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PubMed1979

The mutagenicity of dialkyl nitrosamines in the Salmonella plate assay.

N-nitrosodimethylamine (DMN) is not mutagenic in the standard Salmonella plate incorporation assay (Ames test) in the presence of an in vitro metabolic activation system (S-9) derived from rat liver. When the S-9 was derived from Aroclor- or phenobarbital-induced mouse or hamster liver or from uninduced hamster liver, mutagenic activity was observed. Increasing the amount of S-9 above the usual maximum level of 50 microliter per plate increased the mutagenic response. Similarly, the mutagenicity of N-nitrosodiethylamine (DEN) and N-nitrosodi(n-butyl)amine (DBN) was greater in the presence of hamster liver S-9 than when mouse or rat liver was used. Data are also presented indicating that the ability of rat liver S-9 to mediate the mutagenic activity of DMN in the "preincubation" assay is due to the fact that the various components are present in this assay at several times the concentrations attained in the standard plate incorporation assay.

Animals↗

PubMed2005

Suppressive effect of 1,4-phenylene diisothiocyanate on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice.

The modifying effects of dietary administration of 1,4-phenylene diisothiocyanate (DITC) on N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced urinary bladder carcinogenesis during the initiation and post-initiation phases were examined in male ICR mice. Five-week-old animals were divided into 5 groups. Groups 1-3 were given BBN (500 ppm) in drinking water for 6 weeks starting at age 6 week. Mice in Group 2 were given the diet containing 100 ppm DITC for 8 weeks during the initiation phase, starting 1 week before BBN exposure. Animals in Group 3 were fed the experimental diet for 24 weeks during the post-initiation phase starting 1 week after the cessation of BBN exposure. Mice in Group 4 were given only the diet containing the test compound, and those in Group 5 were given the basal diet alone throughout the experiment (32 weeks). The frequency of bladder lesions, neoplasms, dysplasia and hyperplasia, was analyzed histopathologically. The cell-proliferation activity estimated by the 5-bromodeoxyuridine labeling index (BrdU-LI), and cell cycle progression by counting cyclin D1-positive cell ratios were compared among the groups using immunohistochemistry. Administration of DITC in the initiation phase reduced significantly the incidence of urinary bladder carcinoma and dysplasia. The frequencies of any lesions of urinary bladder were not reduced by DITC in post-initiation phase. Dietary exposure of this agent in initiation phase reduced significantly both BrdU-LI and cyclin D1-positive cell ratios in any bladder lesions. Administration of DITC in post-initiation phase also significantly reduced BrdU-LI in bladder neoplasms and hyperplasia and cyclin D1-positive cell ratios in urinary bladder carcinoma as well as dysplasia. These results suggest that dietary DITC could be a preventive agent against BBN-induced bladder carcinogenesis in mice when fed during the initiation phase.

Animals↗

PubMed1990

Oncogene expression of FANFT- or BBN-induced rat urothelial cells.

Proto-oncogene expression by cultured urothelial cells prepared from the bladders of male F344 rats that had been treated with N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT) or N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined. Although all of the cultured cells showed varying degrees of anchorage-independent growth, only 9 of them were transplantable into nude mice. A Northern blot technique was employed for the detection of proto-oncogene transcripts. The c-Ha-ras transcripts were detected in all the cultured urothelial cells prepared from the carcinogen-treated rats and in normal urothelial cells. However, the transcript levels were several-fold higher in the former than in normal cells. Increased expression of p21, as determined by immunohistochemical techniques, was also observed in all the original bladder tissues from which the cultures were derived. c-myc transcripts were detected in the cells from carcinogen-treated rats but not in the normal cells. The presence of myc product in hyperplastic urothelial lesions and carcinomas of original bladder tissues was confirmed by immunohistochemical methods. Transcripts of mos, erb B, Ki-ras, abl and src were not detected. Since increased expression of c-myc and c-Ha-ras were present in both transplantable and non-transplantable cell lines, and the expression of p21 occurs in preneoplastic cells, this suggests that elevated expression of these 2 genes may be an early genetic event during bladder carcinogenesis in the rat and further alteration of these 2 genes or mutation of additional genes may be required for the completion of malignant transformation.

Animals↗

PubMed2004

Gene expression in the bladder carcinoma rat model.

