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PubMed1999

Increased expression of cyclooxygenase-2 protein in rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

The anti-inflammatory drugs, aspirin and piroxicam, are known to possess chemopreventive potential against rat superficial urinary bladder carcinogenesis induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Recently, we found similar inhibitory effects with a selective cyclooxygenase (COX)-2 inhibitor, nimesulide. In order to clarify the inhibitory mechanisms, we have further studied the expression of COX-2 protein in urinary bladder tumors induced by BBN in Fischer 344 male rats. For comparison, papillomatosis caused by uracil-induced urolithiasis, and normal epithelial cells, were also investigated. Western blot analysis revealed COX-2 protein to be barely expressed in the normal epithelial cells, whereas it was increased 13-22-fold in varying sizes of urinary bladder tumors and 7-fold in papillomatosis. Immunohistochemically, COX-2 protein was diffusely expressed in transitional cell carcinomas and nodulo-papillary hyperplasia but weakly expressed only in basal cells in simple hyperplasia and normal-looking surrounding epithelia. In papillomatosis, it was moderately expressed only in endothelial cells in stroma. These results indicate that COX-2 plays important roles in the development of preneoplastic and neoplastic lesions in the rat urinary bladder, and therefore could be a good target for chemoprevention of superficial lesions.

Animals↗
PubMed1999

LOH and mutational analysis of p53 alleles in mouse urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl) nitrosamine.

In human urinary bladder carcinogenesis, alterations in the p53 tumor suppressor gene are common events. We have previously reported that they are also frequent in invasive urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in NON/Shi mice. To further investigate the significance of the p53 gene status for mouse urinary bladder carcinogenesis, we examined both allele loss and mutational alterations in urinary bladder cancers of (NON/Shi x C3H/He/Shi) F1 hybrid mice exposed to the carcinogen for 12 weeks and then maintained for a further 9 weeks without treatment. An intragenic silent polymorphism within exon 7 of the p53 gene between NON/Shi and C3H/He/Shi mice allows assessment of allele loss of the p53 gene and determination of the parental origin of mutated and/or lost alleles. A tissue microdissection method was employed to obtain carcinoma samples without excessive contamination with normal tissue. Allele losses were detected in one of 14 tumors (7.1%) and nine mutations in eight of 14 (57%) tumors were found in exons 5-8 by polymerase chain reaction-single strand conformation polymorphism followed by DNA direct sequencing analysis. All mutations involved one base substitution with an amino acid change, although the types of base substitution were random. In conclusion, the high incidence of p53 alterations suggests a significant role in the genesis of invasive urinary bladder tumors in BBN-treated mice.

Alleles↗
PubMed1999

Metallothionein modulates the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine in mice.

We examined the carcinogenicity of N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in transgenic mice deficient in the metallothionein (MT) I and II genes and in control (129/Sv) mice. Both strains of mice were given BBN for 8 weeks with or without Zn treatment. All mice were killed at 12 weeks after the cessation of BBN administration. BBN induced bladder tumors in 75% of MT null mice and in 43% of 129/Sv mice. The average number of bladder tumors per mouse was significantly higher in MT null mice (1. 18 +/- 0.27) than in 129/Sv mice (0.43 +/- 0.20). Zn treatment suppressed the carcinogenicity of BBN in 129/Sv mice but not in MT null mice. Histopathological examination of the tumors revealed that the malignant potential of bladder tumors in 129/Sv mice was greater than that in MT null mice. These results indicate that MT is an important modulator of carcinogenicity of BBN in the bladder of mice.

