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A Rivenson

Publications and source records attributed to A Rivenson.

At least 55 records · Page 3Linked to original sources
PubMed1993

Chemoprevention of colon carcinogenesis by organosulfur compounds.

It has been reported that several naturally occurring and related synthetic organosulfur compounds exert chemopreventive effects in several target organs in rodent models. The chemopreventive actions of 40 and 80% maximum tolerated doses (MTD) of organosulfur compounds, namely anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine, administered in AIN-76A diet, on azoxymethane (AOM)-induced neoplasia were investigated in male F344 rats. Also, the effects of these agents on the activities of phase II enzymes, namely glutathione S-transferase (GST), NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase, in the liver and colonic mucosa and tumors were assessed. The MTD levels of anethole trithione, diallyl disulfide, N-acetylcysteine, and taurine were determined in male F344 rats and found to be 250, 250, 1500, and 1500 ppm, respectively. At 5 weeks of age, animals were fed the control diet (AIN-76A) or experimental diets containing 40 or 80% MTD levels of each test agent. All animals in each group, except those allotted for vehicle (saline) treatment, were administered AOM s.c. at a dose rate of 15 mg/kg body weight once weekly for 2 weeks. All animals were necropsied during week 52 after the second AOM injection. Colonic mucosal and tumor and liver enzyme activities were measured in animals fed 80% MTD levels of each test agent. Colon tumors were subjected to histopathological evaluation and classified as invasive or noninvasive adenocarcinomas. Colon tumor incidence (percentage of animals with tumors) and tumor multiplicity (tumors/animal) were compared among various dietary groups. The results indicated that administration of 200 ppm (80% MTD) anethole trithione significantly inhibited the incidence and multiplicity of both invasive and noninvasive adenocarcinomas, whereas feeding of 100 ppm (40% MTD) anethole trithione or 100 (40% MTD) or 200 ppm (80% MTD) diallyl disulfide suppressed only invasive adenocarcinomas of the colon. Although diets containing N-acetylcysteine and taurine inhibited colon tumor multiplicity, the effect was somewhat marginal. GST, NAD-(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase activities in colonic mucosa and tumor and liver were significantly elevated in animals fed anethole trithione or diallyl disulfide, compared to those fed the control diet. N-Acetylcysteine and taurine slightly but significantly increased only the GST activity in the liver. Although other mechanisms are not excluded, inhibition of AOM-induced colon carcinogenesis by anethole trithione and diallyl disulfide may be associated, in part, with increased activities of phase II enzymes such as GST, NAD(P)H-dependent quinone reductase, and UDP-glucuronosyl transferase in the liver and colon.

Acetylcysteine↗
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

A study of tobacco carcinogenesis: effect of the fat content of the diet on the carcinogenic activity of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.

3 Epidemiological studies indicate that the risk of cigarette smokers for cancer of the lung and of the pancreas is influenced by the fat content of the daily diet. In a long-term bioassay (24 months), we gave F344 rats 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific and strongly carcinogenic N-nitrosamine, as a 2 ppm solution in the drinking water. One group of rats was given a high-corn oil diet (23.5%), and the second group received a low-corn oil diet (5.0%). The animals on the high-corn oil diet and NNK (NNK-HF), and the control animals on the same diet but on tap water (HF) had significantly higher body weights and shorter life spans than the rats on a low-corn oil diet and NNK (NNK-LF) and the corresponding control rats receiving the low-corn oil diet and tap water (LF). Eighteen months into the bioassay, 16 of 60 rats in the NNK-HF group had developed lung tumors averaging 6.8 mm2, while 3 of 60 rats in the NNK-LF group had tumors averaging 2.5 mm2. At the termination of the experiment after 24 months, the numbers of rats with lung tumors in the NNK-HF and NNK-LF groups did not significantly differ from each other, nor was there a difference in the size of the lung tumors. The effect of dietary fat on the pancreas tumor incidence was more pronounced. After 18 months, 11 of 60 rats treated with NNK-HF but only one of 60 rats treated with NNK-LF had developed pancreas tumors. At the termination of the study, 28 NNK-HF-treated rats had pancreas tumors (17.5 +/- 13.5 mm) compared to 19 NNK-LF-treated rats (9.6 +/- 11.7 mm2). After 24 months 6 of 20 rats in each of the control groups (HF and LF) had developed pancreas tumors. In fact, there was an increasing trend of development of pancreas tumors in these control rats with aging regardless of dietary fat variance. However, in view of the observed tumor acceleration and enhancement this study points to the importance of evaluating both exposure to tobacco carcinogens and dietary fat intake as risk factors for tobacco users.

