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PubMed1983

Therapeutic effect of a retinoid (Ro 10-9359) on rats with bladder tumours induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine upon administration alone or in combination with mitomycin C.

The therapeutic effect of an aromatic retinoic acid analogue (Ro 10-9359) and mitomycin C (MMC) on rats with bladder tumours induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was examined. Eight-week-old female Wistar rats were given 0.05% BBN in drinking water for 8 weeks. Therapy was started at week 26 and all rats were killed at week 30. MMC at a dose of 0.3 mg/kg twice a week ip for 3 weeks significantly reduced the incidence and the mean number of tumours. With oral Ro 10-9359 at a dose of 100 mg/kg once weekly for 4 weeks, no significant effect was observed. The combination of MMC and Ro 10-9359 significantly reduced the mean number, but not the incidence, of tumours. The difference between the effect of MMC alone and that of MMC given in combination with Ro 10-9359 was not statistically significant. Thus no favorable effect of the retinoid could be demonstrated either alone or in combination with MMC.

Animals↗
PubMed1990

Anti-tumor effect of intravesical instillation of OK432 against rat bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

The anti-tumor effect of OK432 instilled into the bladder was evaluated in rat bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). In experiment I, the rate of the natural killer (NK) activity was determined with cells from spleen and mesenteric lymph nodes. Intravesical OK432 instillation enhanced NK activity; however, this activity was not dose-dependent and was not augmented by OK432 inoculation into the foot pad. In experiment 2, the therapeutic effect of intravesical OK432 instillation was examined in rat bladder tumors induced by BBN. OK432 was instilled weekly for six weeks. Rats given BBN for 10 weeks were divided into six groups: 1) control; 2) saline; 3) OK432 0.05 KE/ml; 4) OK432 0.05 KE/ml bladder instillation with 0.01 KE/ml foot pad inoculation; 5) OK432 0.05 KE/ml, every other week; and 6) OK432 0.5 KE/ml. Weekly OK432 instillation significantly reduced tumor weight and the incidence of tumor development; however, this inhibition was not dose-dependent and was not enhanced by OK432 inoculation into the foot pad. In rats given OK432 weekly, the augmentation of NK activity and increase in tissue infiltrating lymphocytes were significant. These results suggest that intravesical OK432 instillation is effective in the management of superficial bladder tumors. The study further emphasizes that the dose and method of administration are critical variables in determining the efficacy of immunotherapy.

Administration, Intravesical↗
PubMed1994

Basement membrane and tumor invasion: ultrastructural observations in the basement membrane of rat bladder with invasive transitional cell carcinoma induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

This study describes ultrastructural alterations in the basement membrane (BM) of rat bladder with invasive transitional cell carcinoma (TCC) induced by N-butyl-N-(4-hydroxybutyl)nitrosamine. Various alterations including thickening, degradation and neosynthesis were found in the bladder BM of one rat with invasive TCC. Focal destruction of both the BM lamina zones was found in addition to partially degraded BMs showing focal degradation and loss of only the BM lamina rara. Neosynthesis of complete BM including the lamina rara and lamina densa was observed surrounding the nests of carcinoma cells deep in the stroma, while neosynthesis of incomplete BM including only a lamina densa-like structure was also found around carcinoma cells which had just crossed the BM into the adjacent stroma from the original tumor masses. There was an increased hemidesmosomal frequency in some areas of thickened BM, and focal loss of hemidesmosome in the areas of degraded BM. It is suggested that BM degradation may take place in two steps, and that BM neosynthesis may also be a two-step process in invasive TCC of rat bladder.

Animals↗
PubMed1990

Development of N-butyl-N-(hydroxybutyl)-nitrosamine-induced tumors in the partially resected, proliferating rat urinary bladder in dependence upon the time of onset of stimulated DNA synthesis.

