Bladder Carcinogenesis

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Shoji Fukushima - One of the best experts on this subject based on the ideXlab platform.

  • Vascular endothelial growth factor mRNA levels as a biomarker for short‐term N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine‐induced rat Bladder Carcinogenesis bioassay
    Journal of Applied Toxicology, 2014
    Co-Authors: Shin Wakui, Hideki Wanibuchi, Tomoko Mutou, Hiroyuki Takahashi, Masahiro Ikegami, Shoji Fukushima
    Abstract:

    Generically, carcinogenic effects of chemicals in Bladder Carcinogenesis are judged by induction of papillary or nodular (PN) hyperplasia in rats given N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 4 weeks and the test chemical for 22–28 weeks. However, upregulation of vascular endothelial growth factor (VEGF) begins early in rat BBN Bladder Carcinogenesis. To establish a short-term rat Bladder carcinogenic bioassay, we analyzed the correlations between VEGF, VEGF mRNA and Bladder lesions inductions at 10 and 26 weeks after BBN treatment. Six-week-old male Wistar (slc) rats were given 0.05% BBN for 4, 10 or 26 weeks. To avoid individual rat bias, the Bladders were investigated by partial cystectomy at 10 weeks and total cystectomy at 26 weeks. After induction, PN hyperplasia and carcinoma in rats increased with the length of BBN treatment and immunohistochemical VEGF expression also increased following Carcinogenesis, but the immunoreactivity of individual lesions was quite variable. Moreover, induction of PN hyperplasia at 10 weeks’ BBN treatment was not significantly correlated with that at 26 weeks' treatment; thus, it was not possible to predict the carcinogenic effect due to the induction of PN hyperplasia at 26 weeks' BBN treatment by that at 10 weeks' treatment. However, VEGF mRNA levels of rat Bladders at 10 weeks' BBN treatment revealed a strong significant correlation with the incidence of Bladder lesions at 26 weeks' treatment. Here, we suggest that quantitative VEGF mRNA levels are a good biomarker for a short-term BBN-induced bioassay for rat Bladder Carcinogenesis. Copyright © 2014 John Wiley & Sons, Ltd.

  • Inhibition of rat urinary Bladder Carcinogenesis by the antiangiogenic drug TNP-470.
    Asian Pacific Journal of Cancer Prevention, 2006
    Co-Authors: Hideki Wanibuchi, Elsayed I Salim, Min Wei, Anna Kinoshita, Keiichirou Morimura, Katsuichi Sudo, Shoji Fukushima
    Abstract:

    Potential inhibitory effects of the antiangiogenic drug TNP-470 on rat urinary Bladder Carcinogenesis were investigated in F344 male rats initiated with 0.05% BBN in the drinking water for 8 weeks. Group 1 was then continuously treated with TNP-470 by subcutaneous injection using osmotic minipump until the end of the experiment; group 2 served as the control with only initiation. The incidences and multiplicities of papillomas and carcinomas in the TNP-470-treated group were significantly decreased compared to the control group values along with the tumor vascular density. In conclusion, TNP-470 can inhibit rat urinary Bladder Carcinogenesis, presumably through its effects on angiogenesis.

  • 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.
    Cancer Letters, 2004
    Co-Authors: Satoru Mori, Yasushi Kurata, Susumu Makino, Yasuyoshi Takeuchi, Motoko Toyama, Toshio Harauchi, Shoji Fukushima
    Abstract:

    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.

  • Lack of Influence of Testicular Castration or Sialoadenectomy on Sodium L-Ascorbate Promotion of Urinary Bladder Carcinogenesis in Male F344 Rats
    Journal of Toxicologic Pathology, 2003
    Co-Authors: Satoru Mori, Keiichirou Morimura, Hideki Wanibuchi, Takashi Murai, Shoji Fukushima
    Abstract:

    The study was designed to investigate whether testicular castration (TC) or sialoadenectomy (SE) can influence sodium L-ascorbate (Na-AsA)-promoting effects on urinary Bladder Carcinogenesis in male F344/DuCrj rats. The animals, 6 weeks old at the commencement of the treatment, were given 0.05% N-butyl-N- (4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and then subjected to TC or SE. Thereafter they received basal diet with or without 5% Na-AsA supplement for 32 weeks. Na-AsA caused significant increase in urinary pH, the concentrations of sodium ion, and total ascorbic acid, whereas these urinary parameters were not influenced by TC and SE. TC significantly decreased the relative organ weights of the accessory sexual glands, kidneys, and livers whereas SE was without effect on these organs. TC and SE decreased very slightly BBN-induced Carcinogenesis, but TC and SE did not influence the Na-AsA-promoting effects. The present results indicate that Na-AsA-promotion of two-stage urinary Bladder Carcinogenesis does not depend on the presence of testes or salivary glands.