Adenoma, Islet Cell↗
PubMed1993

Chemopreventive effect of oltipraz during different stages of experimental colon carcinogenesis induced by azoxymethane in male F344 rats.

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], a substituted 1,2-dithiole-3-thione, protects against the acute and chronic toxicities of many xenobiotics and prevents chemically induced carcinogenicity in several target organs of rodents. The effects of dietary oltipraz, fed during the initiation and postinitiation stages, on azoxymethane-induced colon carcinogenesis and on the levels of several detoxifying enzymes, namely, glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities, were studied in male F344 rats. At 5 weeks of age, groups of animals were fed the control diet (modified AIN-76A diet) or a diet containing 200 ppm (40% maximum tolerated dose) of oltipraz. At 7 weeks of age, all animals except those in the vehicle (normal saline solution)-treated groups were given two weekly s.c. injections of azoxymethane at a dose of 15 mg/kg body weight. Three days after the second injection of azoxymethane, the groups of animals fed the oltipraz diet were transferred to the control diet (termed the initiation period) and the groups of animals receiving the control diet were transferred to the oltipraz diet (termed the postinitiation period). All groups were continued on this regimen until the termination of the experiment at 52 weeks after the carcinogen treatment. Intestinal tumors were evaluated histopathologically using routine procedures. Liver, colonic mucosa, and tumors were analyzed for glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities. The results indicate that oltipraz administered during the initiation stage significantly inhibited the incidence and multiplicity of invasive adenocarcinomas of the colon (P < 0.001), as well as the multiplicity of invasive and noninvasive adenocarcinomas (P < 0.01). Feeding of oltipraz during the postinitiation phase completely suppressed the formation of invasive adenocarcinomas (P < 0.0001) and significantly inhibited the formation of noninvasive and total adenocarcinomas, as well as the multiplicity (tumors/tumor-bearing animal, P < 0.001). Furthermore, oltipraz significantly suppressed the tumor volume when administered during the initiation phase (> 80%) or the postinitiation (> 93%) phase. Animals fed the oltipraz diet during the postinitiation stage showed increased levels of glutathione S-transferase, NAD(P)H:quinone reductase, and UDP-glucurinyl transferase activities (2-6-fold). Although the precise mechanism by which oltipraz inhibits colon tumor initiation and/or promotion remains to be elucidated, it is likely that the effect during the initiation stage may be due to an alteration of carcinogen metabolism.

Adenocarcinoma↗
PubMed1993

Potential inhibitors of tobacco carcinogenesis.

Tobacco smoking is causally associated with cancer of the lung, upper aerodigestive tract, pancreas, renal pelvis and urinary bladder. Tobacco chewers and especially snuff dippers face an increased risk for cancer of the oral cavity and pharynx. Although cessation of the tobacco habits is the only sure way to avoid an increased risk of tobacco-related cancers, certain modified products should be available to lower the incidence rates for cancer among those tobacco chewers and smokers who are unable to give up their tobacco habits. The modified cigarette has been the first approach toward the reduction of cancer risk. In the case of cancer of the lung, the long-term smoker of low-yield filter cigarettes has a risk reduction of 30-50% over that of the smoker of nonfilter cigarettes; however, the risk of filter cigarette smokers for cancer of the lung and cancer at other sites is still many times higher than that of the nonsmoker. A second modality is the application of natural or synthetic chemopreventive agents. Clinical studies with tobacco users have been primarily limited to the application of beta-carotene and retinoids. Although the data appear encouraging in respect to reducing early lesions in the oral cavity of tobacco chewers and smokers and in respect to second primaries in smokers, the benefits of beta-carotene and retinoids are gradually reversed upon withholding these micronutrients. It is understandable that activities in respect to chemopreventive agents in clinical trials on smokers are limited, since cessation of smoking alone leads within only a few years to a significant reduction of the cancer risk. Another reason for the limited interest in clinical trials on smokers may relate to the lack of laboratory data on the actual effects of chemopreventive agents in animals induced with tobacco-specific carcinogens. However, during the last few years, a number of natural or synthetic chemopreventive agents in animals induced with tobacco-specific carcinogens. However, during the last few years, a number of natural or synthetic chemopreventive agents have been tested in mice and rats which were treated with carcinogenic, tobacco-specific N-nitrosamines (TSNA). The results appear most encouraging in respect to lung tumor reduction. It is hoped that this type of research will gain in interest. Human data suggest that the fat content of the diet influences the cancer risk of smokers.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Inhibitory effect of aspirin on azoxymethane-induced colon carcinogenesis in F344 rats.

