder tumours induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). MATERIALS AND METHODS: Fischer-344 rats were allocated to one of four groups of 15 rats each; in group 1, rats were administered AGM-1470 intraperitoneally, with group 2 acting as the control and given only saline; in group 3, AGM-1470 was instillation intravesically and group 4 acting as control (intravesical saline). All rats were given 0.05% BBN in their drinking water for 8 weeks and then given water with no BBN. AGM-1470 was administered at a dose of 30 mg/kg every other day for 6 weeks in group 1 and at 15 mg/kg once a week for 6 weeks in group 3. This treatment was commenced at 21 weeks after the start of BBN treatment, when tumorigenesis was apparent in all rat bladders; approximately 70-80% of the tumours were carcinomas. All rats were killed in the 27th week. The antitumour effects of AGM-1470 on the BBN-induced bladder tumours were evaluated macroscopically and histologically. The inhibitory effect of AGM-1470 on endothelial cell proliferation was assessed in groups 1 and 2 by immunohistochemical staining for Factor VIII-related antigen and by counting the microvessels. RESULTS: The number and volume of bladder tumours were significantly less in group 1 than group 2. In the latter, at least one bladder tumour developed in each of the 15 rats. Histologically, transitional cell carcinoma (TCC) was found in 13 rats and papilloma in two, with invasive cancer in three of the 13 TCCs. Bladder tumours developed in only four of the 15 rats in group 1. Carcinomas were found in three of these four rats and no invasive cancer was detected. The rats in group 1 had significantly fewer microvessels than the controls. The rats in group 4 also showed slightly but insignificantly less tumour growth and fewer carcinomas. In neither experiment were any major side-effects seen except for mild weight loss after AGM-1470 treatment. CONCLUSION: AGM-1470 inhibited the growth and malignant progression of BBN-induced bladder tumours in rats, apparently mainly by the inhibition of tumour vessel development. The intraperitoneal administration of AGM-1470 produced better results than did intravesical instillation. These results suggest that the angiogenesis inhibitor AGM-1470 is a promising agent for the treatment of human bladder cancer.

Animals↗
PubMed1999

Effects of astragali radix extract on carcinogenesis, cytokine production, and cytotoxicity in mice treated with a carcinogen, N-butyl-N'-butanolnitrosoamine.

We studied the effects of astragali radix extract, a Chinese herb and one of eight components in Shikaron, on carcinogenesis, natural killer (NK) cell activity, and the cytokine production of lymphocytes in mice treated with a carcinogen, N-butyl-N'-butanolnitrosoamine (BBN). We found a significantly lower incidence of urinary bladder carcinoma in mice treated with BBN plus 10 mg/kg/day or more of Astragalus extract (7, 2, and 3 mice among 15 mice in 10, 20, and 40 mg/kg/day group, respectively, vs. 14 of 15 mice treated with BBN alone). Astragalus extract prevented the cytotoxic activity of lymphocytes against YAC-1 cells from the depression by BBN. It also protected the production of interleukin-2 and gamma-interferon of lymphocytes from the depression by BBN. These results, including our previous findings, suggest that the Astragalus extract exerts an anticarcinogenic effect in carcinogen-treated mice through activation of cytotoxic activity and the production of cytokines.

Animals↗
PubMed1998

Changes in the activities of mitochondrial enzymes in the progress of tumorigenesis of bladder cancer.

To investigate changes in the activities of mitochondrial enzymes in the progress of tumorigenesis of bladder cancer, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) carcinogen was administered orally to male Sprague-Dawley rats for eight weeks. The urinary bladders were harvested periodically for the evaluation of tumorigenesis. The activities of NADH cytochrome c reductase (NCCR), succinate cytochrone c reductase (SCCR) and cytochrome c oxidase (CCO) were measured. The NCCR and SCCR activities elevated significantly by the exposure of BBN and decreased rapidly when BBN was withdrawn. However, the CCO activity increased and reached plateau at 18 weeks in spite of the discontinuance of BBN. The results indicated that the NCCR, SCCR and CCO activities were significantly elevated in the tumorigenesis. However, the CCO enzyme may be more related to the progress of tumorigenesis of bladder cancer.

Animals↗
PubMed1989

Lack of a modifying effect by the diuretic drug furosemide on the development of neoplastic lesions in rat two-stage urinary bladder carcinogenesis.

The effect of the diuretic drug furosemide on two-stage urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was investigated with regard to possible promoting activity. BBN was administered at 2 doses, 0.01 or 0.05%, in drinking water for 4 wk, and thereafter furosemide was given by gavage 3 times weekly for 32 wk, 250 mg/kg body weight. Furosemide ingestion induced diuresis with an alkaline, hypotonic urine. No significant difference with regard to incidences of bladder lesions were apparent between furosemide and control groups. The present investigation indicated that neither furosemide nor its related polyuria acted as a promoter in two-stage urinary bladder carcinogenesis.

Animals↗
PubMed1989

Changes in aldehyde dehydrogenase during rat urinary bladder carcinogenesis.