We investigated gene expression in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder carcinoma in order to test its applicability as a model for the study of novel therapeutic modalities, particularly gene therapy. We administered BBN in the drinking water to Wistar rats for up to 30 wk and induced papillary transitional cell carcinoma (TCC), which is similar to the most prevalent type of human bladder cancer. Tumor evolution was similar to that found in previous studies. However, we described the morphological stages according to modern human bladder carcinoma terminology. Our main goal was to examine the expression levels of the H19 gene, of the insulin-like growth factor 2 (Igf2) transcripts expressed from promoters P2 and P3 and of the telomerase subunits that we had previously investigated as tools for targeted gene therapy of bladder cancer. We detected at 30 wk of BBN exposure significant upregulation of these sequences in the rat bladder tumors, similar to our previous findings in human bladder cancer. To reinforce the similarity of this model to the corresponding human disease, we searched for additional tumor-specific genes documented as having altered expression in human bladder carcinoma, using cDNA expression arrays (Clontech). We suggest that BBN-induced rat bladder cancer has morphological, biological, and molecular parallels to human bladder cancer and is an attractive model for studying novel alternatives of therapeutic intervention.

Animals↗

PubMed2005

Absence of FGFR3 mutations in urinary bladder tumours of rats and mice treated with N-butyl-N-(-4-hydroxybutyl)nitrosamine.

Frequent activating mutations of FGFR3 (fibroblast growth factor receptor 3) are found in human urothelial cell carcinomas, particularly in superficial papillary tumours (in 74%-84% of pTaG1-G2), but not in carcinomas in situ (CIS) and at a low rate in invasive tumours (in 16%-21% of pT1-4). In mice and rats, BBN (N-butyl-N-(4-hydroxybutyl)nitrosamine) specifically induces bladder tumours. In rats, superficial papillary tumours are mostly observed. In mice, tumour progression follows the CIS pathway: CIS are first observed, followed by tumours that invade surrounding muscle. Therefore, we looked for FGFR3 mutations in these two animal models of bladder cancer. Only the FGFR3b isoform is expressed in human urothelium and derived tumours. We identified the FGFR3b isoform in rats for the first time and showed that this is the main isoform expressed in the bladder urothelium and derived carcinomas in mice and rats, as in humans. SSCP and sequence analysis of FGFR3b showed sequence changes (polymorphisms or silent mutations) in four BBN-induced rat and mouse bladder tumours. The absence of activating mutations of FGFR3 in the mouse model was in agreement with the fact that mouse BBN-induced bladder tumour progression mimics the CIS pathway. The absence of FGFR3 mutations in the rat bladder tumours suggests that, at least at the genetic level, rat superficial papillary tumours differ from their human counterparts.

Animals↗

PubMed1990

Activating missense mutations in Ha-ras-1 genes in a malignant subset of bladder lesions induced by N-butyl-N-(4-hydroxybutyl)nitrosamine or N-[4-(5-nitro-2-furanyl)-2-thiazolyl]formamide.

Urothelial cell cultures generated from urinary bladders from a series of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)- or N-[4-(5-nitro-2-furanyl)-2-thiazolyl]formamide (FANFT)-treated Fischer 344 rats were examined for activating missense mutations in Ha-ras-1 genes. Our overall objective was to identify oncogene-activating mutations in this system and to determine what altered biological properties correlate with such genetic changes. The urinary bladders from the treated animals showed a spectrum of histopathologies, from simple hyperplasia to transitional cell carcinoma (TCC). Using restriction analysis, oligonucleotide hybridization, and DNA sequencing, we found that approximately 20% (3/14) of the bladder cell cultures had acquired oncogenic single-base substitutions in codon 61 of Ha-ras-1 genes (CAA----AAA or CGA). The donor bladder lesions for these three cultures, which also harbored the same ras-activating mutations, were all classified as stage A or B TCCs. However, four other TCCs also arising in this series were found to have normal Ha-ras genes. Whereas approximately half of the bladder cultures derived from the carcinogen-treated rats were nontumorigenic in athymic mice, the three cultures containing ras oncogenes were all highly tumorigenic (forming tumors within 5 wk of injection into athymic mice). These cultures also displayed a high degree of anchorage-independent growth and NIH 3T3-transforming activity in gene transfer assays. The nontumorigenic cultures were derived from bladder lesions that included three hyperplasias and three stage A TCCs. We conclude that ras-activating missense mutations were present in a malignant subset of bladder lesions induced by BBN or FANFT, but most of the lesions in this system appeared to involve genetic alterations elsewhere. Thus other oncogenes besides activated Ha-ras may apparently be associated with the same bladder histopathologies and transformation markers.

