Biomedical subjects

E Zang

Publications and source records attributed to E Zang.

At least 19 recordsLinked to original sources

PubMed1996

Tea polyphenols as inhibitors of mutagenicity of major classes of carcinogens.

Previous research suggested that the mutagenicity of some genotoxic carcinogens, mainly heterocyclic amines, was decreased by green or black tea extracts, or tea polyphenol fractions. Thus, it seemed important to test a variety of genotoxic carcinogens with distinct chemical structures and means of biochemical activation as regards modification of mutagenicity in appropriate strains of Salmonella typhimurium by 3 concentrations of polyphenols 60, 100, or B, standard commercial polyphenol preparations from green or black tea. Polyphenols sharply decreased the mutagenicity of a number of aryl- and heterocyclic amines, of aflatoxin B1, benzo[a]pyrene, 1,2-dibromoethane, and more selectively, of 2-nitropropane, all involving an induced rat liver S9 fraction. Good inhibition was found with 2 nitrosamines that required a hamster S9 fraction for biochemical activation. No effect was found with 1-nitropyrene, and with the direct-acting (no S9) 2-chloro-4-methyl-thiobutanoic acid. Thus, with some exceptions, polyphenols considerably decreased the mutagenicity of diverse types of carcinogens.

Amines↗

PubMed1996

Inhibition of 2-Amino-1-methyl-6-phenylimidazo[4,5]pyridine-induced lymphoma formation by oltipraz.

2-Amino-l-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a mutagenic and carcinogenic heterocyclic amine present in pyrolysate products of meat and fish and has been shown to induce tumors in the colon, mammary gland, and possibly lymphatic system. Experiments were designed to examine the lymphoma-inducing capacity of PhIP and to test the inhibitory effects of oltipraz on PhIP-induced lymphomas in male F344 rats. Beginning at 5 weeks of age, groups of rats were fed the diets containing 0, 200, and 400 ppm oltipraz with or without 100-400 ppm PhIP. All animals were continued on this regimen until the 58th week. The results indicate that administration of PhIP produced lymphomas in 75% of rats. Most of the large lymphomas were thymomas (65%), and these lymphomas developed in less than 6 months. Death of animals during the course of the study was due to suffocation produced by a large lymphoma that filled the entire thoracic cavity, resulting in collapse of the lungs. Administration of 200-400 ppm oltipraz significantly protected rats from PhIP-induced toxicity; most of the rats survived until termination of the experiments. It is noteworthy that the addition of oltipraz at 200 and 400 ppm in the diet suppressed the PhIP-induced lymphomas to 90-100%. In conclusion, PhIP-induced lymphomas in the laboratory rat appears to be a very useful model to analyze the genesis of lymphomas, and oltipraz serves as a potential chemopreventive agent for lymphomas.

Animals↗

PubMed1996

Chemopreventive efficacy of arylalkyl isothiocyanates and N-acetylcysteine for lung tumorigenesis in Fischer rats.

The purpose of this study is to evaluate the efficacy of three promising sulfur-containing compounds, 6-phenylhexyl isothiocyanate (PHITC), phenethyl isothiocyanate (PEITC), and N-acetylcysteine (NAC), as chemopreventive agents in a long-term bioassay for lung tumorigenesis in F344 rats. PEITC occurs as a constituent of certain cruciferous vegetables, PHITC is a synthetic homologue, and NAC is an endogenous substance. Male F344 rats were treated with the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) by s.c. injection at a dose of 1.5 mg/kg body weight three times weekly for 20 weeks. This dose regimen induced a 67% tumor incidence in the lung, a major target organ of NNK. PHITC or PEITC administered in the diet for 22 weeks, a period covering from 1 week before to 1 week after the NNK treatment, exhibited significant inhibition of lung tumorigenesis induced by NNK. The lung tumor incidences in the NNK-treated groups, fed a diet containing 4 mmol/kg (876 ppm) or 2 mmol/kg (438 ppm) PHITC, were 24 and 19% and were 9 and 17% in groups fed PEITC at concentrations of 8 mmol/kg (1304 ppm) or 4 mmol/kg (652 ppm), respectively. In contrast to isothiocyanates, NAC given in the diet at 80 mmol/kg (13056 ppm) or 40 mmol/kg (6528 ppm) exerted no inhibitory effects on the NNK-induced lung tumorigenesis. At the dose studied, NNK did not induce liver and pancreatic tumors in the treated animals, but a significant increase of nasal cavity tumor incidence was observed in the NNK-treated group. However, none of the test compounds showed any effect on the tumorigenesis in this tissue. This study demonstrated that PHITC and PEITC were potent chemopreventive agents for the NNK-induced lung tumorigenesis in F344 rats, whereas NAC was not active at all. These results support further evaluation of these compounds in chemoprevention studies.