We have reported that normal rat urinary bladder possesses significant amounts of an aldehyde dehydrogenase (class 3 ALDH) expressed during hepatocarcinogenesis, but not detectable in normal liver. Changes in expression of both liver and bladder ALDH during N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced bladder carcinogenesis were studied. The ALDH phenotype was determined at intervals over 42 weeks by histochemical analysis, total ALDH activity assays and gel electrophoresis using propionaldehyde and NAD (P-NAD) which characterizes class 1 and 2 ALDH, or benzaldehyde and NADP (B-NADP) to determine class 3 ALDH. By total activity assays and gel electrophoresis, there was a significant decrease in bladder class 3 ALDH activity during weeks 5-15. Histochemical analysis clearly demonstrates changes in ALDH early in neoplastic development. Intense staining with B-NADP in regions of hyperplasia was first detectable at week 10. Staining in hyperplastic regions was accompanied by a significant decrease in ADLH in neighboring, apparently normal urothelium. As the urothelium became more abnormal, class 3 ALDH activity increased. By week 25, the bladder class 3 ALDH activity of BBN-treated animals was 2 times greater than the control group class 3 ALDH activity. Histochemically, all papillomas and carcinomas examined possessed class 3 ALDH. However, staining was heterogeneous within the lesions. Bladder neoplasm class 3 ALDH specific activity was greater than control group class 3 ALDH activity in 70% of papillomas and carcinomas. These results suggest events may be occurring in bladder similar to those in liver which alter expression of aldehyde dehydrogenase during carcinogenesis.

Aldehyde Dehydrogenase↗
PubMed1989

Effects of urinary potassium and sodium ion concentrations and pH on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in rats.

The promoting activities of low and high sodium or potassium ion concentrations, under conditions of neutral as well as elevated urinary pH, in urinary bladder carcinogenesis, were investigated in rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Male Wistar rats were given 0.05% BBN in their drinking water for 4 weeks and then treated for 32 weeks with either control diet (group 1) or this diet supplemented with equimolar amounts of the following minerals: 2.34% NaCl (group 2), 2.98% KCl (group 3), 3.36% NaHCO3 (group 4), 1.68% NaHCO3 + 2% KHCO3 (group 5), or 4% KHCO3 (group 6). The alkalizing salts NaHCO3 and KHCO3 induced comparable increases in urinary pH and elevated urinary sodium or potassium ion concentrations respectively. The combination of NaHCO3 + KHCO3 similarly caused an elevation of the urinary pH and less increased sodium and potassium ion concentrations. In the groups fed NaHCO3 and KHCO3 either alone or in combination, the incidences of papillary/nodular hyperplasia, papillomas and carcinomas in the urinary bladder had increased as compared to controls. NaCl and KCl also induced high urinary sodium or potassium ion concentrations without alteration of urinary pH. This was accompanied by increased incidences of simple hyperplasia, papillary/nodular hyperplasia, and/or papillomas but no carcinomas. The present results indicate that the potassium ion is as potent as the sodium ion in promoting urinary bladder carcinogenesis under conditions of elevated urinary pH, and that both the sodium and potassium ions may exert weak promoting activity under conditions of neutral urinary pH.

Animals↗
PubMed1990

H-ras activation and ras p21 expression in bladder tumors induced in F344/NCr rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Bladder tumors were induced in male F344/NCr rats by administration of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) at 500 p.p.m. in their drinking water for 12 weeks. Twenty-one bladder tumors that developed between 25 and 50 weeks after BBN administration was begun were evaluated for immunoreactivity with polyclonal or monoclonal antibodies raised against ras p21, for amplification of ras genes by Southern blotting, and for activating point mutations in ras genes by selective oligonucleotide hybridization of products from polymerase chain reaction (PCR). Increased expression of ras p21 was detected by avidin-biotin immunohistochemistry in 18/21 (85%) of the neoplastic bladder lesions. By Southern analysis, there was no significant amplification of H-ras, K-ras or N-ras in any of the tumors except one that showed a 5-fold amplification of K-ras. Point mutations in ras genes were detected by selective oligonucleotide hybridization of the products of PCR. Of the 21 bladder tumors, three tumors were shown to have mutations in codon 12 (GGA----GAA), six tumors in codon 61 (two CAA----CTA, four CAA----CGA), and one in both codon 12 (GGA----GAA) and codon 61 (CAA----CGA), all in H-ras. Thus 10 of 21 tumors has ras gene mutations in a portion of the tumor cells. The variable pattern of point mutation in H-ras suggests that these mutations may not all be a direct consequence of interaction of BBN metabolites with H-ras. Enhanced expression of ras p21 was always focal and was not necessarily associated with transforming ras mutations. It is therefore suggested that tumorigenesis in BBN-initiated bladder cells might involve H-ras activation as part of a multistep pathway; however, H-ras involvement is not obligatory for tumor development.

Animals↗
PubMed1990

Correlation between medium-term liver bioassay system data and results of long-term testing in rats.

The effects of hepatocarcinogens (ethionine, thioacetamide, phenobarbital), non-hepatocarcinogens [N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN), N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)] and a hepatoinhibitor [(butylated hydroxyanisole (BHA)] were compared in medium- and long-term in vivo systems. In experiment I, 2 weeks after a single injection of diethylnitrosamine (DEN) groups of male F344 rats received chemical administration for 6 weeks, combined with partial hepatectomy at week 3 and were killed at the end of week 8. In experiment II, animals were treated in the same manner and then given basal diet and tap water (group 1) or chemical continuously (group 2) until the 2 year timepoint. Numbers and areas of glutathione S-transferase placental form (GST-P)-positive foci developing in the liver under medium-term bioassay conditions (experiment I) were found to closely correlate with eventual hepatocellular carcinoma incidences after continuation of test chemical administration (experiment II). Thus all of the hepatocarcinogens enhanced both the induction of GST-P-positive focal lesions and liver tumors. While non-hepatocarcinogens exerted no such effects, their influence being limited to inducing lesions in their own respective target organs such as urinary bladder cancers in the EHBN case and glandular stomach adenocarcinomas with MNNG, BHA demonstrated inhibition potential in both experiments. The observed correlation between long- and medium-term results strongly indicates the applicability of our medium-term bioassay system for detection of liver carcinogens.

Animals↗