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PubMed2006

Combined genotoxic effects of radiation and a tobacco-specific nitrosamine in the lung of gpt delta transgenic mice.

It is important to evaluate the health effects of low-dose-rate or low-dose radiation in combination with chemicals as humans are exposed to a variety of chemical agents. Here, we examined combined genotoxic effects of low-dose-rate radiation and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the most carcinogenic tobacco-specific nitrosamine, in the lung of gpt delta transgenic mice. In this mouse model, base substitutions and deletions can be separately analyzed by gpt and Spi- selections, respectively. Female gpt delta mice were either treated with gamma-irradiation alone at a dose rate of 0.5, 1.0 or 1.5 mGy/h for 22 h/day for 31 days or combined with NNK treatments at a dose of 2 mg/mouse/day, i.p. for four consecutive days in the middle course of irradiation. In the gpt selection, the NNK treatments enhanced the mutation frequencies (MFs) significantly, but no obvious combined effects of gamma-irradiation were observable at any given radiation dose. In contrast, NNK treatments appeared to suppress the Spi- large deletions. In the Spi- selection, the MFs of deletions more than 1 kb in size increased in a dose-dependent manner. When NNK treatments were combined, the dose-response curve became bell-shaped where the MF at the highest radiation dose decreased substantially. These results suggest that NNK treatments may elicit an adaptive response that eliminates cells bearing radiation-induced double-strand breaks in DNA. Possible mechanisms underlying the combined genotoxicity of radiation and NNK are discussed, and the importance of evaluation of combined genotoxicity of more than one agent is emphasized.

Animals↗

PubMed2005

Acute and subacute effects of tobacco alkaloids, tobacco-specific nitrosamines and phenethyl isothiocyanate on N'-nitrosonornicotine metabolism in rats.

N'-Nitrosonornicotine (NNN) was the first tobacco-specific nitrosamine (TSNA) identified as carcinogen in tobacco smoke, but no data exist on in vivo interactions between NNN and other tobacco alkaloids, TSNA or phenethyl isothiocyanate (PEITC) which have been demonstrated in various studies on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Acute effects on NNN metabolism were tested in male Fischer F344 rats injected s.c. with 30nmol/kg body weight (bw) [5-(3)H]NNN either alone or simultaneously with 15mumol/kg bw nicotine, nornicotine, anatabine, or anabasine, 150mumol/kg bw cotinine, 3mumol/kg bw myosmine, or 300nmol/kg bw of either N'-nitrosoanatabine or N'-nitrosoanabasine. Another group of rats was fed a diet supplemented with PEITC at 1mumol/g diet starting 24h before NNN treatment. Within 24h more than 80% and about 10% of the radioactivity was excreted with urine and feces, respectively. Urinary metabolites were separated by reversed-phase radio-HPLC and identified by co-chromatography with UV standards. In two sets of experiments with control rats treated with NNN only, 4-hydroxy-4-(3-pyridyl)butanoic acid (hydroxy acid, 44.4/44.8%), 4-oxo-4-(3-pyridyl)butanoic acid (keto acid, 32.4/31.5%), NNN-N-oxide (5.0/3.8%), 4-(3-pyridyl)butane-1,4-diol (diol, 1.1/1.0%) and norcotinine (2.3/1.0%) were consistently detected besides unmetabolised NNN (4.7/3.3%). Co-treatment with nicotine, cotinine, nornicotine and PEITC shifted the contribution of the two major metabolites significantly in favor of hydroxy acid (108-113% of control) as compared to keto acid (86-90% of control). The same treatments also increased norcotinine (135-170% of control). These changes are consistent with a decreased metabolic activation of NNN. In subacute studies rats received NNN in drinking water for 4 weeks at a daily dose of 30 nmol/kg bw with or without nornicotine at 15 micromol/kg bw or myosmine at 3 micromol/kg bw. On the last day of the experiment all rats received [5-(3)H]NNN at 30 nmol/kg bw with a contaminated apple bite followed by collection of urine and feces for 18h. Most of the radioactivity, 87-96% of the dose, was recovered in urine and only minor amounts have been excreted in feces or persisted in blood. In urine of the NNN-control group keto acid (32.2%) and unmetabolised NNN (3.9%) were present in identical amounts as in the acute experiment whereas hydroxy acid (41.4% of total radioactivity in urine, 93% of acute NNN control) was reduced in expense of the minor NNN metabolites. Co-administration of nornicotine resulted in a small but significant rise of keto acid (107% of control) and a significant decrease in NNN-N-oxide (76% of control). After co-treatment with myosmine the increase of keto acid (104% of control) was even less but still significant whereas NNN-N-oxide and diol were significantly reduced to 72% and 79% of control, respectively. Our experiments with rats indicate significant mutual effects of some of the major tobacco alkaloids and most relevant TSNA. Further studies on the impact on smokers and the inhibitory effects of isothiocyanates are needed for a final risk assessment.