Animals↗
PubMed2000

Inhibitory effects of 1,3-diaminopropane, an ornithine decarboxylase inhibitor, on rat two-stage urinary bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Overexpression of ornithine decarboxylase (ODC) has been shown to be characteristic of tumor development and progression in humans and experimental animals. Therefore, we have examined the effects of 1, 3-diaminopropane dihydrochloride (DAP), a potent inhibitor of ODC, on rat two-stage urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). In experiment 1 (36 weeks), 6-week-old F344 male rats were administered 0.05% BBN in drinking water for 4 weeks and then divided into four groups. Animals of groups 1 and 2 received basal diet and drinking water supplemented with or without DAP (2 g/l). Groups 3 and 4 were given diet containing 5% sodium L-ascorbate (NaAsA), a typical urinary bladder tumor promoter, and drinking water with or without DAP. Administration of DAP to group 1 significantly reduced tumor size, multiplicity and incidence, particularly of papillomas, when compared with group 2 values. DAP together with NaAsA (group 3) also decreased tumor size relative to the group 4 case. To determine the effects of DAP on the early stages of bladder carcinogenesis and its mechanisms, a similar protocol was conducted (experiment 2) with death after 20 weeks. DAP treatment caused complete inhibition (0% incidence) of papillary and/or nodular hyperplasia in group 1 but was without influence in group 3, as compared with the respective controls. Moreover, the ODC activity, bromodeoxyuridine labeling indices and mRNA expression levels of cyclin D1 in the urinary bladder mucosa, determined by northern blotting, were markedly lower in group 1 than in group 2, but values were comparable for both groups administered NaAsA. Assessment of mRNA expression levels of the angiogenic vascular endothelial growth factor suggested no involvement in the inhibitory effects of DAP on urinary bladder carcinogenesis. The results indicate that inhibition of ODC could reduce urinary bladder carcinogenesis in rats, particularly in the early stages, through antiproliferative mechanisms.

Acetyltransferases↗
PubMed2000

Significant overexpression of metallothionein and cyclin D1 and apoptosis in the early process of rat urinary bladder carcinogenesis induced by treatment with N-butyl-N-(4-hydroxybutyl)nitrosamine or sodium L-ascorbate.

Effects of a genotoxic bladder carcinogen, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and a non-genotoxic bladder promoter, sodium L-ascorbate (Na-AsA), on protein expression, cell proliferation and apoptosis of the bladder epithelium with or without the influence of testicular castration were investigated. Male F344 rats were divided into six groups (groups 1-6). BBN was given with 0.05% drinking water to groups 1 and 4 for 8 weeks, groups 2 and 5 received diet with 5% Na-AsA. Then the animals were treated without any chemicals. Groups 3 and 6 were non-treated controls. Testicular castration was carried out 2 weeks before commencement of chemical treatment on groups 4-6. The total observation period was 18 weeks. Overexpression of cyclin D1 was induced by BBN but not Na-AsA and the degree of overexpression was higher in the order simple hyperplasia, papillary or nodular hyperplasia, papilloma and carcinoma. Metallothionein (MT) was also overexpressed in bladder epithelium treated with BBN but not Na-AsA, but was decreased in papillomas and never found in a carcinoma. Cyclin D1-positive cells were essentially MT-negative. Therefore, it is speculated that MT protects genes from insult by genotoxic carcinogens and its lack is associated with tumor development. Apoptotic cell death occurred during treatment with BBN and Na-AsA and after their withdrawal. Chromatin condensation of many G0/G(1) cells was particularly marked on flow cytometry analysis 1 week after cessation of treatment, this being considered as an early apoptotic change. Although testicular castration had no influence on the above events, it resulted in decreased tumor formation as compared with the case of similarly treated intact animals. Our data demonstrate that overexpression of MT and cyclin D1 is specific for treatment with a genotoxic carcinogen, and suggest that MT overexpression may play an important suppressive role in the early stages of rat urinary bladder carcinogenesis.

Animals↗
PubMed2004

4-Hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers in mice: characterization of FHIT and survivin expression and chemopreventive effects of indomethacin.

The administration of 4-hydroxybutyl(butyl)nitrosamine (OH-BBN) to male B6D2F1 mice yielded a high incidence of large palpable urinary bladder cancers. Since prior studies demonstrated chemopreventive effects of non-steroidal anti-inflammatory drugs (NSAIDs), we further explored the efficacy of the NSAID indomethacin using different treatment regimens. OH-BBN was administered twice per week for 12 weeks (the first week of treatment was designated week 1). In Experiment I continual indomethacin treatment (20 mg/kg diet) was initiated either prior to (week -1) or following (week 13) OH-BBN dosing. Palpable bladder masses (subsequently diagnosed as cancers) developed in 32% of carcinogen-treated only mice by 32 weeks, while mice administered indomethacin either prior to or after OH-BBN developed palpable masses in 3 and 6% of the animals, respectively. In Experiment II mice were treated with indomethacin beginning 1 week after OH-BBN for either 12 weeks (limited treatment, weeks 13-24) or for 30 weeks (weeks 13-42). Continual treatment resulted in a 77% decrease in palpable bladder masses and an 82% decrease in all cancers (palpable and microscopic), while limited treatment decreased palpable masses by 48% but failed to decrease the number of bladder cancers (palpable plus microscopic). In Experiment III OH-BBN-treated mice were followed for 61 weeks. Palpable masses developed in 66% of control mice, while 26% of mice treated with indomethacin continually from 1 week after OH-BBN (weeks 13-61) developed palpable masses. A separate group in this study treated with indomethacin beginning when 5% of the mice had palpable bladder masses continued to develop new masses for an additional 4 weeks. By 6 weeks after beginning indomethacin treatment, however, these animals showed a profound decrease in the development of additional cancers. The expressions of FHIT and survivin in normal urinary bladder epithelium and in bladder cancers were determined by immunohistochemical analysis. FHIT was expressed at high levels in normal epithelium, but was minimally expressed in cancers, and even showed decreased expression in papillomas. The anti-apoptotic protein survivin was not expressed in normal bladder epithelium, but was variably expressed in cancers. FHIT and survivin expressions were similar in cancers from indomethacin-treated and non-treated mice.