Acetylcysteine↗

PubMed1996

Dose-response effects of dietary fiber on NMU-induced mammary tumorigenesis, estrogen levels and estrogen excretion in female rats.

The dose-related effects of the fiber-rich isolate, soft white wheat bran (SWWB), and the pure fiber, cellulose, on N-nitrosomethylurea (NMU)-induced mammary tumorigenesis was assessed in F344 female rats. SWWB (45% total dietary fiber, TDF) was added to the AIN-76A high-fat diet at 9, 12, 15 and 18%; cellulose (98% TDF) was added to the same diet at 4.5, 6, 7.5 and 9%, to give equivalent amounts of TDF. The experimental diets were fed 3 days post-NMU and continued for a period of 25 weeks, at which time the experiment was terminated and tumors enumerated. It was found that significant inhibition of mammary carcinoma occurred only at 9% SWWB, non-significant inhibition occurred at 12% SWWB, and no inhibition was seen at higher doses. Cellulose-fed animals exhibited consistently higher tumor yields regardless of dose. The difference in tumor yields between the 9% SWWB group and the remaining seven groups was attributable to an increased incidence in tumors characterized histologically as intraductal proliferation and ductal carcinoma in situ in the latter. Analysis of blood, urine and fecal estrogens was conducted to test whether dietary fiber exerted its tumor-inhibiting effect by altering the enterohepatic recycling of estrogens. Although SWWB, in general, lowered urinary estrogen excretion, increased fecal estrogen excretion and lowered blood estrogens, there was no consistent correlation between the amount of SWWB consumed, estrogen status and tumor yields. These results suggest that (i) wheat bran fiber at 9%, or minor constituents associated with it, contain anti-promoting properties that cellulose lacks; (ii) SWWB appears to exert its effects by suppressing the clonal expansion phase of mammary carcinogenesis; (iii) there is an upper limit (12-15% w/w) to the protective effects of SWWB; and (iv) the effects of SWWB on mammary tumorigenesis may not be attributed to alterations in the enterohepatic recycling of estrogens.

Animals↗

PubMed1995

Five leading U.S. commercial brands of moist snuff in 1994: assessment of carcinogenic N-nitrosamines.