  • Lack of Inhibition of BBN-induced Bladder Carcinogenesis in C57BL/6 Mice by Intravesical Instillation of KRN 7000
    Journal of Toxicologic Pathology, 2003
    Co-Authors: Makoto Mitsuhashi, Hideki Wanibuchi, Min Wei, Keiichirou Morimura, Tadao Kakizoe, Chikayoshi Masuda, Seiji Wada, Tatsuya Nakatani, Kenichiro Doi, Shoji Fukushima
    Abstract:

    The immunostimulatory α-galactosylceramide, KRN 7000 or (2S, 3S, 4R)-1-0-(α-D-galactopyranosyl)-2-(N-hexacosnoylamino)-1,3,4-octadecatrienol, might be anticipated to have antitumor activity in vivo apart from any direct toxicity to cancer cells. We investigated inhibition of mouse Bladder Carcinogenesis by intravesically instillated KRN 7000. C57BL/6 mice were divided into 4 groups; all first receiving the carcinogen 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in drinking water for 8 weeks. Next, groups 1 and 2, respectively were administered 10 and 0.1 μg/kg of KRN 7000 intravesically once weekly for 17 weeks. Group 3 received only 0.3 ml of saline (vehicle control). Group 4 did not undergo Bladder catheterization. By histologic examination at 26 weeks, the incidence of Bladder carcinoma of all types tended to be higher in group 1 than in group 3, but without significance. The incidence of Bladder carcinoma in group 4, (no catheterization), was similar to that in group 1. Only one precancerous lesion (papillary or nodular dysplasia) was seen in each of groups 3 and 4. Thus vesical instillation of KRN 7000 did not inhibit Bladder Carcinogenesis in mice, exposed to the carcinogen studied.

Hideki Wanibuchi - One of the best experts on this subject based on the ideXlab platform.

  • Isoleucine, Leucine and Their Role in Experimental Models of Bladder Carcinogenesis
    Branched Chain Amino Acids in Clinical Nutrition, 2015
    Co-Authors: Min Wei, Xiao-li Xie, Shotaro Yamano, Anna Kakehashi, Hideki Wanibuchi
    Abstract:

    Branched chain amino acids (BCAA) may facilitate tumor growth; consequently, it is reasonable to assume that the dietary intake of BCAA may play a role in Bladder Carcinogenesis. To date, however, there is no epidemiological data relevant to a relationship of dietary BCAA with the risk of Bladder cancer. On the other hand, there are a few experimental studies reported in the literature. This chapter focuses on the studies evaluating the effects of l-isoleucine and l-leucine on Bladder Carcinogenesis in experimental animals. These three studies employed a two-stage (initiation–promotion) Carcinogenesis protocol with male F344 rats. The results show that the effects of dietary BCAA on rat Bladder Carcinogenesis is dependent on the type of basal diet used.

  • Ethanol-extracted propolis enhances BBN-initiated urinary Bladder Carcinogenesis via non-mutagenic mechanisms in rats
    Food and Chemical Toxicology, 2015
    Co-Authors: Xiao-li Xie, Shotaro Yamano, Anna Kakehashi, Masaki Fujioka, Kenichiro Doi, Hirokazu Tachibana, He Fang, Hideki Wanibuchi
    Abstract:

    Abstract Ethanol-extracted propolis (EEP) is used for medical, dietetic and cosmetic purposes. In this study, the effects of EEP on urinary Bladder Carcinogenesis, its underlying mechanism and in vivo genotoxicity were investigated. In experiment 1, rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 or 4 weeks followed by dietary administration of 0.125, 0.25, 0.5 or 1% EEP for 4 or 32 weeks, respectively. At week 6, the mRNA levels of top2a, cyclin D1 and survivin were significantly elevated in the 0.5 and 1% EEP groups. At week 36, the incidence and multiplicity of urothelial carcinomas and total tumors were markedly elevated in all EEP groups. In experiment 2, rats were fed basal diet or the 1% EEP diet for 13 weeks without carcinogen initiation. Increases in urinary precipitate, cell proliferation and incidence of simple hyperplasia were observed in the 1% EEP group. In experiment 3, dietary administration of 2.5% EEP to gpt delta rats for 13 weeks did not induce any obvious mutagenicity in the urinary Bladder urothelium. Taken together, EEP enhanced BBN-initiated rat urinary Bladder Carcinogenesis in a non-genotoxic manner through increasing formation of urinary precipitate, enhancing cell proliferation and inhibiting apoptosis during the early stages of Carcinogenesis.

  • Vascular endothelial growth factor mRNA levels as a biomarker for short‐term N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine‐induced rat Bladder Carcinogenesis bioassay
    Journal of Applied Toxicology, 2014
    Co-Authors: Shin Wakui, Hideki Wanibuchi, Tomoko Mutou, Hiroyuki Takahashi, Masahiro Ikegami, Shoji Fukushima
    Abstract:

    Generically, carcinogenic effects of chemicals in Bladder Carcinogenesis are judged by induction of papillary or nodular (PN) hyperplasia in rats given N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 4 weeks and the test chemical for 22–28 weeks. However, upregulation of vascular endothelial growth factor (VEGF) begins early in rat BBN Bladder Carcinogenesis. To establish a short-term rat Bladder carcinogenic bioassay, we analyzed the correlations between VEGF, VEGF mRNA and Bladder lesions inductions at 10 and 26 weeks after BBN treatment. Six-week-old male Wistar (slc) rats were given 0.05% BBN for 4, 10 or 26 weeks. To avoid individual rat bias, the Bladders were investigated by partial cystectomy at 10 weeks and total cystectomy at 26 weeks. After induction, PN hyperplasia and carcinoma in rats increased with the length of BBN treatment and immunohistochemical VEGF expression also increased following Carcinogenesis, but the immunoreactivity of individual lesions was quite variable. Moreover, induction of PN hyperplasia at 10 weeks’ BBN treatment was not significantly correlated with that at 26 weeks' treatment; thus, it was not possible to predict the carcinogenic effect due to the induction of PN hyperplasia at 26 weeks' BBN treatment by that at 10 weeks' treatment. However, VEGF mRNA levels of rat Bladders at 10 weeks' BBN treatment revealed a strong significant correlation with the incidence of Bladder lesions at 26 weeks' treatment. Here, we suggest that quantitative VEGF mRNA levels are a good biomarker for a short-term BBN-induced bioassay for rat Bladder Carcinogenesis. Copyright © 2014 John Wiley & Sons, Ltd.

  • Evaluation of the Modifying Effect of Inhalation of Mainstream Cigarette Smoke on Mouse Bladder Carcinogenesis
    Journal of Toxicologic Pathology, 2013
    Co-Authors: Minoru Kato, Min Wei, Shotaro Yamano, Anna Kakehashi, Masaki Fujioka, Hideki Wanibuchi
    Abstract:

    Cigarette smoking is one of the major risk factors of Bladder cancer in humans. To date, however, there is no experimental evidence for the effects of inhalation exposure to mainstream cigarette smoke on Bladder Carcinogenesis. The purpose of the present study was to evaluate the effect of inhalation of mainstream cigarette smoke on mouse Bladder Carcinogenesis using a cigarette smoke inhalation exposure system. Six-week-old male C57BL mice were administered 0.025% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) in their drinking water for 8 weeks and then divided into 2 groups and exposed to 0 or 300 mg/m(3) wet total particulate matter mainstream cigarette smoke for 2 h per day, five times per week, for 22 weeks. The incidences of Bladder tumors (papilloma and urothelial carcinoma) tended to increase in the cigarette smoke-exposed group (25.0%) compared with the controls (15.8%), albeit without a statistically significant difference. We also evaluated mRNA expression levels of cytochrome P450 (cyp) enzymes and proliferating cell nuclear antigen (PCNA) in the Bladder epithelium. Expression of cyp1a1 was significantly increased in the cigarette smoke-exposed group. Cigarette smoke exposure did not have a significant effect on the expression of cyp1a2, cyp 1b1, cyp 2a4, cyp 2b10, cyp 2e1, or PCNA. In conclusion, limited exposure to mainstream cigarette smoke for 22 weeks, caused a significant increase in cyp1a1 expression. This increase coupled with the nonsignificant increase in Bladder tumors suggests that a longer period of exposure is required to clarify the effects of cigarette smoke on Bladder Carcinogenesis.