Alkaloids↗

PubMed2005

Indomethacin induces small intestinal damage and inhibits amitrole-associated thyroid carcinogenesis in rats initiated with N-bis(2-hydroxypropyl)nitrosamine.

Effects of intestinal damage on thyroid carcinogenesis due to amitrole (AT) were examined in F344 male rats initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). In experiment 1, rats were provided with diet containing 0.03% AT for 20 weeks after a single subcutaneous injection of DHPN (2800 mg/kg body weight), and concomitantly received 0.01% indomethacin (IM) in the diet to cause small intestinal damage or 1% dextran sodium sulfate (DSS) in the drinking water for induction of colitis following a schedule of intermittent 1-week administration and 1-week withdrawal for a total of 10 times. Groups without AT- and/or IM or DSS treatment were also included. Histopathological examination revealed significant reduction in the incidence and multiplicity of follicular cell adenomas and adenocarcinomas in the group concomitantly treated with IM, but no change in the DSS group, as compared with the AT alone group. In experiment 2, rats were similarly fed diet containing AT for 3 weeks with concomitant IM or DSS treatment after a DHPN initiation, and serum thyroid stimulating hormone levels were found to be significantly elevated only in the IM case. The increase in thyroid follicular cell proliferation due to AT was also clearly suppressed in the group concomitantly treated with IM. From these findings, IM-induced intestinal damage may inhibit thyroid carcinogeneisis in rats, although contributions of other factors, such as a direct inhibitory effect of IM to thyroid follicular cell proliferation cannot be ruled out.

Amitrole↗

PubMed2001

The effect of a 2-h exposure to cigarette smoke on the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice.

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, induces lung adenomas in A/J mice following a single intraperitoneal (i.p.) injection. However, inhalation of mainstream cigarette smoke does not induce or promote NNK-induced lung tumors in this mouse strain purported to be sensitive to chemically-induced lung tumorigenesis. The critical events for NNK-induced lung tumorigenesis in A/J mice is thought to involve O(6)-methylguanine (O(6)MeG) adduct formation, GC-->AT transitional mispairing, and activation of the K-ras proto-oncogene. The objective of this study was to test the hypothesis that a smoke-induced shift in NNK metabolism led to the observed decrease in O(6)MeG adducts in the lung and liver of A/J mice co-administered NNK with a concomitant 2-h exposure to cigarette smoke as observed in previous studies. Following 2 h nose-only exposure to mainstream cigarette smoke (600 mg total suspended particulates/m(3) of air), mice (n=12) were administered 7.5 micromol NNK (10 microCi [5-3H]NNK) by i.p. injection. A control group of 12 mice was sham-exposed to HEPA-filtered air for 2 h prior to i.p. administration of 7.5 micromol NNK (10 microCi [5-3H]NNK). Exposure to mainstream cigarette smoke had no effect on total excretion of NNK metabolites in 24 h urine; however, the metabolite pattern was significantly changed. Mice exposed to mainstream cigarette smoke excreted 25% more 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) than control mice, a statistically significant increase (P<0.0001). Cigarette smoke exposure significantly reduced alpha-hydroxylation of NNK to potential methylating species; this is based on the 15% reduction in excretion of the 4-(3-pyridyl)-4-hydroxybutanoic acid and 42% reduction in excretion of 4-(3-pyridyl)-4-oxobutanoic acid versus control. Detoxication of NNK and NNAL by pyridine-N-oxidation, and glucuronidation of NNAL were not significantly different in the two groups of mice. The observed reduction in alpha-hydroxylation of NNK to potential methylating species in mainstream cigarette smoke-exposed A/J mice provides further mechanistic support for earlier studies demonstrating that concurrent inhalation of mainstream cigarette smoke results in a significant reduction of NNK-induced O(6)MeG adduct formation in lung and liver of A/J mice compared to mice treated only with NNK.