BACKGROUND: Moist snuff is the only tobacco product in the United States with increasing sales (an increase of 38.4% between 1981 and 1993) and with increased consumption, primarily by male adolescents aged 12-18 years old and young adults aged 19 years old or older. It is known from previous studies that levels of nicotine and the proportion of unprotonated (free) nicotine, as well as the pH, which affects nicotine delivery, vary considerably among the leading snuff brands. Whether concentrations of major carcinogens, such as the nicotine-derived tobacco-specific N-nitrosamines (TSNAs), like N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), also vary among these brands has not been determined previously. PURPOSE: Our purpose was threefold: 1) to determine the concentrations of major carcinogenic nicotine-derived N-nitrosamines in each of the five most popular moist snuff brands; 2) to analyze the quantitative differences in the various snuff components (e.g., NNN) between two major brand categories: a category comprising the brands known to have high levels of unprotonated nicotine (Copenhagen, Skoal fine cut, and Kodiak) versus a category comprising the brands known to have low levels (Hawken and Skoal Bandits); and 3) to compare the differences in the concentrations of nicotine (previously determined), NNN, NNK, and total TSNAs between these two major brand categories. METHODS: Three boxes of each of the five leading U.S. moist snuff brands were bought in July 1994 from retailers in six areas and transferred immediately to the analytical laboratory. After extraction, N-nitrosamino acids and TSNAs were determined on a gas chromatograph interfaced with a thermal energy analyzer (GC-TEA) and integrator. Each 5-g sample of ground, freeze-dried tobacco was extracted twice, and each extract was analyzed twice by GC-TEA. All P values reported are two sided. RESULTS: Copenhagen, Skoal fine cut, and Kodiak as a group had statistically significant higher levels of nicotine (P = .0017), NNN (P < .0001), NNK (P = .0119), and total TSNAs (P < .0001) than the Hawken and Skoal Bandits group. Concentrations (means +/- SD) of nicotine, NNN, NNK, and total TSNAs comparing the two major brand categories are as follows: nicotine--11.6 +/- 1.01 mg/g versus 6.96 +/- 3.62 mg/g (P = .0017), NNN--7.74 +/- 1.70 micrograms/g versus 4.17 +/- 1.35 micrograms/g (P < .0001), NNK--1.23 +/- 0.68 micrograms/g versus 0.61 +/- 0.41 micrograms/g (P = .0119), and total TSNAs--14.3 +/- 3.82 micrograms/g versus 6.3 +/- 2.56 micrograms/g (P < .0001). CONCLUSIONS: The three leading U.S. snuff brands (Copenhagen, Skoal fine cut, and Kodiak; making up 92% of the U.S. market) showed not only high levels of pH, nicotine, and unprotonated (free) nicotine, but also high concentrations of the strongly carcinogenic TSNAs in comparison with the fourth and fifth best selling moist snuff brands, Hawken and Skoal Bandits (3% of the U.S. market).

Carcinogens↗

PubMed1995

Enhancement of experimental colon carcinogenesis by dietary 6-phenylhexyl isothiocyanate.

Naturally occurring and related synthetic isothiocyanates are known to exert chemopreventive effects in several organs in rodent models. The present study was designed to investigate the efficacy of 6-phenylhexyl isothiocyanate (PHITC), a potent chemopreventive agent in the lung tumor model in strain A mice, on azoxymethane-induced colon tumorigenesis. Another aim was to study the modulating effect of PHITC on colonic mucosal and tumor phospholipase A2 (PLA2), phosphatidylinositol-specific phospholipase C (PI-PLC), lipoxygenase (LOX), and cyclooxygenase (COX) activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 320 or 640 ppm of PHITC representing 40 and 80% maximum tolerated dose levels, respectively. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. All animals continued on their respective dietary regimen for 52 weeks after the carcinogen treatment; then the study was terminated. Colonic mucosa and tumors were analyzed for PLA2, PI-PLC, prostaglandin (PG) E2, COX, and LOX activities. Intestinal tumors were evaluated histopathologically and classified as invasive or noninvasive adenocarcinomas. Intestinal tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal; tumors/tumor-bearing animal) were compared among the dietary groups. At the 640-ppm dose level, dietary PHITC significantly increased the incidence of intestinal (small intestine plus colon) adenocarcinomas (P < 0.05) as well as the multiplicities of invasive and noninvasive adenocarcinomas of the colon (P < 0.05 to 0.01). At the 320-ppm dose level, PHITC increased the multiplicity (tumors/animal) of noninvasive adenocarcinomas and total (invasive plus noninvasive) adenocarcinomas of the colon (P < 0.05). Dietary PHITC also increased the colon tumor volume (2- to 4.3-fold) in a dose-dependent manner. Moreover, PHITC significantly enhanced the activities of PLA2 (50-100%) and levels of PGE2 (2-fold) in the colonic mucosa and in tumors, but it had no significant effect (P > 0.05) on PI-PLC activity. The formation of COX metabolites, particularly PGE2, PGF2 alpha, PGD2, 6-keto PGF1 alpha, and thromboxane B2, as well as LOX metabolites such as 8(S)-, 12(S)- and 15 (S)-hydroxyeicosatetraenoic acids, were significantly increased in the colonic mucosa and tumors of animals that were fed 640 ppm of PHITC. Although the exact mechanism by which PHITC promotes colon tumorigenesis remains to be elucidated, it is likely that the tumor-promoting effects of PHITC may, at least in part, be related to increased eicosanoid metabolism in the colon.

