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PubMed1991

Modulation of mycotoxin and nitrosamine carcinogenesis by indole-3-carbinol: quantitative analysis of inhibition versus promotion.

The value of chemopreventive agents for reducing human response to mycotoxins and N-nitrosamines remains uncertain, especially since many such agents also can act as tumour promoters. Indole-3-carbinol (I3C) from cruciferous vegetables can inhibit DNA adduction and hepatocarcinogenesis induced by aflatoxin B1 (AFB1) or N-nitroso-diethylamine in trout if given before and with the carcinogen but promotes carcinogenesis when given after initiation. Similar results have been obtained with I3C and AFB1 in rats. In detailed studies using 10,000 trout, inhibition of AFB1 carcinogenesis was found to be saturable at high doses of I3C, approximately proportional to dose of I3C through the range of human intake and, within this range, quantitatively predicted by I3C-mediated reduction of AFB1-DNA adduction in liver. In a second study, post-initiation promotion of AFB1 carcinogenesis was approximately proportional to I3C dose, increased with duration of exposure, decreased with delayed onset of exposure, and reduced but still significant when I3C was given on alternate months or weeks or twice per week only. Hence, promotion by this common component of cruciferous vegetables required prolonged exposure but not necessarily on a daily basis.

Aflatoxin B1↗
PubMed1985

Squamous and transitional elements in rat bladder carcinomas induced by N-butyl-N-4-hydroxybutyl-nitrosamine (BBN). A study of cytokeratin expression.

Three hundred rat bladders bearing tumors induced by N-butyl-N-4-(OH)butyl-nitrosamine (BBN) were examined by routine histologic study and immunohistochemical staining of intermediate filament types. Smaller lesions were similar to human urothelial dysplasia histologically and immunohistochemically. Progression of the lesions demonstrated large exophytic papillomas with extensive endophytic epithelial growth into abundant stroma. These lesions showed increasing predominance of squamous over transitional elements. Immunohistochemical findings confirmed these results and also demonstrated that morphologically indifferent cells, even in early lesions, express heavier cytokeratins characteristic of keratinizing squamous epithelium. These results demonstrate that BBN-induced bladder tumors show marked quantitative and qualitative differences from the most common, purely transitional, human bladder carcinomas. However, the development in BBN-treated rat bladders of two tumor types, squamous and transitional, from an altered urothelium may serve as an attractive model for further study of the molecular genetics of keratin expression.

Animals↗
PubMed1989

Inhibitory action of alpha-difluoromethylornithine on N-butyl-N-(4-hydroxybutyl)nitrosamine-induced rat urinary bladder carcinogenesis.

We previously have shown that urine components capable of stimulating ornithine decarboxylase activity of urothelium can enhance rat urinary bladder carcinogenesis, and that alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, suppresses carcinogen-initiated rat urinary bladder carcinogenesis. The present investigation was conducted to determine whether DFMO's suppressive effect is stage specific during carcinogenesis and whether the suppressive effect lasts with its continued use. Following initiation with 0.05% N-butyl-N-(4-hydroxybutyl)-nitrosamine in drinking water for 6 wk, male Fischer 344 rats initially weighing 125 to 150 g were randomly divided into two groups, the first receiving 0.2% DFMO in drinking water ad libitum and the second receiving tap water only. Groups of animals were killed at regular intervals until the completion of the experiment at 75 wk. The effect of DFMO was evaluated by monitoring the incidence of tumors, the mean number of tumors per rat, the mean volume of individual tumors, and the mean total tumor volume per rat. The results showed that continuous treatment with DFMO significantly reduced tumor formation until 60 wk (P less than 0.017). The effect was only of borderline significance (0.017 less than P less than 0.035) at 75 wk. Discontinuation of DFMO treatment at 40 wk resulted in the loss of protective effect in all comparisons except for the borderline effect on the tumor number and total tumor volume per rat. DFMO had no significant effect on the incidence or development of preneoplastic early lesions. Mucosal polyamine (spermidine and spermine) levels were reduced and correlated well with the reduction in tumor growth, suggesting that the reduction in tumor growth rate by DFMO may be due to its ability to reduce polyamine levels in urothelium. There were no side effects attributable to DFMO treatment. DFMO may be a useful chemopreventive agent to retard the recurrence of human superficial bladder cancer.

Animals↗
PubMed1989

[Mechanism of riboflavin deficiency facilitating carcinogenesis of N-nitrosamine--effect on carcinogen-metabolizing enzymes].