Animals↗

PubMed1980

Carcinogenic effect of N-bis-(2-hydroxypropyl)nitrosamine in newborn rats.

The carcinogenic effect of N-bis(2-hydroxypropyl)nitrosamine (BHP) was studied in newborn Wistar rats. Tumors were induced in the lung (adenoma), pancreas (adenoma), kidney (nephroblastoma), and ovary (benign granulosa cell tumor) at 24 weeks after the treatment and in the lung (adenoma and adenocarcinoma), liver (hemangioma, hemangioendothelioma, and hepatocellular carcinoma), pancreas (adenoma), kidney (renal cell carcinoma and nephroblastoma), thyroid (adenocarcinoma) and ovary (benign and malignant granulosa cell tumors) at 52 weeks. The highest incidence of tumor was seen in the liver of rats applied BHP within 24 hours after birth. These results indicate that newborn Wistar rats are more susceptible to BHP than are adult rats.

Animals↗

PubMed1978

Direct gas chromatographic analysis of cyclic N-nitrosamines.

A rapid gas chromatographic technique has been developed for quantitative estimation of cyclic N-nitrosamines. Cumbersome clean-up procedures are unnecessary and quantitative estimation can be done by injecting hexane extract without further pretreatment. The detection limit for the procedures is ca. 0.5 ng.

Chromatography, Gas↗

PubMed1987

Effects of intravesical instillation of antitumor chemotherapeutic and immunotherapeutic agents on bladder lesion development in rats pretreated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The effects of 12 weeks of intravesical instillation of bleomycin, cisplatinum and picibanyl on development of urinary bladder tumors and preneoplastic lesions were examined in rats pretreated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) for four weeks. Upon sacrifice at week 36, histopathological examination revealed a significantly reduced incidence of PN hyperplasia and a tendency for decreased papilloma generation in rats given cisplatinum. However, the other treatments were not associated with any effect on carcinogen-induced lesion development. The results demonstrate that cisplatinum has a potential for postinitiation inhibition of rat bladder carcinogenesis.

Administration, Intravesical↗

PubMed1987

Analyses of avidin-biotin complexes with lectins of membrane glycoproteins in the urinary bladder of rats treated with N-butyl-N-(4-hydroxybutyl)nitrosamine.

The bladder epithelium was examined by staining with avidin-biotin complexes with lectins to determine the early membrane changes during bladder carcinogenesis in rats treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BHBN). Concanavalia ensiformis (Con A), Triticum vulgaris (WGA), Ricinus communis (RCA) and Arachis hypogaea (PNA) were used as probes. The cellular distributions of lectin particles were distinguished into membranous and cytoplasmic patterns. Normal bladder cells stained very slightly and showed a spotty membranous pattern. After treatment of rats with BHBN for two or three weeks, staining became stronger and its pattern changed from a membranous to a cytoplasmic type. The staining of bladder cancer cells induced by BHBN varied from area to area and with different lectins. These data indicated that changes in carbohydrates occur in the bladder cell membrane during the early phase of carcinogenesis.

Animals↗

PubMed1981

Gastric juice N-nitrosamines in health and gastroduodenal disease.

The concentrations of total extractable N-nitroso compounds, pH, and nitrite levels were measured in fasting gastric juice, which was also cultured for bacteria, from 50 healthy volunteers and 217 patients with common upper gastrointestinal complaints. The concentrations of N-nitroso compounds and pH levels rose significantly with age. Sex and cigarette smoking had no significant effect. There was a positive correlation between pH and N-nitroso concentration, and between pH and an increase in the concentration of nitrites. A significant relation was demonstrated between raised N-nitroso and nitrite levels and growth of nitrate reductase-positive microorganisms. These results demonstrate for the first time in man the interrelations of N-nitrosamine concentration, pH, gastric juice nitrite, and nitrate-reducing bacteria. The findings are considered in relation to the risks of development of gastric cancer in man.

Adolescent↗

PubMed2002

Volatile N-nitrosamine inhibition after intake Korean green tea and Maesil (Prunus mume SIEB. et ZACC.) extracts with an amine-rich diet in subjects ingesting nitrate.