Animals↗

PubMed1995

Chemoprevention of colon carcinogenesis by sulindac, a nonsteroidal anti-inflammatory agent.

Epidemiological and laboratory animal model studies have suggested that nonsteroidal anti-inflammatory drugs reduce the risk of development of colon cancer. The present study was designed to investigate the chemopreventive action of 160 and 320 ppm (equivalent to 40 and 80% maximum tolerated doses) sulindac, a nonsteroidal anti-inflammatory drug, fed during initiation and postinitiation stages and 320 ppm sulindac fed during promotion/progression stages of azoxymethane-induced colon carcinogenesis in male F344 rats. Also investigated was the modulating effect of this agent on the colonic mucosal and tumor phospholipase A2, phosphatidylinositol-specific phospholipase C, lipoxygenase, and cyclooxygenase activities. At 5 weeks of age, groups of male F344 rats were fed control diet or diets containing 160 and 320 ppm of sulindac. At 7 weeks of age, all animals except those in the vehicle-treated groups were given two weekly s.c. injections of azoxymethane at a dose rate of 15 mg/kg body weight/week. Animals intended for tumor promotion/progression study were administered 320 ppm of sulindac in diet starting at 14 weeks after a second azoxymethane treatment. All animals continued on their respective dietary regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Colonic tumors were evaluated histopathologically. Colonic mucosa and tumors were analyzed for phospholipase A2, phosphatidylinositol-specific phospholipase C, prostaglandin E2, cyclooxygenase, and lipoxygenase activities. The levels of sulindac and its metabolites in stomach, cecal, and fecal contents and in serum were analyzed. The results indicate that dietary sulindac at 160 and 320 ppm levels inhibited the incidence of invasive and noninvasive adenocarcinomas of the colon (P < 0.01-0.001) as well as their multiplicity (P < 0.01-0.0001) in a dose-dependent manner. Also, feeding sulindac during promotion/progression stages significantly suppressed the incidence (P < 0.0001) and multiplicity (P < 0.0001) of colonic adenocarcinomas. Dietary sulindac also suppressed the colon tumor volume by > 52-62% compared to the control diet. Dietary sulindac significantly decreased the activities of phosphatidylinositol-specific phospholipase C (32-51%) and levels of prostaglandin E2 (> 40%) in the colonic mucosa and tumors, but it had no significant (P > 0.05) effect on phospholipase A2 activity. The formation of cyclooxygenase metabolites, particularly prostaglandin E2, prostaglandin F2 alpha, prostaglandin D2, 6-ketoprostaglandin F1 alpha, and thromboxane B2, and lipoxygenase metabolites such as 8(S)- and 12(S)-hydroxyeicosatetraenoic acids were significantly reduced in colonic mucosa and tumors of animals fed 320 ppm sulindac.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenocarcinoma↗

PubMed1995

Sampling method as a key factor in identifying K-ras oncogene mutations in preneoplastic colorectal lesions.