Animals↗

PubMed2002

Lack of enhancing effect of two Kampo medicines, Sho-saiko-to (TJ-9) and Sairei-to (TJ-114), on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The modifying potential of two Kampo medicines (Japanese traditional herbal medicines), Sho-saiko-to (TJ-9) and Sairei-to (TJ-114), on urinary bladder carcinogenesis in male F344 rats initiated with N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN) was evaluated. Groups of 20 animals were given 0.05% BBN in their drinking water for 4 weeks and then 0.7 or 2.8% TJ-9, 0.9 or 3.6% TJ-114, or 3.0% sodium bicarbonate (NaHCO(3)) as a positive control substance in their diet for 32 weeks. All rats were killed after 36 weeks and examined histopathologically. No adverse effects of the test compounds were found in terms of survival, clinical sign, and body weight. Administration of 0.7 and 2.8% TJ-9 and 0.9 and 3.6% TJ-114 in the diet did not affect the incidences or extent of PN hyperplasia in the BBN-treated rats. Incidences and multiplicities of papillomas were also not affected in rats fed 0.7 or 2.8% TJ-9 and 0.9% TJ-114, while they were significantly decreased in animals given 3.6% TJ-114 in the diet. The results thus demonstrated that neither of the test chemicals exerted any promotional activity on urinary bladder carcinogenesis, in clear contrast to NaHCO(3). In addition, bladder carcinogenesis was reduced by 3.6% TJ-114 in the diet, under the present experimental conditions.

Animals↗

PubMed1991

Comparative promoting activities of phosphate salts on rat two-stage bladder carcinogenesis under conditions of equivalent urinary Na+ or K+ levels.

Promoting effects of Na or K phosphate salts on rat two-stage bladder carcinogenesis were compared. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and thereafter received 1.4% Na3PO4, 2.0% NaH2PO4, 1.0% K3PO4, or 2.5% KH2PO4, these dietary concentrations being selected because they result in approximately equal levels of Na+ and K+ in the urine, equivalent to moderate natriuresis or kaluresis in comparison with our previous data. Treatment with Na3PO4 or K3PO4 induced significant increase in urinary pH compared with control values, whereas urinary pH in the NaH2PO4 and KH2PO4 groups was comparable to control values. With regard to preneoplastic lesion development, both incidences and multiplicity were significantly increased in the groups given Na3PO4 or K3PO4 compared with both controls and NaH2PO4 or KH2PO4 groups, respectively. Furthermore, treatment with Na3PO4 significantly increased multiplicity of papillomas, accompanied by a tendency to increased incidence. No statistically significant difference in promoting potential between Na3PO4 and K3PO4 groups was evident. The present results thus suggest that tumor promotion under conditions of moderate natriuresis or kaluresis depends primarily on high urinary pH.

Animals↗

PubMed1993

Lack of promotion of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in mice by rat cancer promoters.

The effects of dietary exposure to sodium L-ascorbate (Na-AsA), butylated hydroxyanisole (BHA), and diphenyl on the development of urinary bladder tumors in a mouse two-stage carcinogenesis model were examined. Male B6C3F1 mice received 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in the drinking water for 4 weeks and were then treated with 5% Na-AsA, 1% BHA, or 1% diphenyl for 32 weeks. None of these chemicals enhanced the development of either preneoplastic or neoplastic lesions in the urinary bladder. Furthermore, DNA synthesis levels of urinary bladder epithelium in mice treated with each substance alone for 8 weeks were not elevated significantly, although Na-AsA was associated with a significant increase in the urinary pH value and Na+ concentration. The results indicate that Na-AsA, BHA, and diphenyl do not exert an enhancing influence on mouse bladder carcinogenesis, in clear contrast to the case in the rat.

Animals↗

PubMed1994

Effect of phenacetin pretreatment on renal pelvic carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine in NON/Shi mice of both sexes.

Influences of phenacetin (PH) pretreatment on renal pelvic carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were examined in NON/Shi mice of both sexes. Histopathological examination revealed that PH pretreatment enhanced not only the induction of urinary tract carcinoma but also distant metastasis of renal pelvic carcinoma by BBN in male mice. The high incidence of urinary tract carcinoma by PH pretreatment might be due to hydronephrosis and epithelial proliferative lesions enhanced by PH, since a single treatment of PH induced hydronephrosis in all mice and simple hyperplasia in 70-80% of mice used.