Tumor development was investigated in the partially resected, proliferating urinary bladder of rats in dependence upon the onset of stimulated de novo DNA synthesis related to carcinogen dosing. N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) was used as carcinogen and administered by gavage in three fractionated doses (100 mg/kg body weight each) either during the phase of the most pronounced proliferation of the urothelium 30, 45 and 70 h after one-third resection of the bladder or 24 h and 1 week prior to partial cystectomy. When BBN was given during most increased DNA synthesis subsequent to one-third resection, the incidence of bladder tumors was reduced to 8.7% compared with 19.6% found in control animals with a non-resected, quiescent bladder. Tumor formation was neither inhibited nor enhanced when BBN was initially administered, followed by partial cystectomy 24 h or 1 week after the last carcinogen dose, yielding tumor incidences of 18.2% and 22.5%, respectively. Thus, the feeding of BBN during the period of maximum DNA synthesis inhibited tumor development in the partially resected bladder, while stimulation of cell replication subsequent to carcinogen administration did not influence the carcinogenic process initiated. The results obtained indicate that time of onset of stimulated DNA synthesis related to carcinogen dosing is the decisive factor in modifying urothelial carcinogenesis in the proliferating urinary bladder.

Animals↗
PubMed1990

Rat urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)-nitrosamine and N-methyl-N-nitrosourea.

The present investigation was conducted to examine the combination effect of N-butyl-N-(4-hydroxy-butyl)nitrosamine(BBN) and N-methyl-N-nitrosourea(MNU) in rat urinary bladder carcinogenesis. Experiment 1 was performed in the groups treated by oral BBN administration in combination with MNU intravesical instillation and their control groups. In the groups given both BBN and MNU, the ratio of rats with the nonpapillary type to carcinoma-bearing rats was significantly higher than in the controls. Since most of the carcinomas were non-invasive, the observation period was prolonged in the groups given both BBN and MNU in experiment 2. However, even after a longer observation period, no invasive carcinoma was observed. These results suggest that high-grade and invasive carcinomas similar to those induced by BBN and MNU in the heterotopically transplanted rat bladder cannot be induced in the natural bladder of the rat.

Animals↗
PubMed1996

Interstitial stroma and carcinogenesis: ultrastructural observations in the rat bladder treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

This study describes ultrastructural alterations of the interstitial stroma in the rat bladder epithelium during N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder carcinogenesis using scanning (SEM) and transmission (TEM) electron microscopy with NaOH treatment. The results obtained with SEM demonstrated the occurrence and development of stroma protrusions which exhibited pipe-like structures in the rat bladder epithelium following administration of BBN. Number and size of blood vessel sections also gradually increased both in the stroma and within the layer of the proliferated epithelial cells as examined by light microscopy (LM) and TEM. In this study stroma alterations were not only observed in malignant lesions of rat bladder, but hyperplastic lesions were also accompanied by stroma alterations. It is suggested that: (1) the interstitial stroma of the rat bladder epithelium may exhibit pathological changes in structure and these changes may correlate with the progression of epithelial cell proliferation following administration of BBN and (2) one of the most important alterations in the stroma is the occurrence of neovascularization, which may induce structural modification of the stroma in the processes of bladder tumor growth and development.

Animals↗
PubMed1996

Localization of zinc and metallothionein in the rat bladder epithelium during carcinogenesis induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

This study investigated the presence of zinc and expression of metallothionein (MT) in different pathological changes of the rat bladder induced by administration of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Using the Timm staining method, the presence of zinc was observed in normal and benign hyperplastic epithelial cells of the rat bladder, particularly in the malignant bladder tumor, induced by the administration of BBN. Immunohistochemically, MT expression was detected only in noninvasive (30%) and invasive transitional cell carcinoma (80%) of the rat bladder where the tumor cells were rich in zinc. Our data suggest that: (1) growth and development of the rat bladder tumor, especially malignant tumors, may have a high requirement for zinc and (2) MT synthesis may be induced by a high zinc concentration in rat bladder tumor cells.

Animals↗
PubMed1982

Fatal nitrosamine poisoning.

A case is reported in which progressive liver symptoms with rise in bilirubin concentration, hemorrhagic diathesis, and signs of portal hypertension developed three years before death in liver coma. The pathologic and neuropathologic findings are described. The case was clarified after dimethylnitrosamine was demonstrated in food intended for the patient and after it was established that small amounts of nitrosamine could have been repeatedly ingested by the patient over a period of years. Comparable cases of human dimethylnitrosamine poisonings published in the literature are presented. The relatively typical morphologic alterations in the liver are described. Problems involved in the histological interpretation of such liver changes as well as the forensic conclusions to be drawn are discussed.