The development of sensitive polymerase chain reaction (PCR)-based techniques in recent years has enabled us to verify the possible presence of mutated oncogenes and tumor suppressor genes in stages preceding tumor formation. Early detection of mutants serves as a powerful tool for detecting exposure to carcinogens and can assist in diagnosis. In studies performed in the past few years, we have identified mutant ras alleles in preneoplastic samples of patients with and without colorectal cancer. Our studies have shown (i) that mutant ras alleles are present at low incidence in normal appearing tissues of patients with colorectal cancer. Such mutations are also found in colonic effluents of patients at risk for developing this tumor type; and (ii) that the method of sampling is critical to ensure true representation of the entire colonic mucosa. The implications of identifying ras mutations in patients without evidence for neoplasma are discussed.

Biomarkers, Tumor↗

PubMed1994

Genotoxicity and carcinogenicity in rats and mice of 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7- one: an intestinal bacterial metabolite of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline.

BACKGROUND: Compounds formed on the surface of fried or grilled meat and fish may be associated with increased risk of colon cancer. Normal intestinal bacteria can convert one of these compounds, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), to the 7-hydroxy metabolite, 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7-o ne (7-OHIQ), a direct-acting mutagen. PURPOSE: We studied the genotoxicity and carcinogenicity of 7-OHIQ to determine if it is responsible for the colon-specific activity of IQ. METHODS: The effects of pure, synthetic 7-OHIQ on DNA were evaluated in the Ames Salmonella typhimurium TA98 test, with and without an induced rat liver S9 fraction, and in the Williams DNA repair test using freshly explanted rat hepatocytes. 7-OHIQ was also subjected to an in vivo bioassay for 21 months by long-term intrarectal infusion in male F344 rats, using IQ and N-nitrosomethylurea (NMU) given intrarectally as positive tumor-producing controls. The standard NIH-07 rodent diet was supplemented with 15% corn oil to maximize any effect of the infused materials on the colon. A parallel bioassay involved intraperitoneal injection of 7-OHIQ in newborn mice, followed by dietary administration from week 11 to week 67. Again, IQ and NMU were used as positive controls. RESULTS: We confirmed that 7-OHIQ is a direct-acting mutagen in the Ames test, with added S9 liver fraction giving higher mutagenicity. 7-OHIQ was negative in the Williams test, whereas IQ was positive. 7-OHIQ did not induce colon cancer in rats, and in the newborn mouse test it produced only a low incidence of liver neoplasms. CONCLUSIONS: 7-OHIQ is not genotoxic, for to be so classified it must be definitely positive in both the Ames and Williams tests; moreover, it is not carcinogenic, in marked contrast to IQ and NMU.

Animals↗

PubMed1994

Dose response of promotion by butylated hydroxyanisole in chemically initiated tumours of the rat forestomach.

The antioxidant food preservative butylated hydroxyanisole (BHA) was tested in an initiation-promotion protocol in which male F344 rats (6 wk old), 27 per group, were gavaged with a single dose of 200 mg N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)/kg. After 3 wk on control diet, test diets containing 0, 60, 300, 1000, 3000, 6000 or 12,000 ppm BHA were fed until termination of the experiment at approximately 110 wk, at which time most animals had died with stomach tumours. MNNG caused a high incidence of tumours in the glandular stomach and forestomach of all groups. Administration of 12,000 and 6000 ppm BHA, but not 3000 ppm or lower doses, caused statistically significant increases in the time-related incidence of MNNG-induced forestomach tumours as analyzed by life table analysis. BHA had no effect on the incidence of tumours in the glandular stomach or oesophagus. Tumour incidences in other organs were not related to BHA dose. No increase in hyperplasia in the oesophagus was evident in the high-dose BHA-treated animals compared with the MNNG-only group. This study provides corroboration that BHA affects only forestomach tumorigenesis and that the dose for enhancement of tumorigenesis is at least 1500-fold greater than human exposure.

Animals↗

PubMed1994

Interactions between 4-HPR and diet in NMU-induced mammary tumorigenesis.