Acid Anhydride Hydrolases↗
PubMed1990

Promoting effect of the peroxisome proliferator, clofibrate, but not di(2-ethylhexyl)phthalate, on urinary bladder carcinogenesis in F344 rats initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

The modifying potential of clofibrate and di(2-ethylhexyl)phthalate (DEHP) on second stage, N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-initiated urinary bladder carcinogenesis was investigated in male F344 rats, using a uracil-accelerated transitional cell proliferation model. Six-week-old animals received 0.05% BBN in their drinking water for 4 weeks and then clofibrate (1.0, 0.5, and 0.25%) and DEHP (1.2, 0.6, and 0.3%) were given during experimental weeks 5-8 and weeks 12-20. Uracil was administered during weeks 9-11 at a dietary level of 3.0%. Control rats were treated with BBN and uracil without peroxisome proliferator. Surviving animals were killed at the end of week 20 of the experiment, when the densities of putative preneoplastic, papillary or nodular (PN) hyperplasias (numbers per 10 cm of basement membrane) were significantly increased in all clofibrate-treated, but not the DEHP groups. The incidences of PN hyperplasia were similar in both treated animals and controls. In a second experiment, rats fed diets containing 1.0% clofibrate or 1.2% DEHP were assessed for levels of DNA synthesis in urinary bladder epithelium by 5-bromo-2-deoxyuridine immunohistochemistry. Numbers of labeled nuclei remained within normal levels, and no proliferative changes were evident. Thus, the present experiments indicated that while clofibrate, but not DEHP, exerts weak enhancing effects on BBN-initiated urinary bladder carcinogenesis in rats this is not associated with increased levels of DNA synthesis in the affected epithelium.

Animals↗
PubMed1991

Summation effects of uracil and other promoters on epithelial lesion development in the F344 rat urinary bladder initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine.

Five non-genotoxic chemicals previously demonstrated to be bladder cancer promoters in 36-week in vivo assays for carcinogenesis were reevaluated in a 20-week experiment in order to assess the summation influence of dietary uracil, a component of RNA, on the development of (pre)neoplastic lesions. The test chemicals, sodium bicarbonate, sodium L-ascorbate, sodium citrate, butylated hydroxytoluene and ethoxyquin, were mixed into the diet at concentrations of 3%, 5%, 5%, 1% and 0.8%, respectively, and administered to male F344 rats after initiation with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks. The test chemicals were given from the 4th to the 8th and the 11th to 20th experimental weeks, uracil being administered at the level of 3% in the diet during the intervening period. Rats in the control group received only BBN and uracil. All animals were killed at week 20 and the bladders were evaluated for the occurrence of putative preneoplastic papillary or nodular (PN) hyperplasia and tumors. Significant increase in the occurrence of PN hyperplasia was observed in all groups initiated with BBN and fed uracil and test chemicals. Quantitative values for papillomas were also significantly increased except in the ethoxyquin-treated group. The results confirm that uracil given in the middle of the post-initiation stage enhances the promoting activity of chemicals and suggest that the use of this chemical might be useful to reduce the duration of current bioassays for bladder chemical carcinogens.

Animals↗
PubMed1991

Renal pelvic carcinoma which shows metastatic potential to distant organs, induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in NON/Shi mice.