Previous studies have demonstrated the facilitating effect of riboflavin deficiency on the carcinogenesis of the liver of rats induced by N-nitrosamine. However, the mechanism was still not clear. In the present investigation, the alterations of microsomal carcinogen-metabolizing enzymes of rat liver during riboflavin-deficiency with simultaneous administration of nitrosodimethylamine (NDMA) were studied. The results showed that the enzyme activities of hepatic microsomal cytochrome P-450 and NDMA demethylase of riboflavin deficient rats and riboflavin deficient rats receiving NDMA were increased and significantly different from the control rats (P less than 0.05). The enzyme activities of hepatic microsomal NADPH-cytochrome P-450 reductase of riboflavin deficient rats and riboflavin deficient rats receiving NDMA were significantly decreased (P less than 0.01). All the alterations disappeared after supplying riboflavin to the deficient rats. This result indicates that the effect of riboflavin deficiency on carcinogen-metabolizing enzymes of rat liver is reversible.

Animals↗
PubMed1989

Infrequent activation of K-ras, H-ras, and other oncogenes in hepatocellular neoplasms initiated by methyl(acetoxymethyl)nitrosamine, a methylating agent, and promoted by phenobarbital in F344 rats.

Fischer 344/Ncr rats of both sexes were subjected to partial hepatectomy and then initiated 21-24 h later by a single injection of methyl(acetoxymethyl)nitrosamine at 0.1 mmol/kg body weight via the portal vein. Beginning 3 weeks later, development of hepatocellular neoplasms in initiated rats was promoted by feeding 0.05% phenobarbital (PB) in the diet. Not only intrahepatic lesions but also a variety of extrahepatic tumors were induced. High-molecular-weight DNAs were prepared from 67 samples of grossly normal liver containing multiple preneoplastic foci/areas of microscopic dimensions, 137 hepatocellular adenomas (nodules), 93 hepatocellular carcinomas (HCC), 10 cholangiomas, and 25 extrahepatic tumors in 95 rats and tested for transforming activity in the NIH 3T3 transfection assay. DNA preparations from 7 of 93 HCCs, 2 of 10 cholangiomas, 2 of 137 nodules, 1 histiocytic sarcoma, and 1 thyroid carcinoma were positive in the transfection assay. Southern blot analysis showed that NIH 3T3 transformants induced by DNA from 5 HCCs, 1 hepatocellular adenoma, 1 cholangioma, 1 histiocytic sarcoma, and 1 thyroid carcinoma contained an activated K-ras gene of rat origin. Rat-derived H-ras was identified in transformants from 2 additional HCCs and rat c-raf from 1 hepatocellular adenoma. The transforming gene from one cholangioma showed no sequence homology to the ras genes, neu, or c-raf. Immunoprecipitation analysis of ras Mr 21,000 protein in 11 transformants indicated that, based upon protein electrophoretic mobilities, activation of the ras genes consistently resulted from mutations in codon 12 of these genes. Selective oligonucleotide analysis revealed that a G----A transition in the second base of codon 12 of K-ras was present in the 9 K-ras-positive transformants and also in DNAs prepared from the original tumors. In contrast, oligonucleotide hybridization experiments with DNAs from 35 hepatocellular tumors that were negative in transfection assays revealed the presence of mutant K-ras in 1 of 15 HCCs; no mutation could be detected in 20 transfection-negative adenomas. The infrequency of detection of a specific oncogene, more frequent detection of oncogenes in malignant tumors, and failure to observe activated oncogenes in preneoplastic lesions suggest that activation of ras oncogenes may occur as a late and infrequent event in the evolution of some rat hepatocellular neoplasms and that mutation of a specific ras locus is not an obligatory early event in the genesis of these neoplasms.

Animals↗
PubMed1989

[Mechanism of promoting effects of riboflavin deficiency on carcinogenesis of nitrosamines--effects on rat liver glutathione content].

The effect of riboflavin deficiency and simultaneously, nitrosodimethylamine given by gastric intubation on the glutathione content of rat liver is reported. On different days of the experiments, glutathione content in the riboflavin deficient rat liver decreased to 55-61% of the controls. When nitrosodimethylamine was given by gastric intubation, glutathione content decreased markedly to 39-43% of the controls. The hepatic glutathione content of riboflavin deficient rats recovered to the level of the controls by supplying riboflavin. The alteration of rat hepatic glutathione content during riboflavin deficiency may imply as one of the promoting effects of riboflavin deficiency on the carcinogenesis of nitrosamines.