Adult↗
PubMed1981

[Selective induction of tumors in Wistar rats with loop colostomy after administration of methyl-(acetoxymethyl)-nitrosamine (MAOMN) (author's transl)].

A single dose of 7 mg/kg methyl-(acetoxymethyl)-nitrosamine in Wistar rats with double loop colostomy induced adenomas, papillomas, and adenocarcinomas at the site of colostomy in 83% of the treated animals. The mean induction time was 320 days. The pronounced local effect as well as the high tumor yield are discussed in regard to the evident high epithelial sensitivity at the colostomy site.

Adenocarcinoma↗
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↗
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↗
PubMed1994

Mutation studies with dimethyl nitrosamine in young and old lac I transgenic mice.

Young adult (approximately 8 w) and old (approximately 72 w) lac I transgenic mice have been exposed to a single oral dose of dimethyl nitrosamine (NDMA). 2.5 h later unscheduled DNA synthesis was observed in the liver of the young animals (19.5 NG; control value -3.4 NG). The frequency of lac I- mutations in the liver of the young animals was elevated 7, 10 and 20 days after dosing. A similar fold-increase in mutant frequency was seen 7 days after dosing the old animals. It is concluded that mutability of the genome of old animals is not significantly different to that of young animals. Aspects of the minimum Big Blue assay protocol are discussed, as are the differing perceptions of the role of the assay in carcinogen hazard assessment.

Age Factors↗
PubMed1994

Modification of N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated urinary bladder carcinogenesis in rats by phytic acid and its salts.

The effects of dietary phytic acid and its salts on the promotion stage of two-stage urinary bladder carcinogenesis were examined. Male F344 rats were initiated by exposure to 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk, and then treated with basal diet containing a 2% supplement of phytic acid (PA), phytic acid dodecasodium salt (Na-PA), phytic acid dodecapotassium salt (K-PA), phytic acid hexamagnesium salt n-hydrate (Mg-PA) or no added chemical for 32 wk. Na-PA significantly increased the development of preneoplastic and neoplastic lesions of the urinary bladder. K-PA also brought about a tendency for increase in papillomas, whereas Mg-PA and PA were without effect. Both Na-PA and K-PA caused elevation of urinary pH, and Na+ or K+ concentration, respectively. These results confirm the promoting activity of the sodium salt of phytic acid for urinary bladder carcinogenesis and indicate modulation by urinary components, as demonstrated by increases in urinary pH, and Na+ concentration.

Animals↗
PubMed1987

Dose-dependent effects of butylated hydroxyanisole, butylated hydroxytoluene and ethoxyquin for promotion of bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated, unilaterally ureter-ligated rats.

Dose-dependent effects of 3 antioxidants, butylated hydroxyanisole (BHA, 2.0, 1.0 and 0.5%), butylated hydroxytoluene (BHT, 1, 0.5 and 0.25%) and ethoxyquin (0.5, 0.25 and 0.125%) on the development of preneoplastic lesions in the bladder of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-treated rats were investigated. Feeding of the antioxidants after pretreatment of 0.05% BBN commenced and unilateral ureteric ligation was combined at week 3 of the experiment. Surviving rats were killed at the end of week 24. BHA and BHT, but not ethoxyquin increased dose-dependently the incidence and number of preneoplastic lesions, papillary or nodular hyperplasia of the urinary bladder in rats treated with BBN. Particularly, the incidence and number of PN hyperplasia in rats treated with 2.0% BHA and 1.0% BHT were significantly higher than those of the control group. Thus, promoting activities of BHA and BHT, but not ethoxyquin for the urinary bladder were confirmed in this system of BBN-initiated, unilaterally ureter-ligated rats.

Animals↗
PubMed1988

Assessment of L-ascorbic acid requirement for prolonged survival in ODS rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Assessment of L-ascorbic acid requirement for prolonged survival in ODS (genotype: od/od) rats and their susceptibility to urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were examined. In ODS rats without L-ascorbic acid synthesizing ability, the 50 ppm dietary total ascorbic acid (TAA) was insufficient to survive for 4 weeks, the 250 ppm dietary TAA was sufficient to survive for 36 weeks. In examination of BBN treatment, ODS rats--although showing a lower availability of TAA than the heterozygotes (+/od) and normal (+/+) rats with L-ascorbic acid synthesizing ability--were equally susceptible to bladder carcinogenesis.

Animals↗