Renal pelvic carcinoma was induced in mice by giving N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Initially, differences in renal pelvic carcinogenesis by BBN were examined in three male mouse strains: NON/Shi, which demonstrate spontaneous hydronephrosis with incidences of 10-30%, and DS/Shi and B6C3F1, which do not exhibit hydronephrosis. When mice of these strains were given 0.05% BBN in the drinking water for 12 weeks followed by water without BBN for 8 weeks, renal pelvic carcinoma morphologically similar to human carcinomas developed in 8 of 23 NON/Shi mice (35%). Metastasis to the lung was found in one of them (13%). B6C3F1 and DS/Shi mice had no pelvic tumors, but the response to urinary bladder carcinogenesis in NON/Shi mice was nearly equal to that in DS/Shi and B6C3F1 mice. These results suggest that renal pelvic carcinogenesis is related to the presence of stagnant urine containing carcinogen in the renal pelvis. In a second experiment, we examined renal pelvic carcinogenesis in NON/Shi mice given BBN for 4 weeks followed by water without BBN for 32 weeks. The incidence of renal pelvic carcinoma (28%) was similar to that in the first experiment, but the incidence of metastasis was markedly elevated to 60%. These results indicate that BBN treatment can induce renal pelvic carcinoma which often metastasizes to the lung in NON/Shi mice.

Abdominal Neoplasms↗
PubMed1991

Time- and dose-dependent induction of invasive urinary bladder cancers by N-ethyl-N-(4-hydroxybutyl)nitrosamine in B6C3F1 mice.

A sequential investigation of N-ethyl-N-(4-hydroxybutyl)nitrosamine (EHBN) bladder carcinogenesis was performed in male B6C3F1 mice maintained ad libitum on tap water containing 0.025% EHBN for 4, 12, 20, 28 and 36 weeks. A total of 81 invasive tumors, comprising 55 squamous cell carcinomas (SCCs) (68%), 25 transitional cell carcinomas (TCCs) (31%) and 1 adenocarcinoma (1%) were found. Of these, 23 (22 SCCs and 1 TCC) demonstrated invasion to the prostate, 3 metastasized to the lung, and 2 spread by peritoneal seeding. The anaplastic grade and extent of invasion of the SCCs significantly exceeded those of the TCCs. The results suggested a histogenetic pathway from simple dysplasia through papillary or nodular dysplasia and/or carcinoma in situ to eventual development of invasive carcinomas.

Animals↗
PubMed1992

Anti-promoting effect of nordihydroguaiaretic acid on N-butyl-N-(4-hydroxybutyl)nitrosamine and sodium saccharin-induced rat urinary bladder carcinogenesis.

The effects of oral administration of nordihydroguaiaretic acid (NDGA), an antioxidant and inhibitor of arachidonic acid metabolism, on rat bladder carcinogenesis were examined. Six-week-old male Fischer 344 rats were given drinking water containing 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine for 4 weeks. Following this 4-week period, diet containing 5% sodium saccharin (SS) with or without 0.1% NDGA supplement was given to the rats for 36 weeks. The incidences of papillary or nodular (PN) hyperplasia and of papilloma in the group treated with SS plus NDGA were significantly lower than those in the group treated with SS alone. The number of PN hyperplasic foci per 10 cm of basement membrane in rats treated with SS plus NDGA was also lower than that in the group treated with SS alone. These results suggest that NDGA has an anti-tumor-promoting effect on rat bladder carcinogenesis.

Animals↗
PubMed1992

Synergism of environmental carcinogens and promoters on bladder cancer development initiated by N-butyl-N-(4-hydroxybutyl)nitrosamine in F344 rats.

Synergistic or additive effects of combined treatments with carcinogens or promoters on N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-initiated rat bladder carcinogenesis were examined. Male F344 rats were given BBN as an initiator followed by low doses of 3 sodium salts (sodium bicarbonate, sodium L-ascorbate and sodium citrate) and/or 3 antioxidants (butylated hydroxyanisole, butylated hydroxytoluene and tertiary butylhydroxyquinone). Combined treatments with 3 sodium salts or 3 antioxidants, and especially all 6 chemicals together promoted bladder carcinogenesis. In addition, these combined treatments were associated with increased DNA synthesis of the bladder epithelium. Combined administration of the carcinogens, o-anisidine, p-cresidine, and 4-chloro-o-phenylenediamine at low doses also enhanced BBN-initiated bladder carcinogenesis. These results indicate that environmental carcinogens or promoters can exert synergistic or additive actions on bladder cancer induction.

Animals↗
PubMed1997

Chemopreventive efficacy of piroxicam administered alone or in combination with lycopene and beta-carotene on the development of rat urinary bladder carcinoma after N-butyl-N-(4-hydroxybutyl)nitrosamine treatment.