Animals↗
PubMed1987

[Effect of intravesical instillation of the antitumor chemotherapeutic agents mitomycin C and cytosine arabinoside on rat bladder carcinogenesis initiated by N-butyl-N-(4-hydroxybutyl) nitrosamine].

The effects of intravesical instillation of cytosine arabinoside (CA), mitomycin C (MMC) and combination of CA and MMC were examined in rats pretreated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). Rats were given initial treatment with BBN for 4 weeks followed by intravesical instillation of drugs once a week for 12 weeks. The total observation period was 36 weeks. Instillation of MMC markedly increased the development of bladder tumors, although CA did not. Moreover, tumor incidence in the combination group was less than that with MMC only. The results indicate that the intravesical instillation of MMC promotes 2-stage bladder carcinogenesis, whereas CA does not. Moreover, it is suggested that CA inhibits the promoting effect of MMC.

Administration, Intravesical↗
PubMed1986

Urinary bladder carcinogenesis by N-butyl-N-(4-hydroxybutyl)-nitrosamine in an analbuminemic congenic strain of rats with an ACI genetic background.

An analbuminemic congenic strain of rats originating from ACI (ACI-alb) rats was established. The rats were found to be highly susceptible to induction of urinary bladder cancer by N-butyl-N-(4-hydroxy-butyl)nitrosamine. Bladder cancers were observed in all male ACI-alb and normal ACI rats treated with the compound, but the average weight of the bladder including tumors was more in ACI-alb rats than in ACI rats (0.63 +/- 0.24 g and 0.18 +/- 0.05 g, respectively; ratio, 3.5:1).

Animals↗
PubMed1987

Inhibition of N-butyl-N-(4-hydroxybutyl) nitrosamine-induced urinary bladder tumor in rats by alpha-difluoromethylornithine.

The therapeutic effects of alpha-difluoromethylornithine (DFMO) on rats with bladder tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) were examined. Eight-week-old male Wistar rats were given 0.05% BBN in their drinking water for a period of 4 weeks. Therapy (0.1% DFMO in their drinking water) was started at week 4 and all rats were killed at week 60. DFMO was seen to significantly reduce the incidence, the mean number and the total size of tumors. No side-effects of DFMO were noted, except alopecia, which started at month 7 of the therapy.

Animals↗
PubMed1987

Altered expression of immunohistochemically detected cytochrome P-450 component(s) in nitrosamine-induced rat urinary bladder lesion.

Male ACI/N rats were treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water, and in conjunction with histological examination, the changes of the expressed cytochrome P-450 components in the urothelium and other tissues (liver, kidney, esophagus, intestines) were examined by means of immunohistochemistry. Frozen tissue sections were prepared and immunostained with anti-rat cytochrome P-450 monoclonal antibodies and an avidin-biotin-peroxidase complex. Monoclonal antibodies used were APH-3 and APH-8 raised against a high-spin form of cytochrome P-448, APL-1 and APL-2 against a low-spin form of cytochrome P-448, and APF-3 against cytochrome P-450. BBN-induced qualitative and quantitative changes of cytochrome P-450 components recognized by these monoclonal antibodies were not observed in tissues other than the bladder. Untreated rat bladder epithelium was not stained with any of these 5 monoclonal antibodies. The treatment with BBN for more than 3 weeks, however, resulted in the expression of cytochrome P-450 component(s) recognized by APH-8 antibody. This cytochrome P-450 component increased with the advance of carcinogenic changes in the urothelium. The component reactive with AHP-8 was also detected in the cancer tissues of transplantation lines of rat bladder cancers. In contrast, the cytochrome P-450 components recognized by APL-1, APL-2 or APF-3 were undetectable or present at low levels throughout the BBN carcinogenesis. These results suggest that a certain cytochrome P-450 component(s), probably a high-spin form of cytochrome P-448, is selectively induced in urothelium in association with neoplastic bladder lesion.

Animals↗
PubMed1987

Diethyl-nitrosamine hepatocarcinogenesis in cirrhotic rats.

The aim of this study was to clarify how the CCl4-induced cirrhosis modifies the process of diethylin-nitrosamine hepatocarcinogenesis. Two strains of rats (CFY and F-344) were used. CFY rats proved to be resistant toward both the cirrhogenic effect of CCl4 and carcinogenic effect of DEN. In the F-344 rats, on the other hand, a large number of foci, neoplastic nodules and hepatocellular carcinomas occurred following DEN treatment only and fullblown liver cirrhosis did develop in the CCl4-treated group. In F-344 rats with cirrhotic liver, foci and neoplastic nodules appeared in the usual number and at the usual time following DEN treatment, but--opposite to the expectations--much less carcinomas developed than in the rats receiving DEN only. When, however the CCl4-treatment was applied following the DEN administration, a promoting effect was seen. The mechanism of the inhibitory effect of the CCl4-induced liver cirrhosis upon hepatocarcinogenesis is not clarified, similarly to the mechanism of of the promoting effect of the CCl4-treatment applied following the DEN administration.