  • Long-term treatment with l-isoleucine or l-leucine in AIN-93G diet has promoting effects on rat Bladder Carcinogenesis
    Food and Chemical Toxicology, 2012
    Co-Authors: Xiao-li Xie, Min Wei, Shotaro Yamano, Anna Kakehashi, Minoru Kato, Takayuki Yunoki, Hideki Wanibuchi
    Abstract:

    In the present study, effects of L-leucine and L-isoleucine on rat Bladder Carcinogenesis were investigated using AIN-93G and MF basal diet. In Experiment 1, N-butyl-N-(4-hydroxybutyl)-nitrosamine was used as an initiator of Bladder Carcinogenesis. In the AIN-93G diet groups, a significantly higher incidence and multiplicity of Bladder tumors, accompanied by decreased final body weight, was observed in the L-leucine-supplemented group and a significantly higher incidence of papillomas and total tumors was observed in the L-isoleucine-supplemented group. In the MF diet groups, the multiplicity of papillary and nodular hyperplasia was significantly increased in the L-isoleucine-supplemented group. Urinary pH values were not affected by supplementing either type of diet with L-leucine or L-isoleucine. In Experiment 2, the amino acid was administered in the basal diets for 2 weeks without initiator. No pathological lesions were observed in the Bladder urothelium in any of the groups, and no significant differences in urinary pH values, microcrystals or aggregates were observed between the amino acid-supplemented groups and their respective control groups. In conclusion, long-term treatment with L-leucine or L-isoleucine has a promoting effect on rat Bladder Carcinogenesis; therefore, their long-term use as a dietary supplement for Bladder cancer patients should be avoided until more is known.

Samuel M. Cohen - One of the best experts on this subject based on the ideXlab platform.

  • Urinary Bladder Carcinogenesis
    Toxicologic Pathology, 2016
    Co-Authors: Samuel M. Cohen
    Abstract:

    Urinary Bladder Carcinogenesis in rodents bears numerous similarities to the diseases in humans. In rats, the process progresses through the morphologic stages of simple hyperplasia, papillary and nodular hyperplasia, papilloma, noninvasive, and invasive carcinoma. In mice, the pathogenesis can be similar or can follow a sequence of marked dysplasia with or without hyperplasia, leading to carcinoma in situ and ultimately to high-grade invasive carcinoma. Although the papillary and nonpapillary diseases appear to be related in rodents and in humans, they are distinct morphologically, biologically, and molecularly. Numerous classes of genotoxic chemicals have been identified as Bladder carcinogens in rodents, and some of these have also been identified as carcinogenic in humans, most notably, aromatic amines, nitrosamines, and cyclophosphamide. In contrast, nongenotoxic chemicals appear to be highly specific with respect to species, strain, diet, agent, dose, and mechanism. For some, it is unclear whether t...

  • Effects of Diet on Urinary Bladder Carcinogenesis and Cancer Prevention
    Journal of Nutrition, 1997
    Co-Authors: Samuel M. Cohen, Tsuneo Masui, Emily M. Garland, Lora L. Arnold
    Abstract:

    Urine plays a major role in Bladder Carcinogenesis, acting as a transport mechanism for carcinogens, containing several growth factors stimulating cell proliferation, and indirectly affecting chemicals by alterations in concentrations of normal urinary components such as electrolytes, water and proteins. These latter effects are greatly modified by diet composition and consumption and also by water consumption. Several examples of these effects are presented.

  • Effects of diet on urinary Bladder Carcinogenesis and cancer prevention : Symposium: Animal diets for nutritional and toxicological research
    Journal of Nutrition, 1997
    Co-Authors: Samuel M. Cohen, Tsuneo Masui, Emily M. Garland, Lora L. Arnold
    Abstract:

    Urine plays a major role in Bladder Carcinogenesis, acting as a transport mechanism for carcinogens, containing several growth factors stimulating cell proliferation, and indirectly affecting chemicals by alterations in concentrations of normal urinary components such as electrolytes, water and proteins. These latter effects are greatly modified by diet composition and consumption and also by water consumption. Several examples of these effects are presented.

