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PubMed1987

Lipid composition of the plasma membrane isolated from normal and precancerous rat bladder epithelium.

Four-week-old Wistar strain rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) solution for 12 weeks and used as a precancerous model. Sixteen-week-old rats of the same strain were used as controls. Plasma membranes (PMs) were prepared from normal and precancerous bladder epithelium. The lipid content and the fatty acid compositions of total lipids, phospholipids, and their subclasses were analysed. The following observations were made: 1) Precancerous PMs had longer chains composed of more unsaturated fatty acids than the normal ones. 2) There were high amounts of arachidonic acid in rat bladder epithelium, and it accounted for more than fifty percent of phosphatidylethanolamine. PMs of precancerous epithelium had more arachidonic acid than those of the normal epithelium. These findings may be useful for the early detection of precancerous epithelium.

Animals↗
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↗
PubMed1976

Stages of transformation in the development of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced transitional cell carcinomas in the urinary bladder of rats.

The histogenesis of papillary and nonpapillary transitional cell carcinomas were studied morphologically and autoradiographically in 177 female Wistar rats after oral application of N-butyl-N-(4-hydroxybutyl)-nitrosamine with varying exposure and induction times. By far the largest proportion of carcinomas developed by a malignant transformation of preexisting papillomas or their precursors, the papillary hyperplasias. The transition into a focally malignant growth did not take place abruptly, but occurred stepwise through different successive stages of transformation, each having its own distinct morphological character. The first stage consisted of a focal, sharpely defined cellular atypia. In a further stage carcinomata in situ developed out of the atypical foci and progressed finally in a last stage of transformation into a circumscript infiltrative growth. The successive development of each stage occurred independent of any further carcinogen application after transformation was initiated at the molecular level. The number of papillomas with transformation stages increased with a lengthening of the exposure and induction time. 74.4% of all the registered papillomas had been transformed. Consequently papillomas must be considered potentially highly malignant. The 3H-TdR index was 4.2 times higher in atypical urothelial areas (7.6%) and 7.5 times higher in carcinomata in situ (14.3%) than in the surrounding papillomatous structures which appeared light microscopically benign. The latter demonstrated a rather constant 3H-TdR index, whether they bordered on atypical foci (1.8%) or carcinomata in situ (1.9%). The length of exposure and induction time exercised no significant influence on the degree of proliferative activity. The development of transitional cell carcinomas from a primary carcinoma in situ (intraurothelial carcinoma) played a much less significant role.

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↗
PubMed1990

Effects of alpha-difluromethylornithine on the development of deeply invasive urinary bladder carcinomas in mice.

alpha-Difluoromethylornithine (DFMO), was examined for its ability to suppress the development of invasive urinary bladder carcinoma in C3H/He male mice. Continuous administration of 0.2% DFMO in water following carcinogen treatment (0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine, BHBN, in drinking water for 8 weeks) was effective in suppressing urinary bladder carcinomas (P less than 0.05) as compared with the control group. However, when comparison was made based on tumors involving the entire urinary tract, protective effects could not be demonstrated. Coadministration of DFMO (0.2%) and BHBN (0.01%) did not alter tumor induction by the latter. These results were in sharp contrast to the protective effects in rats. Since bladder tumors in rats are of low grade and superficial whereas those in mice are of high grade and deeply invasive, our data indicate that DFMO has little to no effects against the development of aggressive forms of bladder carcinoma.

Animals↗
PubMed1996

Enhanced gene expression of transforming growth factor-alpha and c-met in rat urinary bladder cancer.

To investigate the roles of growth factors in bladder cancer, changes in the expression of messenger RNAs (mRNAs) for several growth factors and their receptors were examined during rat bladder carcinogenesis induced with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Northern blot analysis showed that the contents of mRNAs for transforming growth factor-alpha (TGF-alpha) and c-met/hepatocyte growth factor (HGF) receptor increased with BBN treatment. Epidermal growth factor (EGF) receptor mRNA was hardly affected by the treatment; while mRNA for fibroblast growth factor (FGF) receptor 1 and transforming growth factor-beta (TGF-beta) type II receptor decreased with BBN treatment. A rat bladder tumor cell line, NBT-II, expressed both TGF-alpha and c-met mRNAs, and HGF showed apparent scattering and growth-stimulating effects on the cells. These results indicate the possibility that TGF-alpha produced by a bladder cancer, in addition to urinary EGF, plays a role in the development of bladder cancer, and that enhanced cell motility due to activation of the c-met/HGF receptor participates in the invasion and metastasis of the cancer cells.

Animals↗
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↗
PubMed1977

Morphology, classification and histogenesis of N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced carcinomas in the urinary bladder of rats.

The aim of the experiments was to determine whether the various types of carcinomas found in the human urinary bladder were reproducible in animals. We added n-butyl-n-(4-hydroxybutyl)-nitrosamine at a dose of 20 mg/kg/day to the drinking water of 177 female Wistar rats for a period of 40 to 150 days. After a total experimental time of between 150 and 250 days the animals were sacrified. The spectrum of carcinomas induced, includes all the types known to occur in man. The various tumor types occurred with the same frequency as in man and exhibited the same growth patterns. Variously differentiated papillary and non-papillary transitional cell carcinomas comprised 88.8% of tumors registered. 5.1% were keratinized and nonkeratinized squamous cell carcinomas, 2.2% adenocarcinomas. 1.1% were undifferentiated carcinomas and 2.8% were carcinomas of the mixed type with squamous cell and transitional cell differentiation. Histogenetically adenocarcinomas were found to originate from glandular metaplasia and squamous cell carcinomas from squamous metaplasia within completely developed transitional cell carcinomas. Furthermore it was possible to induce proliferative lesions such as von Brunn's nests, cystitis cystica and cystitis glandularis. However, we found no clues to substantiate the development of adenocarcinomas from these proliferative lesions, or for that matter squamous cell carcinomas from squamous metaplasia of the otherwise unchanged urothelium. The present experimental model seems particulary suited for the search of further information regarding the development of tumors in the human bladder.