Animals↗
PubMed1988

Hyperbaric oxygenation for experimental bladder tumor. II. Hyperbaric oxygenation in combination with chemotherapy in N-butyl-N-(4-hydroxybutyl)nitrosamine-induced bladder tumors.

Two series of experiments were conducted to ascertain whether hyperbaric oxygenation (HBO) treatment with or without antineoplastic chemotherapy can really suppress tumor development in N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced bladder tumor in rats. HBO treatment of 2 ATA of air saturating with 30-35% of oxygen for 90 min daily plus 0.5 mg/100 g body weight of 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) administration for 5 times suppressed the neoplastic spread of the bladder for 9 weeks and reduced the bladder weight in BBN-treated rats. Similar effects were also obtained in ACNU-treated rats, but to a lesser extent. HBO treatment associated with or without doxorubicin failed to suppress tumor growth in BBN-treated animals. Based on these findings combined with the previous study (part I), HBO treatment associated with ACNU might be available for the treatment of some cases of bladder tumors.

Animals↗
PubMed1988

Nonspecific esterase reaction in hyperplastic urinary bladder epithelium induced by administration of N-butyl-N-(4-hydroxybutyl)nitrosamine, freezing and formalin instillation in rats.

Chronological changes in nonspecific esterase (NSE) activity in hyperplasia of the bladder mucosa in Wistar rats induced by the administration of 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for up to 20 weeks and in reversible regenerative hyperplasia by freeze ulceration and 20% formalin instillation in the bladder were compared. In regenerative hyperplasia foci with strong NSE activity could not be proved throughout the experimental period, while the foci were detected in hyperplastic epithelium induced by BBN treatment for more than 3 weeks. The focus of NSE high activity persisted for 56 weeks after withdrawal of the carcinogen and the focus or area with the same NSE reaction appeared in papilloma and transitional cell carcinoma seen in weeks 7 to 20 of BBN treatment. The appearance of focal strong activity of NSE seemed to be a promising marker for the precursor lesions of bladder tumors. Short uniform, pleomorphic microvilli were observed on the cell surface of preneoplastic and carcinomatous lesions by BBN as well as on that of regenerative hyperplasia after freeze ulceration and formalin instillation.

Animals↗
PubMed1987

Long-term persistence of nitrosamine-induced structural damage to heterochromatic DNA.

Different levels of damage and repair to eu- and heterochromatic DNA from the livers of rats receiving a dose of 10 mg/kg N-nitrosodimethylamine (NDMA) were apparent. Preincorporated 3H-thymidine was lost rapidly from euchromatic DNA but persisted in the heterochromatic fraction. Persistent damage, determined as single-stranded regions binding to benzoylated DEAE-cellulose (BD-cellulose), was evident in heterochromatic DNA for up to three months. By subjecting rats treated with NDMA to partial hepatectomy, generation of single-stranded regions in the newly synthesized heterochromatic DNA could be demonstrated. Such structural defects were evident when hepatectomy was performed two months after administration of the carcinogen. These findings indicate that structural damage to nontranscribed DNA is one of the most persistent molecular lesions following exposure to nitrosamines.

Animals↗
PubMed1986

[Characteristics of the carcinogenic action of methyl(acetoxymethyl)nitrosamine and DNA repair in rats of different ages].

A pattern of DNA methylation and carcinogenesis has been studied in young (3 month-old) and old (14 month-old) female rats following a single intravenous injection (13 mg/kg) of methyl(acetoxymethyl)nitrosamine (DMN-OAc). The incidence of various tumours as well as the incidence of tumours in some peculiar sites were found to be similar in young and old DMN-OAc-treated rats. The life time of old rats was less than that in young animals; the average period of tumour detection was also shorter in old rats. In both young and old animals the highest concentrations of methylated purines were found in lung and kidney DNA. However, the level of DNA methylation in old rats was higher than in corresponding tissues of young animals. Efficiency of O6-meG repair in methylated template DNA was found to be the highest in liver extracts of 1- and 12-month-old rats. Further, by the age of 2 years, the activity of O6-meGT decreased. The findings suggest that different age periods could be characterized by different efficiency of DNA alkylation, synthesis and repair.