  • Analysis of differentiation-associated proteins in rat Bladder Carcinogenesis
    Carcinogenesis, 1996
    Co-Authors: Kumiko Ogawa, Tung-tien Sun, Samuel M. Cohen
    Abstract:

    Uroplakins are the major integral membrane proteins synthesized in terminally differentiated, superficial urothelial cells. Alteration of cell differentiation during rat urinary Bladder Carcinogenesis was analyzed immunohistochemically for the expression of uroplakins. Expression of uroplakins was compared in N-[4-(5-nitro-2-furyl)-2-thiazolyl]-formamide (FANFT)-, uracil-, sodium saccharin- or sodium ascorbate-induced urothelial simple hyperplasia, papillary-nodular hyperplasia, papilloma and carcinoma. In controls, uroplakins were located only in superficial cells, especially the luminal surface membrane. In FANFT-induced hyperplasia, including simple hyperplasia, intermediate cells also stained and the staining pattern was disorderly and intermittent. In uracil-induced simple hyperplasia, intermediate cells were stained but in an orderly fashion. In sodium saccharin- or sodium ascorbate-induced simple hyperplasia, superficial cells were swollen but alterations were not observed in the staining pattern. In carcinoma induced by FANFT and uracil, uroplakin expression was very disorderly and focal, usually with no expression on surface cells. It appears that disorderly differentiation is an index of Bladder malignancy and is an early event in FANFT-induced lesions but a late event in uracil-, sodium saccharin- and sodium ascorbate-induced lesions.

  • p53 mutation is infrequent and might not give a growth advantage in rat Bladder Carcinogenesis in vivo.
    Carcinogenesis, 1994
    Co-Authors: Makoto Asamoto, Angela M. Mann, Samuel M. Cohen
    Abstract:

    Abnormalities of the p53 gene are frequently observed in human tumors, including urinary Bladder carcinoma, suggesting that p53 plays an important role in human Carcinogenesis. However, its role in rat Bladder Carcinogenesis is unclear. In this study, we investigated the presence of p53 mutations in 122 urinary Bladder tumors induced in F344 rats in the following Carcinogenesis models: (i) 0.2% N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide (FANFT; 6 weeks) in the diet followed by 3% or 5% sodium saccharin in the diet, 5% sodium ascorbate, 3.12% calcium saccharin (CaSac), 1.34% sodium chloride (NaCl), 5.2% CaSac plus 1.34% NaCl, or basal diet alone (72 weeks); and (ii) 0.2% FANFT, 0.05% N-(4-hydroxybutyl)nitrosamine in the drinking water, N-methyl-N-nitrosourea 20 mg/kg body wt, i.p. twice per week, or basal diet alone (4 weeks), followed by 3% uracil in the diet (20 weeks). Polymerase chain reaction-single-strand conformation polymorphism analysis and direct sequencing were performed for exons 5-8 in the rat p53 gene. We found nine tumors (7.4%) with p53 mutations. Two tumors had two mutations in the p53 gene. The tumors that had p53 mutations were relatively smaller than those that did not have p53 mutations. There were no mutation clusters among the treatments or hot-spots for p53 mutations. These results indicate that p53 mutation is infrequent in Bladder Carcinogenesis in rats, and when it does occur, it does not appear to provide a growth advantage.

Shinji Yamamoto - One of the best experts on this subject based on the ideXlab platform.

  • Reduced expression of the CDK inhibitor p27KIP1 in rat two-stage Bladder Carcinogenesis and its association with expression profiles of p21WAF1/Cip1 and p53
    Carcinogenesis, 1999
    Co-Authors: Chyi-chia Richard Lee, Shinji Yamamoto, Hideki Wanibuchi, Seiji Wada, Kazunobu Sugimura, Toshio Ichihara, Taketoshi Kishimoto, Shoji Fukushima
    Abstract:

    The cyclin-dependent kinase (CDK) inhibitor p27(KIP1) exerts its growth suppressive effects by targeting the cyclin-CDK complexes. Reduced protein levels of p27(KIP1) have been reported in numerous human cancers and this has been attributed to increased degradation. However, few reports have addressed the significance of p27(KIP1) expression in chemical Carcinogenesis of rodents. In a rat two-stage urinary Bladder Carcinogenesis model, with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) initiation followed by promotion with sodium L-ascorbate (Na-AsA), we evaluated the expression of p27(KIP1) protein using immunohistochemistry during various stages of urinary Bladder Carcinogenesis. In addition, we evaluated the mRNA expression profiles for p27(KIP1), p21(WAF1/Cip1) and p53 in tumors. Fisher 344 rats were initiated with 0.05% BBN in the drinking water for 4 weeks and then administered 5% Na-AsA in the diet. Immunohistochemical examination revealed p27(KIP1) protein to be constitutively expressed in normal urothelium, simple hyperplasia and in most papillary and nodular (PN) hyperplasias and small papillomas, but diminished or absent in large papillomas and in transitional cell carcinomas. An inverse correlation between expression of p27(KIP1) and cell proliferation was generally observed. Quantitation of mRNA by multiplex reverse transcription-PCR showed a significant downregulaton of p27(KIP1), p21(WAF1/Cip1) and p53 mRNA in tumors. More than 50% reduction in p27(KIP1) mRNA expression was observed in 42 and 47% of tumors at weeks 18 and 24, respectively; similar reduction in p21(WAF1/Cip1) mRNA expression was observed in 58 and 73% of tumors at weeks 18 and 24, and in p53 mRNA expression in 50 and 73% of tumors at weeks 18 and 24, respectively. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis had p53 mutations. These data imply that abnormal down-regulation of p27(KIP1), p21(WAF1/Cip1) and/or p53 in tumor cells may contribute to the malignant progression of tumors during rat two-stage Bladder Carcinogenesis.

  • Enhancement of urinary Bladder Carcinogenesis in nullizygous p53-deficient mice by N-butyl-N-(4-hydroxybutyl)nitrosamine
    Cancer Letters, 1999
    Co-Authors: Shinji Yamamoto, Elsayed I Salim, Hideki Wanibuchi, Wei Min, Chyi-chia Richard Lee, Tokuo Sukata, Shoji Fukushima
    Abstract:

    We recently reported p53 mutations to be frequent in mouse invasive urinary Bladder carcinomas, with and without metastasis. However, the role of p53 dysfunctions during Carcinogenesis remains unclear. In the present study, heterozygous and nullizygous p53-deficient mice and their littermates were treated with the urinary Bladder carcinogen, N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), at a concentration of 0.01% in the drinking water throughout the experiment. This markedly accelerated urinary Bladder Carcinogenesis but not development of other tumors in the nullizygous p53-deficient mice. Thus the appearance of neoplastic urothelial lesions in nullizygotes (at day 60 of the experiment) was earlier than in wild-type mice and heterozygotes (at day 125). Moreover, malignant vascular tumors (hemangiosarcomas (HS)) were found in all four nullizygotes killed later than day 108. Mutational inactivation of the wild-type allele was not apparent in either the single transitional cell carcinoma observed in a wild-type mouse and a hemangiosarcoma in a heterozygote. Overall, it can be concluded that the number of normal p53 alleles is a significant determining factor in the susceptibility of urothelial cells to carcinogens. The role of the p53 defect in mouse urinary Bladder Carcinogenesis may thus be to diminish the threshold for occurrence of additional genetic alterations.

  • promotion by sodium l ascorbate in rat two stage urinary Bladder Carcinogenesis is dependent on the interval of administration
    Japanese Journal of Cancer Research, 1999
    Co-Authors: Tianxin Chen, Shinji Yamamoto, Hideki Wanibuchi, Takashi Murai, Mitsuaki Kitano, Shoji Fukushima
    Abstract:

    In our two-stage model of rat urinary Bladder Carcinogenesis employing N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) as the initiator, sodium L-ascorbate (Na-AsA) exhibits dose-dependent promotion. In the present study, in order to assess the possible reversibility of the promoting effects, we investigated how different administration periods of Na-AsA influence its promoting activity. In experiment 1, rats were treated with 5% Na-AsA for different administration periods with or without withdrawal and injected with 5-bromo-2'-deoxyuridine (BrdU) to allow determination of the cell proliferation status. Replicative DNA synthesis in the urinary Bladder epithelium was shown to return to normal after removal of the promoting stimulus. In experiment 2, rats were initially given BBN for 4 weeks and subsequently received 16 weeks of Na-AsA, alternating with basal diet, at intervals of 4, 8 or 16 weeks, within a total 32-week period. The longer the continuous exposure to Na-AsA, the greater the yield of papillomas and carcinomas in the urinary Bladder. In experiment 3, Na-AsA was given for 4 or 8 weeks after BBN initiation and the animals were killed at weeks 8 and 12. Both promotion of lesion development and increase of DNA synthesis in the urinary Bladder epithelium were dependent on the length of exposure to Na-AsA and the total period of exposure. The results indicate that the promoting effects of Na-AsA in urinary Bladder Carcinogenesis are reversible to a certain extent after its withdrawal, and the existence of a cumulative exposure time threshold seems likely.

  • promotion of nci black reiter male rat Bladder Carcinogenesis by dimethylarsinic acid an organic arsenic compound
    Cancer Letters, 1998
    Co-Authors: Wei Li, Elsayed I Salim, Kaoru Yoshida, Shinji Yamamoto, Ginji Endo, Hideki Wanibuchi, Shoji Fukushima
    Abstract:

    Abstract Dimethylarsinic acid (DMAA) is a major metabolite of inorganic arsenicals in mammals. In the present study, we investigated its promoting effects on urinary Bladder Carcinogenesis in NCI-Black-Reiter (NBR) rats, which lack α 2u-globulin synthesizing ability. Male 9–14-week-old NBR rats were treated sequentially with 0.05% N -butyl- N -(4-hydroxybutyl)-nitrosamine (BBN) for 4 weeks and then given 100 ppm DMAA in their drinking water (group 1) for 32 weeks. Induction of preneoplastic lesions (papillary or nodular hyperplasia) in this DMAA-treated group was significantly increased as compared to the carcinogen alone control group ( P α 2u-globulin.

  • cyclin d1 overexpression in rat two stage Bladder Carcinogenesis and its relationship with oncogenes tumor suppressor genes and cell proliferation
    Cancer Research, 1997
    Co-Authors: Chyi-chia Richard Lee, Shinji Yamamoto, Hideki Wanibuchi, Seiji Wada, T Kishimoto, Kazunobu Sugimura, Soji Fukushima
    Abstract:

    Overexpression of cyclin D1 has been implicated in the malignant transformation of a variety of human cancers, including urinary Bladder carcinomas. However, few reports have addressed the significance of cyclin D1 overexpression in chemical Carcinogenesis in rodents. In the present study, we evaluated the oncogenic potential of cyclin D1 in experimental rat urinary Bladder Carcinogenesis and its relationships to the oncogenes cyclin E , K- ras , and H- ras as well as tumor suppressor genes p53 and p21WAF1/Cip1 . In addition, proliferation status of preneoplastic lesions and tumors was assessed by proliferating cell nuclear antigen immunohistochemistry. Fisher 344 rats were initiated with 0.05% N -butyl- N -(4-hydroxybutyl)nitrosamine in the drinking water for 4 weeks and then administered 5% sodium l-ascorbate in diet. Animals were sacrificed at weeks 4, 8, 12, 18, and 24. Preneoplastic lesions such as papillary or nodular hyperplasia and neoplastic lesions of the urinary Bladder were observed during Carcinogenesis. By immunohistochemical examination, overexpression of cyclin D1 protein was observed in 17% of papillary or nodular hyperplasias, 66% of papillomas, and 69% of transitional cell carcinomas, whereas nuclear accumulation of p53 was observed in none of the preneoplastic lesions and in fewer than 2% of transitional cell carcinomas. Overexpression of cyclin D1 in preneoplastic lesions and tumors was not dependent on the size of the tumors or their proliferation status. Quantitation of mRNA in tumors by multiplex reverse transcription-PCR showed that average mRNA expression of cyclin D1 and cyclin E was increased, whereas average p21WAF1/Cip1 mRNA expression was decreased. More than 2-fold overexpression of cyclin D1 mRNA was observed in 50 and 60% of tumors at weeks 18 and 24, respectively. Localization of cyclin D1 mRNA expression was demonstrated by in situ hybridization, and the results were comparable to immunohistochemistry findings. None of the 25 tumors we examined by PCR-single-strand conformational polymorphism analysis harbored p53 mutations, H- ras mutations, or K- ras mutations. Thus, during the promotion phase of two-stage Bladder Carcinogenesis, overexpression of cyclin D1 in tumor cells may provide yet another mechanism by which tumors can gain a growth advantage. In contrast, tumors with mutated p53 may not have a growth advantage. Our results suggest that overexpression of cyclin D1 plays a critical role during urinary Bladder Carcinogenesis.