Animals↗

PubMed1995

Absence of promoting potential of bracken fern (Pteridium aquilinum) in rat urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine and uracil.

Conventional studies on bracken fern (Pteridium aquilinum; PA) carcinogenicity have used high dietary concentrations (around 30%) and long-term exposure (up to 52-70 weeks) without consideration of the multistep character of the chemical carcinogenesis process. The present study evaluated specifically the promoting potential of 3-5% dietary crude PA in the rat urinary bladder mucosa in a 32-week-long initiation-promotion assay for chemical carcinogenesis. Initiation of urothelial carcinogenesis was accomplished with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Uracil (U) was provided through the diet in order to expand the population of initiated cells. Seven groups (G) of male Wistar rats were submitted to the following treatments: G1 = BBN (n = 8); G2 = U (n = 10); G3 = BBN-U (n = 9); G4 = BBN-PA-U-PA (n = 16); G5 = PA (n = 8); G6 = BBN-PA (n = 10); G7 = PA-U-PA (n = 12). At the end of the experiment rats presenting epithelial papillary or nodular hyperplasia (PNH), papillomas (PAP), or simultaneous PNH plus PAP numbered, respectively G1: 2-0-1; G2: 0-0-0; G3: 3-0-2; G4: 4-3-2; G5: 1-0-1; G6: 8-0-0; and G7: 0-0-0, with no significant differences in the incidence of lesions among the groups. More frequent and more severe lesions occurred in BBN-initiated animals, predominantly in those also exposed to uracil (G3 and G4). Low-dose crude bracken fern in the diet does not promote rat urinary bladder carcinogenesis after a 32-week period of exposure, even when the initiated urothelial cell population has been expanded through a mechanical stimulus.

Animals↗

PubMed1996

Immunohistochemically demonstrated variation in expression of cathepsin E between uracil-induced papillomatosis and N-butyl-N-(4-hydroxybutyl)nitrosamine-induced preneoplastic and neoplastic changes in rat urinary bladder.

Expression of rat urinary bladder cathepsin E in benign papillomatosis induced by uracil and various stages of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced carcinogenesis was investigated immunohistochemically. Seven-week-old, male F344/DuCrj rats were used. In the normal urothelium of control rats, cathepsin E stained in all layers of cells, although in umbrella cells and some basal cells the reaction was relatively weak. In rats given a diet containing 3% uracil for 5 weeks immunoreactivity of cathepsin E in uracil-induced papillomatosis was consistently homogeneous in all layers, but weaker than in normal urothelium. In rats given 0.05% BBN in drinking water for 12 weeks and subsequently maintained without treatment for 48 weeks cells with little cathepsin E, never observed in normal urothelium, appeared at 5 weeks above the basement membrane in the earliest stage of BBN-induced urinary bladder cancer (simple hyperplasia). Throughout the neoplastic process, groups of cells with a little cathepsin E were randomly distributed, with expression in the urothelium being markedly unstable. Almost all areas of squamous cell proliferation in TCC were negative for cathepsin E. Instability of cathepsin E expression in rat urothelium therefore appears characteristic for carcinogenesis and offers the possibility of using this feature as an early biomarker for urinary bladder carcinogenesis.

Animals↗

PubMed1982

Effect of partial cystectomy on the induction of pre-neoplastic lesions in rat bladder initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by bladder carcinogens and promoters.

The effect of partial cystectomy on the occurrence of pre-neoplastic lesions, papillary or nodular hyperplasia (PN hyperplasia), of the bladder in male F344 rats was studied in an experiment in which bladder carcinogens and promoters were given to the rats after initiation with BBN. The bladder carcinogens tested were N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) and N-4[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT) and the bladder promoters were sodium saccharin, sodium cyclamate, and DL-tryptophan. Partial cystectomy significantly decreased the occurrence of PN hyperplasia in rats treated with EHBN and tended to inhibit that in rats given saccharin or tryptophan. Thus partial cystectomy inhibited rather than enhanced the induction of PN hyperplasia.

Animals↗

PubMed1975

Effects of sex hormones on development of urinary bladder tumours in rats induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

Male and female Wistar strain rats were given 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 6 weeks and then water without BBN for 18 weeks. Diethylstilbestrol and testosterone were implanted subcutaneously into both intact and gonadectomised animals before or after treatment with BBN to evaluate their effects on the development of bladder tumours. Diethylstilboestrol reduced the incidence of bladder tumours significantly in male rats. The incidence was higher in female rats after spaying and administration of testosterone after BBN treatment, than in the intact female. These results suggest that diethylstilboestrol inhibits carcinogenesis of the urinary bladder induced by BBN and growth of bladder tumours induced by BBN, in male rats. On the other hand, testosterone seems to stimulate the growth of bladder tumours induced by BBN in female rats.