The present study was designed to determine whether the chemopreventive effect of the synthetic retinoid N(4-hydroxyphenyl)retinamide (4-HPR) on mammary tumorigenesis was influenced by diet. Three diets were used: the closed-formula grain-based Wayne Lab Blox, the open-formula grain-based NIH-07, and the casein-based semipurified AIN-76A. Groups of 25 virgin female F-344 rats were fed the experimental diets beginning one week before a single injection of N-methyl-N-nitrosourea (NMU, 45 mg/kg body wt i.v.) at 50 days of age. The experimental design was as follows: Group 1, unsupplemented AIN-76A; Group 2, AIN-76A supplemented with 4-HPR starting seven days before NMU until termination (-7); Group 3, AIN-76A supplemented with 4-HPR seven days after NMU until termination (+7); Group 4, Wayne (no 4-HPR); Group 5, Wayne (4-HPR, -7); Group 6, Wayne (4-HPR, +7); Group 7, NIH-07; Group 8, NIH-07 (4-HPR, -7). 4-HPR [782 mg/kg diet (2 mM)] was given to all supplemented groups. Termination was 25 weeks post-NMU. Analysis of tumor incidence, multiplicity, and latency indicated that 1) control rats fed the AIN-76A diet exhibited significantly higher mammary tumor yields than rats fed unsupplemented natural-ingredient diets (Wayne and NIH-07) and 2) 4-HPR inhibited mammary tumor development in the two grain-based diets but enhanced tumor development in the AIN-76A diet. Animals fed the AIN-76A diet gained weight to a greater extent than those fed the Wayne or NIH-07 diets and exhibited lower levels of circulating 4-HPR.

Animals↗

PubMed1994

Effects of green and black tea on hepatic xenobiotic metabolizing systems in the male F344 rat.

1. The induction of phase I and II enzymes in the liver of the male F344 rat drinking 2% (w/v) solutions of green or black tea for 6 weeks was investigated. Also studied were glutathione (GSH) and cyst(e)ine in blood, liver and kidney, as well as serum cholesterol, HDL cholesterol, triglycerides, and total and free testosterone. 2. The total carbon monoxide-discernible liver P450, b5 and NADPH-cytochrome c(P450) reductase activities were similar in all groups. 3. There were significant increases in liver of rat drinking green or black tea of P4501A1, 1A2 and 2B1 activities, but no change in P4502E1 and 3A4 activities. Of the phase II enzymes, UDP-glucuronyltransferase was increased, but glutathione S-transferase was not. 4. Serum GSH was higher in the group administered black tea, but GSH and cyst(e)ine in other groups was at control levels. Serum cholesterol was lower in rat given black compared with green tea. Triglycerides had a declining trend after green and black tea exposure compared with water controls. Free and total testosterone were not affected. 5. Thus, beverages widely used by man altered host biochemistry as regards specific phase I and II enzymes in liver of rat and specific serum parameters.

Animals↗

PubMed1994

Role of fat and calcium in cancer causation by food mutagens, heterocyclic amines.

We investigated the modulation by dietary corn oil and calcium levels of carcinogenesis by heterocyclic amines (HCA), a new class of important carcinogens in the human nutritional environment, since they are formed during cooking. Two approaches involved (i) a chronic bioassay in male and female F344 rats, and (ii) an abbreviated test, the induction of foci of aberrant crypts in the colon in male F344 rats. One typical HCA, 2-amino-3-methylimidazo [4,5-f]quinoline (IQ) was fed at 75 ppm for 12 months to male and female rats that were held three and six months longer, respectively, on control diets. Neoplasms were induced in the Zymbal gland, skin (predominantly in male rats), liver, mammary and preputial glands, colon, and lung. Diets with 23.5% corn oil increased carcinomas in the liver in males, and in the mammary gland in females, compared with a 5% corn oil diet. Males on the low-fat diet had more cancers in the lip, and females had more ear duct cancers, than did rats on the high-fat diet. Another HCA, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), fed at 400 ppm for nine weeks induced foci of aberrant crypts in the lower intestinal tract of male F344 rats. There were significantly more aberrant crypts on the high-fat than on the low-fat diet. On the low-fat diet, there were fewer aberrant crypts on the higher calcium level. Thus, dietary fat modulates the carcinogenic action of HCA food carcinogens in specific organs of male and female F344 rats. Also, both fat and calcium affected the induction of aberrant crypts in the distal intestinal tract of male F344 rats.