Adenocarcinoma↗
PubMed1984

Dose-response study of urinary bladder carcinogenesis in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine.

A dose-response study was carried out in male F344 rats with a specific urinary bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), which was administered as a solution in drinking water for up to 112 weeks. BBN was given in four different concentrations, 50, 10, 5, and 1 ppm, to groups of 30 rats. The highest dose induced urinary bladder cancer in all rats treated by week 91, decreasing yields being associated with lower dose levels: an incidence of 76.7% was observed with 10 ppm, followed by 20.0% with 5 ppm. The lowest dose (1 ppm) only induced two cases of papilloma (6.9%).

Animals↗
PubMed1983

Inhibitory effect of partial cystectomy on experimental carcinogenesis in the urinary bladder.

It was our aim in the present animal experiments to study the influence of stimulation of proliferative activity on carcinogenesis in the urinary bladder. Stimulation of urothelial proliferation was achieved by a one-third resection of the bladder. N-butyl-N-(4-hydroxybutyl)- nitrosamine (BBN), which was used as a carcinogen, was administered by gavage in three fractionated doses when proliferative activity was highest at 30, 45, and 70 h postoperatively. Contrary to our working hypothesis, the incidence of urinary bladder tumors proved to be significantly reduced by partial cystectomy. After administration of a low total dose of BBN (300 mg/kg bodyweight) and an experimental period of 6, 12, and 18 months, only 2.6% of the rats with a partial cystectomy, but 12.6% of the control animals with an intact bladder had developed papillomas and noninvasive papillary transitional cell carcinomas. Following administration of BBN at a higher total dose (1,300 mg/kg bodyweight), bladder tumors occurred after an induction period of 4, 6, and 12 months in 27.4% of the partially cystectomized and 48.1% of the nonoperated rats. Multiple tumors were found more frequently in the controls than in the operated animals. The reduction in the tumor incidence following one-third resection of the bladder evidently does not depend on a prolongation of the latency period or induction time. From findings in analogous experimental models it is conceivable that the observed inhibition of experimental bladder carcinogenesis is brought about by an increased capacity of the proliferating urothelial cells to repair carcinogen-induced DNA damage. Further studies are required to elucidate the significance of a stimulated proliferation for the repair system and neoplastic transformation of the urothelium.

Animals↗
PubMed1986

Strain differences in mice with invasive bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Papillary superficial and nonpapillary invasive bladder carcinomas of humans are two disease entities exhibiting completely different biological behavior. Studies were performed on the susceptibilities of various strains of mice to induction of bladder carcinomas by N-butyl-N-(4-hydroxybutyl)nitrosamine (BHBN), and the type of carcinomas that developed. BHBN at concentrations of 0.05% and 0.01% in drinking water was given to female mice of strains A/Jax, AKR/Jax, C3H/He, DBA/2, and C57BL/6 for 22 weeks. The incidence of nonpapillary invasive bladder carcinomas in these strains was 40%, 100%, 100%, 89%, and 89%, respectively, in groups treated with 0.05% BHBN and 30%, 60%, 60%, 90%, and 40%, respectively, in groups treated with 0.01% BHBN. At both levels BHBN and in all strains the bladder carcinomas induced were of the nonpapillary invasive type.

Animals↗
PubMed1986

Promoting effect of sodium chloride in 2-stage urinary bladder carcinogenesis in rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The promoting effect of sodium chloride (NaCl) in 2-stage urinary bladder carcinogenesis in F344 rats initiated by 2 doses of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was investigated. The incidences of PN hyperplasia were significantly higher in rats initiated with 0.01 or 0.05% BBN when they were given diet containing 10% NaCl for 32 weeks than when they were given control diet. The incidence of papilloma in rats given 0.05% BBN followed by diet containing 10% or 5% NaCl tended to be higher than that in control rats. The urine of rats given diet containing NaCl was larger in volume and had lower osmolality than that of controls. The total urinary sodium and chloride contents were also increased, whereas those of potassium and phosphorus were decreased. No calculus formation or crystalluria was observed. These data suggest that excess intake of sodium as NaCl has a weak promoting effect in 2-stage urinary bladder carcinogenesis.

Animals↗
PubMed1994

Elevated concentrations of the beta-subunit of S100 protein in renal cell tumors in rats.

Concentrations of alpha and beta-subunits of S100 protein (S100-alpha and S100-beta) in rat kidney neoplasms, including renal cell and mesenchymal tumors, were determined using a highly sensitive enzyme immunoassay, and both types immunohistochemically localized in tissue sections. Concentrations of S100-alpha in each histological type of rat tumor were lower than in normal kidney, whereas levels of S100-beta (mean +/- SE: 29.7 +/- 14.2 ng/mg protein, n = 15) in renal cell tumors were significantly higher than in normal kidneys (0.55 +/- 0.06 ng/mg protein, n = 7), or mesenchymal tumors (1.21 +/- 0.43 ng/mg protein, n = 9). In normal rat kidney tissues S100-alpha was immunohistochemically positive in epithelial cells of the distal tubules, the thin limbs of loops of Henle, and the collecting ducts. No appreciable immunostaining for S100-beta was found in any nephron segment. Both S100-alpha and S100-beta were positive for renal cell tumors, indicating new appearance of the latter during renal carcinogenesis in rats.

Animals↗