The effects of the non-steroidal anti-inflammatory drug (NSAID) piroxicam and the carotenoids lycopene and beta-carotene, alone or in combination, on the development of rat superficial urinary bladder carcinomas induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) were studied. Male Fischer 344 rats, 6 weeks old, were given 0.05% BBN in the drinking water for 8 weeks followed by administration of piroxicam (0.0075% in the diet), lycopene (0.0025% in the drinking water) and/or beta-carotene (0.0025% in the drinking water) for 12 weeks, then killed for histological analysis of urinary bladder lesions. Cell proliferation potential was analyzed by immunohistochemical staining of the proliferative cell nuclear antigen (PCNA). Piroxicam alone, piroxicam+lycopene, and piroxicam +lycopene+ beta-carotene all significantly decreased the incidences and numbers of transitional cell carcinomas (TCCs), but the combination of piroxicam with carotenoids did not result in a clear improvement in the preventive potential of piroxicam. Piroxicam+ beta-carotene also caused a significant reduction and lycopene alone a slight but not significant reduction in the number of TCCs. In contrast, beta-carotene alone and lycopene+ beta-carotene were without inhibitory influence on any of the lesion categories examined, and the latter significantly increased the proportion of high-grade TCCs. Nevertheless, all of the chemopreventive agents, either alone or in combination, significantly decreased the TCC PCNA index, the effect extending to the surrounding epithelium in the piroxicam+lycopene and piroxicam+lycopene+beta-carotene groups. These results indicate that the NSAID piroxicam may be a more effective chemopreventive agent than lycopene and beta-carotene for superficial urinary bladder carcinogenesis.

Animals↗
PubMed1998

Inhibitory effect of tomato juice on rat urinary bladder carcinogenesis after N-butyl-N-(4-hydroxybutyl)nitrosamine initiation.

The effects of tomato juice on urinary bladder carcinogenesis were studied in male Fischer 344 rats initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in rats. The animals (6 weeks old) were given 0.05% BBN in their drinking water for 8 weeks, followed by diluted tomato juice for 12 weeks, and killed at 20 weeks after the beginning of the experiment. Lycopene concentrations in the livers of rats given tomato juice were elevated. Histopathological analysis of urinary bladder lesions revealed the numbers, but not incidences, of urinary bladder transitional cell carcinomas (TCCs) to be decreased in the group given tomato juice. No influence on the incidence of simple and nodullopapillary hyperplasias, invasion or differentiation of TCC was noted. These results indicate that tomato juice, presumably the contained lycopene and other anti-oxidants in combination, exerts an inhibitory effect on the development of TCCs in the rat urinary bladder.

Animals↗
PubMed1999

Loss of heterozygosity in (LewisxF344)F1 rat urinary bladder tumors induced with N-butyl-N-(4-hydroxybutyl)nitrosamine followed by dimethylarsinic acid or sodium L-ascorbate.

Dimethylarsinic acid (DMA), a main metabolite of arsenicals which are carcinogenic in man, exerts tumor-promoting activity on rat urinary bladder carcinogenesis initiated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN). Sodium L-ascorbate (Na-AsA) is also a strong tumor promoter in this animal model. In this study, we used (LewisxF344)F, rats to compare molecular alterations in urinary bladder tumors caused by BBN followed by DMA or Na-AsA. Male, 6-week-old rats were given 0.05% BBN in their drinking water for 4 weeks, and then the rats in group 1 were maintained with no further treatment for 40 weeks. The animals of groups 2 and 3 were administered 0.01% DMA in their drinking water (group 2) or 5% Na-AsA in the powder diet (group 3) after the BBN treatment. Group 4 rats were given 0.05% BBN continuously for 36 weeks. At weeks 12, 20, 36 and 44, subgroups of rats were killed. Histopathological examination revealed promoting activity for DMA and, to a greater extent, Na-AsA on urinary bladder carcinogenesis. Loss of heterozygosity (LOH), detected with the polymerase chain reaction using 36 microsatellite markers, was found to be present in 2 of 9 (22%) urinary bladder tumors after treatment with DMA and 3 of 22 (14%) induced by continuous administration with BBN. No LOH was, however, detected in urinary bladder tumors after treatment with Na-AsA. The results thus suggest that the mechanisms of action of these two promoters, DMA and Na-AsA, may differ in rat urinary bladder carcinogenesis.

Animals↗
PubMed2000

Chemopreventive effects of bovine lactoferrin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat bladder carcinogenesis.