Amines↗

PubMed1993

A study of tobacco carcinogenesis. LI. Relative potencies of tobacco-specific N-nitrosamines as inducers of lung tumours in A/J mice.

Tobacco-specific N-nitrosamines (TSNA) are formed from nicotine and the minor Nicotiana tabacum alkaloids during tobacco processing and tobacco smoking. The TSNA are the most abundant strong carcinogens in smokeless tobacco and in smoke. In this comparative study six TSNA and two major volatile N-nitrosamines of cigarette smoke are assayed for their relative tumorigenicities in strain A/J female mice and for their potential to induce lung tumors. N-nitrosodimethylamine was the most potent inducer of lung adenoma in the A/J mouse model followed in order of decreasing potencies by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, N-nitrosopyrrolidine, N'-nitrosonornicotine and N'-nitrosoanabasine. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol and 4-(methylnitrosamino)-4-(3-pyridyl)butyric acid were inactive. The relative tumorigenic activities of the tobacco-specific nitrosamines in strain A/J mice compare well with the available data for their relative tumorigenic activities in F344 rats and Syrian golden hamsters.

Adenoma↗

PubMed1993

Effect of high fat corn oil, olive oil and fish oil on phospholipid fatty acid composition in male F344 rats.

Epidemiological and laboratory animal model studies have provided evidence that the effect of dietary fat on colon tumorigenesis depends on the amount of fat and its composition. Because of the importance of the composition of dietary fat and of tissue membrane fatty acid composition in tumor promotion, experiments were designed to investigate the relative effects of high fat diets rich in omega 3, omega 6 and omega 9 fatty acids and colon carcinogen on the phospholipid fatty acid composition of liver, colon, small intestine, erythrocytes and blood plasma. At 6 wk of age, groups of animals were fed diets containing 5% corn oil (LFCO), 23.5% corn oil (HFCO), 23.5% olive oil (HFOO), and 20.5% fish oil plus 3% corn oil (HFFO). Two weeks later all the animals except the vehicle-treated animals received azoxymethane s.c. once weekly for 2 wk at a dose rate of 15 mg/kg body weight. Animals were sacrificed 5 d later and liver, colon, small intestine and erythrocytes and blood plasma were analyzed for phospholipid fatty acids. The results indicate that the phospholipid fatty acid composition of liver, colon and small intestine of HFCO diet fed animals, were not significantly different from those fed the LFCO diet. The levels of palmitoleic acid and linoleic acid were increased in erythrocytes and blood plasma of the animals fed the HFCO diet compared to those fed the LFCO diet. Feeding the HFOO diet significantly increased the oleic acid content and decreased the linoleic acid and arachidonic acid levels in various organs when compared to the HFCO diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

N-ethyl-N-nitrosourea induced brain tumors in rats monitored by nuclear magnetic resonance imaging, plasma proton nuclear magnetic resonance spectroscopy and microscopy.