Aging↗
PubMed1985

[Effect of UFT on urinary bladder tumors in rats induced by N-butyl-N-(4-hydroxybutyl)nitrosamine].

The effect of combined tegafur and uracil (UFT) on the development of rat urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) was studied. Two hundred F344 male rats were divided into 10 groups. Groups 1 to 5 were given 0.05% BBN in drinking water for the initial 8 weeks of the experiment, and Groups 6 to 10 were the controls of the prior 5 groups treated with BBN. UFT in commercial diet was administered at daily doses of 100mg (30.9 mg as FT-207) per kg of body weight in Groups 2 and 4 and 200 mg (61.7 mg as FT-207) per kg of body weight in Groups 3 and 5. Groups 2 and 3 received UFT throughout the period of the experiment, and Groups 4 and 5 for 12 weeks after 8 week treatment with BBN. All animals were sacrificed at 20 weeks, and studied histopathologically. In Groups 1 to 5, urinary bladder tumors developed in 20 of 20, 13 of 20, 6 of 20, 14 of 20 and 6 of 20, respectively. Incidences of tumors in the 4 groups treated with UFT were significantly lower than that in Group 1 treated with BBN alone. This result shows that UFT inhibits the development of urinary bladder tumors in rats induced by BBN.

Animals↗
PubMed1985

Dose-dependent promoting effect of trisodium nitrilotriacetate monohydrate on urinary bladder carcinogenesis in Wistar rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The dose-dependent effect of trisodium nitrilotriacetate monohydrate (Na3.NTA.H2O) as a promoter in 2-stage carcinogenesis in the urinary bladder of male Wistar rats was investigated. Carcinogenesis was initiated by administration of 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in the drinking water for 4 weeks, then Na3.NTA.H2O was given at 1%, 0.5% and 0.3% in the diet for 28 weeks, and rats were killed in week 32. The incidences and numbers of preneoplastic lesions [papillary or nodular hyperplasia (PN hyperplasia)] in rats treated with 0.3% to 1% Na3.NTA.H2O increased progressively with increasing concentration of Na3.NTA.H2O. The incidences of papillomas in rats treated with 1% and 0.5% Na3.NTA.H20 in the diet and the incidence of transitional cell carcinoma (TCC) of the urinary bladder in the rats treated with 1% Na3.NTA.H2O (P less than 0.05) were significantly higher than those in rats treated with BBN only. Administration of various doses of Na3.NTA.H2O without BBN did not cause any histological changes (PN hyperplasia, papilloma or TCC) in the urinary bladder. These findings showed that Na3.NTA.H2O is a potent promoter of urinary bladder carcinogenesis initiated by BBN in rats, and that its effect is dose-dependent.

Acetates↗
PubMed1985

Short-term screening of promoters of bladder carcinogenesis in N-butyl-N-(4-hydroxybutyl)nitrosamine-initiated, unilaterally ureter-ligated rats.

The modifying effects of 17 environmental chemicals on the development of lesions in the urinary bladder of rats with unilateral ureteric ligation were investigated. Lesions were initiated by treatment of the animals with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 2 weeks, and then test chemicals were given for 22 weeks. The lesions of the urinary bladder found were preneoplastic papillary or nodular hyperplasias (PN hyperplasias) and papillomas. Additions of sodium saccharin (5%), sodium o-phenylphenate (2%), butylated hydroxyanisole (2%), and sodium L-ascorbate (5%) to the diet had significant promoting effects on the incidences and numbers of PN hyperplasias and papillomas per 10 cm of basement membrane of the urinary bladder in this system. Sodium erythorbate (5%), ethoxyquin (0.8%) and carbazole (0.6%) significantly increased the incidence of PN hyperplasias. N-Nitrosopyrrolidine (0.02%) did not affect the incidence or number of PN hyperplasias but increased those of papillomas. Sodium o-phenylphenate also induced PN hyperplasias in rats without BBN-initiation. Ascorbic acid, ascorbic stearate, three dihydroxyphenols, methylhydroquinone, pyrogallol, quinoline, and uric acid did not show promoting activity in this test system. Thus, 8 of 17 chemicals tested had various promoting effects on urinary bladder carcinogenesis. These results show that this test system of BBN-initiated, unilaterally ureter-ligated rats should be useful for the detection of new bladder carcinogens and promoters.

Animals↗