Warren Davis - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of urinary Bladder Carcinogenesis by broccoli sprouts
    Cancer Research, 2008
    Co-Authors: Rex Munday, Paulette Mhawechfauceglia, Christine M Munday, Joseph D Paonessa, Li Tang, John S Munday, Carolyn E Lister, Paula Wilson, Jed W Fahey, Warren Davis
    Abstract:

    Isothiocyanates are a well-known class of cancer chemopreventive agents, and broccoli sprouts are a rich source of several isothiocyanates. We report herein that dietary administration to rats of a freeze-dried aqueous extract of broccoli sprouts significantly and dose-dependently inhibited Bladder cancer development induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The incidence, multiplicity, size, and progression of Bladder cancer were all inhibited by the extract, while the extract itself caused no histologic changes in the Bladder. Moreover, inhibition of Bladder Carcinogenesis by the extract was associated with significant induction of glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1 in the Bladder, enzymes that are important protectants against oxidants and carcinogens. Isothiocyanates are metabolized to dithiocarbamates in vivo, but dithiocarbamates readily dissociate to isothiocyanates. We found that >70% of the isothiocyanates present in the extract were excreted in the urine as isothiocyanate equivalents (isothiocyanates + dithiocarbamates) in 12 h after a single p.o. dose, indicating high bioavailability and rapid urinary excretion. In addition, the concentrations of isothiocyanate equivalents in the urine of extract-treated rats were 2 to 3 orders of magnitude higher than those in plasma, indicating that the Bladder epithelium, the major site of Bladder cancer development, is most exposed to p.o. dosed isothiocyanate. Indeed, tissue levels of isothiocyanate equivalents in the Bladder were significantly higher than in the liver. In conclusion, broccoli sprout extract is a highly promising substance for Bladder cancer prevention and the isothiocyanates in the extract are selectively delivered to the Bladder epithelium through urinary excretion.

  • inhibition of urinary Bladder Carcinogenesis by broccoli sprouts
    Cancer Epidemiology and Prevention Biomarkers, 2007
    Co-Authors: Rex Munday, Paulette Mhawechfauceglia, Christine M Munday, Joseph D Paonessa, Li Tang, John S Munday, Carolyn E Lister, Paula Wilson, Jed W Fahey, Warren Davis
    Abstract:

    B149 Isothiocyanates (ITCs) are a well-known class of cancer chemopreventive agents, and broccoli sprouts are a rich source of several ITCs. We report herein that dietary administration to rats of a freeze-dried aqueous extract of broccoli sprouts significantly and dose-dependently inhibited Bladder cancer development induced by N-butyl-N-(4-hydroxybutyl) nitrosamine. The incidence, multiplicity, size and progression of Bladder cancer were all inhibited by the extract, while the extract itself caused no histological changes in the Bladder. Moreover, inhibition of Bladder Carcinogenesis by the extract was associated with significant induction of glutathione S-transferase and NAD(P)H:quinone oxidoreductase 1 in the Bladder, enzymes that are known to be important protectants against oxidants and carcinogens. ITCs are metabolized to dithiocarbamates (DTCs) in vivo, but DTCs readily dissociate to ITCs. We found that more than 70% of the ITCs present in the extract were excreted in the urine as ITC equivalents (ITCs + DTCs) in 12 h after a single oral dose, indicating high bioavailability and rapid urinary excretion. In addition, the concentrations of ITC equivalents in the urine of extract-treated rats were 2-3 orders of magnitude higher than those in plasma, indicating that the Bladder epithelium, the major site of Bladder cancer development, is most exposed to orally dosed ITC. Indeed, tissue levels of ITC equivalents in the Bladder were significantly higher than in the liver. In conclusion, broccoli sprout extract is a highly promising substance for Bladder cancer prevention and the ITCs in the extract are selectively delivered to the Bladder epithelium through urinary excretion.