Characteristic slow growing brain gliomas were induced in rats by a single subcutaneous injection of N-ethyl-N-nitrosourea (ENU) within 24 h of birth. A parallel control group of rats was injected with saline. Seven treated rats developed gliomas within 2 years. Periodic nuclear magnetic resonance imaging (MRI) of the brain in 3-mm slices at 1.5 Tesla and monthly plasma sampling for proton magnetic resonance spectroscopy (MRS) at 360 MHz were started 6 months after the injection of ENU. In the MRS experiments, the Fossel index, average of the line widths of the methylene and methyl peaks at 360 MHz, was determined from half-line widths of methyl and methylene peaks at 0.8 ppm and 1.3 ppm. In five of the ENU injected animals that developed histologically verified brain tumors, these were also observed by MRI without contrast agents. There was no consistent correlation between the imaged tumors and the Fossel index obtained through MRS during the course of the study where repeated observations were performed on individual animals, nor was there any consistent statistical difference in the Fossel index between ENU-treated and control animals. The results of this study demonstrate that slowly developing carcinogen-induced brain tumors in rats can be successfully and reliably monitored noninvasively by MRI but not by MRS of plasma.

Animals↗

PubMed1992

Voluntary exercise and experimental mammary cancer.

The results of these studies indicate that voluntary activity suppresses the development of chemically and virally induced primary mammary tumors in rats and mice fed high-fat diets. These diets were chosen to mimic the current U.S. fat consumption of approximately 40% of calories as fat. It remains to be seen if activity exerts a similar suppressive effect on animals fed their customary low-fat diet (10% calories as fat). In general, the activity profiles of the female Fischer F-344 and Sprague-Dawley rat and the C3H/o mu j mouse exhibited a similar pattern with an early peak followed by a gradual plateau over time. The effects of activity on body fat composition showed a trend toward a decreased percent of body fat when compared to sedentary animals but a statistically significant decrease was found only in the F-344 female rat. In the DMBA model, carcinogen dose did alter outcome parameters. For example, time to first tumor was extended under low- but not high-DMBA conditions, and, conversely, tumor multiplicity was significantly decreased in the high- but not low-DMBA group. In the NMU model, an inverse association was found between the amount of activity and tumor incidence. A similar association was not found with the DMBA model. The reason for this is uncertain, but further analysis in terms of other parameters such as total tumor number may shed more light on this discrepancy. The suppressive effect of activity on the MMTV-induced mouse mammary tumor is of particular interest since it raises the possibility that activity may exert effects on the process of provirus insertion, and/or oncogene activation--an area of great potential promise in cancer prevention. Activity appeared to enhance the volume and to a lesser degree the number of metastatic foci in the lungs of F-344 retired breeders under high-fat but not medium-fat conditions. In addition, the most active animals in the high-fat group exhibited the greatest volume of metastases. These results, together with those in the NMU model, point to the critical importance of the quantity of voluntary activity an animal engages in and its relation to both primary and secondary cancer prevention. They imply that beyond a certain point of either frequency or intensity, the beneficial effect of exercise may be nullified by competing deleterious effects. The metastases study has also brought to light the importance of dietary fat as a potential intervening variable.(ABSTRACT TRUNCATED AT 400 WORDS)

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

A study of betel quid carcinogenesis--VIII. Carcinogenicity of 3-(methylnitrosamino)propionaldehyde in F344 rats.

In assays of Areca-specific N-nitrosamines, 3-(methylnitrosamino)propionaldehyde (MNPA) exhibits higher cytotoxicity than nitrosoguvacine (NGC), nitrosoguvacoline (NG) and 3-(methylnitrosamino)propionitrile (MNPN). NGC is not mutagenic. However, NG is a weak carcinogen in F344 rats while MNPN is a potent carcinogen; MNPA had thus far not been tested. In this study MNPA was injected s.c. at a dose of 6.57 mg three times weekly for 15 weeks (total dose 2.6 mmol/rat). During the 100 weeks of the bioassay, the treated F344 rats, and especially the females, showed significantly less weight gain than the control animals, indicating high toxicity for MNPA at the tested dose. Upon termination of the bioassay, the MNPA-treated animals were found to have tumors of the lung, liver, nasal cavity, forestomach and kidneys. The control animals showed no tumors in these organs. The incidence of lung tumors in the MNPA group was statistically significant (P less than 0.025). The results of this study show that MNPA is a carcinogen in F344 rats.

Adenocarcinoma↗