The formation of carcinogenic nitrosamines under simulated gastric conditions was studied during the incubation of amine rich food and nitrate, and its possible inhibition by adding kumquat, sweet orange, strawberry, garlic, kale juices, Maesil (Prunus mume) and green tea extracts. The strawberry, kale juices, Maesil and green tea extracts were equally effective in reducing the formation of N-nitrosodimethylamine (NDMA). The fruits of P. mume SIEB. et ZACC. (Korean name, Maesil) have been used as a traditional drug and health food in Korea. During four weeks of test (designated EW1, EW2, EW3 and EW4; experiment week 1, 2, 3 and 4 diets) volunteers consumed a diet of low nitrate and amine (EW1) and consumed a fish meal rich in amines as nitrosatable precursors in combination with intake of nitrate-containing drinking water without (EW2) or with Maesil and green tea extracts (EW3 and EW4, respectively). The intake of nitrate-containing drinking water (340 mg nitrate/100 ml) resulted in a significant rise in mean salivary nitrate and nitrite concentrations and in mean urinary nitrate levels. Mean urinary nitrate was increased to 455.0+/-66.2, 334.6+/-67.8 and 333.4+/-50.7 mg/18 h after the nitrate intake of EW2, EW3 and EW4, respectively. Significant increases in urinary dimethylamine and trimethylamine levels were observed in consumption of diets (EW2, EW3, and EW4) rich in amine and nitrate. Maesil and green tea extract in EW3 and EW4 enhanced the increase of urinary dimethylamine and trimethylamine levels. Urinary excretion of N-nitrosodimethylamine in consumption of diet rich in nitrate and amine (EW2) increased to 6504.4+/-2638.7 ng/18 h from 257.0+/-112.0 ng/18 h of low nitrate and amine diet (EW1). Korean green tea and Maesil extracts in nitrate and amine rich diet reduced the excretion of N-nitrosodimethylamine to 249.7+/-90.6 and 752.7+/-595.3 ng/18 h, respectively, compared with 6504.4+/-2638.7 ng /18 h after ingestion of TD1 diet.

Adult↗

PubMed2003

Lack of modifying effects of atrazine and/or tamoxifen on thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine (DHPN).

The modifying effects of atrazine, and/or tamoxifen, on thyroid carcinogenesis were investigated in a rat two-stage carcinogenesis model following N-bis(2-hydroxypropyl)nitrosamine (DHPN) initiation. Five-week-old male F344 rats were given a single subcutaneous injection of DHPN (2800 mg/kg, body weight) or vehicle alone. Starting 1 week later, the animals were fed a diet supplemented with 0, 5, 50 or 500 ppm of atrazine, 500 ppm atrazine plus 5 ppm tamoxifen, or 5 ppm tamoxifen in the DHPN-treated groups, and 0 or 500 ppm of atrazine in the DHPN-untreated groups for 24 weeks. At autopsy major organs, including the thyroid, pituitary, liver, kidney, testis, epididymis, and brain, were collected and histopathologically examined. Body weights were significantly (P<0.05) decreased by the high doses of atrazine or tamoxifen, the effect being enhanced in combination. Relative thyroid weights were significantly increased (P<0.05) only in the tamoxifen-treated group and pituitary weights were elevated with 500 ppm atrazine plus tamoxifen (P<0.05). Relative liver weights were increased by the high dose of atrazine. However, the atrazine and/or tamoxifen treatments did not induce significant histopathological changes in the major organs, including the thyroid, nor cause significant changes in serum TSH levels. These results suggest that neither atrazine nor tamoxifen may promote thyroid carcinogenesis, alone as well as in combination.

Animals↗

PubMed1999

Carbonyl reduction of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in cytosol of mouse liver and lung.