Animals↗

PubMed1987

Scanning electron microscopy of changes in the urinary bladder in dogs treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN).

The fine structures of the bladder mucosa during BBN carcinogenesis and of bladder tumors induced by BBN in dogs were examined by scanning electron microscopy. Normal dog bladder mucosa was covered with polygonal superficial cells with peaked microridges, but no microvilli. Microridges and uniform microvilli were observed in hyperplastic mucosa. In low grade papillary tumors induced by low doses of BBN, pleomorphic microvilli predominated. In dogs which received high doses of BBN, bizarre pleomorphic microvilli and blebs were observed in papillary lesions, whereas bumpy surfaces with thick short microvilli were observed in non-papillary lesions. These sequential changes which were observed in dog bladder mucosa during BBN carcinogenesis parallelled the changes that occurred in the process of chemical carcinogenesis in rodents, and dog bladder tumors were similar to those of rodents and of human bladder cancers.

Animals↗

PubMed1983

Effects of intravesical instillation of antitumor drugs on the induction of preneoplastic bladder lesions in rats.

The effects of adriamycin (ADR) and mitomycin C (MMC) as inhibitors of the development of bladder tumors in rats were studied. Six-week-old female F344 rats were divided into nine groups, five of which received 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for the first 4 weeks, no treatment for 1 week, and then intravesical instillation once a week of ADR, MMC, or physiological saline or no instillation (no catheterization) for 12 weeks. The other four groups received no BBN for the first 5 weeks of the experiment and then received ADR, MMC, or physiological saline as above for 12 weeks. The bladders were examined by light microscopy 17 weeks after the beginning of the experiment. Results showed that development of preneoplastic lesions induced in the bladders of the rats by BBN was stimulated by subsequent instillation of ADR or MMC. This result suggests that ADR and MMC have promoting activities in bladder carcinogenesis of rats.

Animals↗

PubMed1989

Morphological changes of urothelial and intestinal mucosa after ureterosigmoidostomy during experimental urogenic carcinogenesis.

To analyze the effect of chemical carcinogens on urothelial and intestinal mucosa on 214 female Wistar rats an ureterosigmoidostomy was performed. After 10-14 days 123 surviving rats were randomly divided into 4 groups: Group I-III received 0.05 per cent N-Butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) in drinking water over a period of 15 weeks. Group IV received normal drinking water over the same period. The defunctionalized bladders were instilled each second day: Group I: physiologic saline solution, Group II: urine of normal rats, Group III and IV: urine of BBN-treated rats. 30 rats without diversion but BBN treatment served as a control. The evaluation of the histological data gave the following results: In the control group urothelial tumors were found in the bladder exclusively. Dependent on the grade of obstruction in the BBN-treated groups, with diversion urothelial tumors in the renal pelvis and ureter could be documented, whereas in the bladder no tumor growth could be shown. In the intestinal mucosa of BBN-treated animals a high incidence of adenocarcinoma was found. The chemical tumor induction by BBN is related to the urine and takes place by direct contact to the mucosa when the metabolites excreted by the kidneys are activated in the urine. BBN or other urogenic carcinogens seem to have no urothelial specificity. The incidence of bowel carcinoma after diversion must lead to intensive long-term follow up.

Adenocarcinoma↗

PubMed1987

Effects of single chemotherapeutic agents on development of urinary bladder tumor induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in rats.

Chemotherapeutic agents were evaluated for effect on the development of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in male Wistar strain rats. Seven hundred and two rats were given 0.05% BBN in drinking water for 8 weeks. After BBN treatment, the animals were divided into 26 groups to follow regimens of single chemotherapy. All drugs were administered intraperitoneally except in one group that was treated orally. In our experimental series, 5-fluorouracil (5-FU), N-(2-tetrahydrofuryl)-5-fluorouracil (FT-207), carbazilquinone (CQ), vincristine (VCR) and cis-diamminedichloroplatinum (CDDP) were effective in inhibiting the incidence of bladder tumor, however, adriamycin (ADM), mitomycin C (MMC), neocarsinostatin (NCS), cyclophosphamide (CPM) and bleomycin (BLM) were not effective.

Administration, Oral↗