Chemopreventive effects of bovine lactoferrin (bLF), which is found at high concentrations in colostrum, on rat bladder carcinogenesis were investigated using a rat bladder medium-term bioassay. In experiment 1, a total of 80 F344 male rats, 6 weeks old, were divided into 5 groups. Groups 1 and 2 were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 8 weeks and after a 1-week interval, received dietary supplementation with 2% and 0.2% bLF, respectively. Group 3 received 0.05% BBN for 8 weeks and then no treatment. Group 4 was administered 2% bLF alone from week 9, without prior carcinogen exposure. Group 5 was maintained without any treatment throughout the experiment. All rats were killed at the end of week 36. Group 1 demonstrated a significantly decreased multiplicity of the bladder tumors (carcinomas and papillomas) as compared with group 3. Maximum cut surface areas of bladder tumors were also significantly decreased in groups 1 and 2 compared with group 3. No bladder tumors were observed in groups 4 or 5. In experiment 2, a total of 60 rats were divided into two groups (30 rats each); both were treated with 0.05% BBN for 4 weeks and after a 1-week interval, one received 2% bLF (group 1) and the other, basal diet (group 2) for 4 weeks. Group 1 demonstrated a tendency for decrease of the 5-bromo-2'-deoxyuridine (BrdU) labeling index. bLF was detected in the urine of rats fed bLF by ELISA as well as western blot analysis. The findings indicate that 2% bLF can inhibit BBN-induced rat bladder carcinogenesis, and that this may be due to bLF in the urine.

Acetyltransferases↗
PubMed2001

p53 and H-ras mutations and microsatellite instability in renal pelvic carcinomas of NON / Shi mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine: different genetic alteration from urinary bladder carcinoma.

We previously reported p53 mutations to be frequent (greater than 70%), whereas both H-ras mutations and microsatellite instability (MSI) were infrequent (about 10%), in urinary bladder carcinomas (UBCs) and their metastatic foci in the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced mouse urothelial carcinogenesis model. In the present study, an analysis of p53 and H-ras mutations as well as MSI was performed on 12 renal pelvic carcinomas (RPCs) and 8 metastatic or invading foci produced by the same experimental procedure. Histologically, 10 of the RPCs were transitional cell carcinomas and the remaining 2 were squamous cell carcinomas. p53 mutations were infrequent and only found in one primary RPC (8%), its metastatic foci and an invading lesion in another animal (in a total 2 of 12; 17%). H-ras mutations were slightly more frequent (found in 3 of 12 animals; 25%), 4 of 5 involving codon 44, GTG to GCG, not a hot-spot reported for human cancers. In two cases, H-ras mutations were confined to lung metastasis and not detectable in their primary RPCs. MSI analysis was available for 6 pairs of primary RPCs and their metastatic foci, and 4 animals (67%) had MSI at one or more microsatellite loci. Overall, the distribution of genetic alterations differed from that in UBCs produced by the same experimental protocol. The results thus suggest that different genetic pathways may participate in carcinogenesis of the upper and lower urinary tract due to BBN.

Animals↗
PubMed2002

Chemopreventive effects of a flavonoid antioxidant silymarin on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced urinary bladder carcinogenesis in male ICR mice.

The modifying effects of dietary administration of a flavonoid antioxidant, silymarin, a mixture of three flavonoids isolated from milk thistle seeds, on N-butyl-N-(4-hydroxybutyl)nitrosamine (OH-BBN)-induced urinary bladder carcinogenesis were examined in male ICR mice. Animals were divided into 5 groups, and groups 1 to 3 were given OH-BBN (500 ppm) in drinking water for 6 weeks. Mice in group 2 were fed a diet containing 1000 ppm silymarin for 8 weeks during the initiation phase starting 1 week before OH-BBN exposure, and mice in group 3 were fed the diet for 24 weeks during the postinitiation phase. Animals in group 4 were given only the test compound, and those in group 5 were given the basal diet alone throughout the experiment. Animals were sacrificed at the end of week 32. The frequency of bladder lesions, cell proliferation and cell cycle progression activity estimated in terms of the 5-bromodeoxyuridine (BrdU) labeling index or cyclin D1-positive cell ratio were compared among the groups. Administration of silymarin in the initiation or postinitiation phase significantly decreased the incidences of bladder neoplasms and preneoplastic lesions. Dietary exposure to this agent significantly reduced the labeling index for BrdU and the cyclin D1-positive cell ratio in various bladder lesions. These findings suggest that silymarin is effective in preventing OH-BBN-induced bladder carcinogenesis in mice.

Administration, Oral↗