The tobacco specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a strong lung carcinogen in all species tested. To elicit its tumorigenic effects, NNK requires metabolic activation which is supposed to occur via alpha-hydroxylation by cytochrome P450 enzymes. Carbonyl reduction to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) followed by glucuronosylation is considered to be the main detoxification pathway in humans. Therefore, NNK carbonyl reducing activity is crucial for NNK inactivation since it initiates the final excretion of this lung carcinogen. Until the present work, studies on NNK metabolism have focused exclusively on microsomal fractions, and several cytochrome P450 enzymes have been shown to be involved in alpha-hydroxylation of NNK. In addition, 11beta-hydroxysteroid dehydrogenase type 1(11beta-HSD1) which is located in the endoplasmic reticulum of the cell has been identified to catalyze the carbonyl reduction of NNK in microsomes. In this study, we provide evidence that carbonyl reduction of NNK does also take place in the cytosolic fraction of mouse liver and lung, and that cytosolic carbonyl reductase contributes to the detoxification of NNK. At a fixed substrate concentration of 1 mM NNK, the specific activity of cytosolic NNAL formation amounts to 72% (liver) and 28% (lung) compared with that in the respective microsomal fractions. Although considerable NNK carbonyl reduction occurred with NADH, the preferred cosubstrate in cytosol is either NADPH or an NADPH-regenerating system. Due to the inhibitor sensitivity to menadione, ethacrynic acid, dicoumarol and quercitrin, it is concluded that carbonyl reductase (EC 1.1.1.184) is mainly responsible for NNAL formation in liver and lung cytosol. The expression of cytosolic carbonyl reductase and microsomal 11beta-HSD1 was established on the mRNA level by reverse transcription-PCR in both liver and lung. Enzyme kinetic studies revealed a nonsaturable Michaelis-Menten kinetic of NNK carbonyl reduction in cytosol. Possibly some other cytosolic NNK carbonyl reducing enzymes are also involved in NNAL formation. In conclusion, this is the first report to show that carbonyl reduction of NNK does occur in cytosol. Further studies with purified enzyme preparations are needed to explore the detailed contribution of the cytosolic enzymes participating in the final elimination of this lung carcinogen.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2000

The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK.

DNA repair plays a critical role in protecting the genome of the cell from the insults of cancer-causing agents such as those found in tobacco smoke. Reduced DNA repair capacity would, therefore, constitute a significant risk factor for smoking-related cancers. Recently, a number of polymorphisms in several DNA repair genes have been discovered, and it is possible that these polymorphisms may affect DNA repair capacity and thus modulate cancer susceptibility in exposed populations. In the current study, we explored the relationship between two polymorphisms in the DNA repair gene XRCC1 (polymorphisms in codons 194 and 399) and the genotoxic response induced by the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). The sister chromatid exchange (SCE) assay was used as a marker of genetic damage. Our results, using whole blood cultures from 47 volunteers, indicated that treatment of cells with 0.24, 0.72 and 1.44 mM of NNK induced a concentration-dependent increase in the mean number of SCE (P<0.001). There was a significant difference (P<0.05) in response to NNK treatment between cells from individuals with the 399Gln allele (either homozygous or heterozygous) and cells from individuals with the homozygous 399 Arg/Arg genotype. Treatment of cells that have the 399Gln allele with 0.24, 0.72 and 1.44 mM NNK resulted in 22.8, 35.8 and 52.8% increases in NNK-induced SCE, respectively. Treatment of cells with the 399 Arg/Arg genotype using the same NNK concentrations resulted in 16.0, 15.5 and 32.6% increases in NNK-induced SCE, respectively. In contrast, no significant difference in NNK-induced SCE was observed between cells with the codon 194 Arg/Arg genotype and cells with the codon 194 Arg/Trp genotype at all concentrations of NNK tested. These data suggest that the Arg399Gln amino acid change may alter the phenotype of the XRCC1 protein, resulting in deficient DNA repair. Our study underscores the important role of polymorphisms in DNA repair genes in influencing the genotoxic responses to environmental mutagens, and justifies additional studies to investigate their potential role in susceptibility to cancer.

Adult↗

PubMed2002

Lack of promoting effect due to oral administration of dimethylarsinic acid on rat lung carcinogenesis initiated with N-bis(2-hydroxypropyl)nitrosamine.

Dimethylarsinic acid (DMA), a major metabolite of inorganic arsenics, and arsenic exposure is associated with tumor development in a wide variety of human tissues. In the present study, we examined whether DMA has tumor-promoting activity on rat lung carcinogenesis initiated with N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male, 8-week-old, F344 rats were treated with DHPN at a concentration of 0.1% in drinking water for 1 week, and starting 1 week thereafter, DMA was administered at concentrations of 0, 100, 200 or 400 ppm in the drinking water for 30 weeks. Induction of epithelial lesions, classified as alveolar epithelial hyperplasia, adenoma, and adenocarcinoma was evident in the lungs of DHPN-initiated animals, but no significant differences were found between DMA-treated groups and control groups. Furthermore, no significant differences in 5-bromo-2'-deoxyuridine labeling indices, as a marker of cell proliferation were observed among the groups. An additional group treated with DMA at concentrations of 200 ppm alone, without prior DHPN initiation was found to develop no epithelial lesions in the lung. There was no significant gain in 8-hydroxydeoxyguanosine formation, as a marker of oxidative stress, in the lungs of rats treated with DMA in their drinking water. In conclusion, oral-administered DMA does not exert promoting effects on rat lung carcinogenesis initiated with DHPN.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2003

Prolonged effects of beta-estradiol 3-benzoate on thyroid tumorigenesis in gonadectomized rats pretreated with N-bis(2-hydroxypropyl)nitrosamine.

The prolonged modulatory effects of beta-estradiol 3-benzoate (EB), a synthetic estrogenic compound, were investigated in a rat two-stage thyroid tumorigenesis model. One week after a single subcutaneous (s.c.) injection of N-bis(2-hydroxypropyl)nitrosamine, gonadectomized F344 rats of both sexes were s.c. implanted with fused pellets containing EB for 32 weeks. Doses of EB at 0, 0.004, 0.02 and 0.1mg were achieved by varying the ratio of EB to cholesterol in the pellet. Major organs including the thyroid, pituitary, liver, kidneys, uterus and brain were weighed and histopathological observation was performed. Serum was assayed for triiodothyronine (T(3)), thyroxine (T(4)) and thyroid-stimulating hormone (TSH). Thyroid weights were increased by the EB pellet implantation in a dose-dependent manner and significantly (P<0.05) elevated in the 0.1mg EB male group and in the 0.02 and 0.1mg EB female groups. The EB treatments dose-dependently suppressed serum T(4) levels and inversely elevated serum TSH levels in both sexes but without statistical significance in females. Histopathologically, EB increased the occurrence of thyroid proliferative lesions in males and showed a tendency for increase in females. Interestingly, the effect of EB was more intensive in males than in females, even the lowest dose inducing a follicular carcinoma in a male. These results, thus indicate the possible contribution of prolonged EB stimulation at lower doses to thyroid tumorigenesis without additional promotive condition.

Animals↗

PubMed1976

Investigations on esophageal carcinogenicity by methyl-phenyl-nitrosamine and ethyl alcohol in rats.

Methyl-phenyl-nitrosamine was administered subcutaneously or orally to Sprague-Dawley rats. Carcinomas of the esophagus were found in 46-87% of the animals. The induction period of tumors was 170-290 days. Simultaneous application of 25% ethyl alcohol given instead of drinking water did not alter tumor incidences and induction periods. Hepatotoxic effects of ethyl alcohol were not observed. Mean life expectancies of animals were not reduced.

Animals↗

PubMed1978

Liver ornithine decarboxylase during phenobarbital promotion of nitrosamine carcinogenesis.

The incidence of liver tumors induced in rats by N-diethylnitrosamine was increased by the feeding of phenobarbital. Liver ornithine decarboxylase activity did not increase in animals receiving phenobarbital in the diet, and the concentration of polyamines in the liver was similarly unchanged. No relationship between the promotion of N-nitrosamine-induced liver tumors by phenobarbital and the ornithine decarboxylase activity of the liver was indicated by these experiments.

Animals↗

PubMed1978

Heterotransplantation into nude mice of pancreatic carcinoma induced by N-bis(2-hydroxypropyl)nitrosamine in hamsters.

Heterotransplantation into nude mice by the subcutaneous (s.c.) and intraperitoneal (i.p.) routes of hamster pancreatic ductal cell carcinomas induced by N-bis(2-hydroxypropyl)nitrosamine (DHPN) was studied. By s.c. transplantation, tumors occurred in 1 of 4 mice at the first trial, and the tumor incidence was 100% for shorter periods by serial transfer. By i.p. transplantation, the malignant potential of hamster pancreatic ductal cell carcinoma was expressed as intra-abdominal invasive tumors with bloody ascites (carcinomatous peritonitis). Tumors in nude mice basically retained the histology of the original hamster pancreatic ductal cell carcinoma.

Animals↗