Epidemiologic studies suggest that sustained use of aspirin may reduce the risk of development of and mortality due to colon cancer. Previous preclinical studies have shown that several non-steroidal anti-inflammatory drugs act as potential chemopreventive agents in experimentally induced colon cancer models. The present study was designed to investigate the chemopreventive effect of 40 and 80% maximum tolerated dose (MTD) levels of aspirin administered in the diet on azoxymethane (AOM)-induced colon carcinogenesis in male F344 rats. The MTD of aspirin as determined in male F344 rats was 500 p.p.m. Beginning at 5 weeks of age, all animals were randomly divided into various experimental groups (48 rats/group) and fed one of the semipurified diets containing 0, 200 p.p.m. (40% MTD), or 400 ppm (80% MTD) of aspirin. Two weeks later, all animals (36 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM at a dose level of 15 mg/kg body wt, once weekly for 2 weeks. All animals were continued on their respective dietary regimen for additional 52 weeks and necropsied. Histopathologic evaluation of colon tumors was performed by routine procedures. Basal levels and ex vivo production of colonic mucosal and tumor prostaglandin E2 (PGE2) were measured in all groups. The results indicate that daily oral administration of 200 and 400 p.p.m. aspirin significantly inhibited the incidence (% animals with tumors) and multiplicity (tumors/animal) of invasive adenocarcinomas of the colon as well as the size of adenocarcinomas. Colonic mucosal and tumor PGE2 levels (basal and ex vivo production) were significantly reduced in animals administered 200 and 400 p.p.m. aspirin. The results of this study support the epidemiologic evidence that ingestion of aspirin inhibits colon carcinogenesis. Although the precise mechanisms of aspirin-induced colon tumor inhibition remain to be determined, it is likely that the effect may be mediated through the modulation of prostaglandin synthesis.

Adenocarcinoma↗
PubMed1992

Chemoprevention of colon carcinogenesis by the synthetic organoselenium compound 1,4-phenylenebis(methylene)selenocyanate.

The chemopreventive effect of 40% and 80% maximum tolerated dose (MTD) levels of 1,4-phenylenebis(methylene)selenocyanate (p-XSC) administered in the diet during the initiation phase (2 weeks before, during, and up to 3 days after carcinogen administration) and the post-initiation phase (3 days after carcinogen treatment until termination) of azoxymethane (AOM)-induced colon carcinogenesis was studied in male F344 rats. The MTD of p-XSC was determined in male F344 rats and found to be 50 ppm. Beginning at 5 weeks of age, all animals were divided into various experimental groups (42 rats/group) and fed the high-fat semipurified diet or diets containing 20 (40% MTD) and 40 (80% MTD) ppm p-XSC. At 7 weeks of age, all animals (30 rats/group) except the vehicle-treated groups (12 rats/group) were administered s.c. injections of AOM (15 mg/kg body weight/week for 2 weeks). Three days after the second injection of AOM or vehicle (normal saline), groups of animals fed the p-XSC diets and control diet were transferred, respectively, to control diet and p-XSC diets and continued on these diets until the termination of the study. All animals were necropsied during the 36th week after AOM treatment. Colonic mucosal prostaglandin E2 and selenium-dependent glutathione peroxidase were measured in animals fed the control and p-XSC diets at the termination of the study. The results indicate that 40 ppm p-XSC administered during the initiation phase significantly inhibited the colon tumor incidence (percentage of animals with tumors). Dietary p-XSC administered at 20 and 40 ppm levels during the initiation phase significantly inhibited colon tumor multiplicity (tumors/animal and tumors/tumor-bearing animal). Colon tumor incidence and multiplicity were significantly reduced in groups fed 20 and 40 ppm p-XSC diets at the postinitiation phase of carcinogenesis. Colonic mucosal selenium-dependent glutathione peroxidase activity was increased, and prostaglandin E2 was reduced in animals fed the p-XSC diet compared to animals fed the control diet. Whereas the precise mechanisms of p-XSC-induced inhibition of colon carcinogenesis remain to be elucidated, it is likely that the effect during the initiation and postinitiation phases may be due to alteration in carcinogen metabolism and to modulation of prostaglandin synthesis and selenium-dependent glutathione peroxidase activity.

Adenocarcinoma↗
PubMed1992

A study of tobacco carcinogenesis. XLVII. Bioassays of vinylpyridines for genotoxicity and for tumorigenicity in A/J mice.

3-Vinylpyridine is formed from nicotine during the smoking of tobacco products. Consequently it is found in mainstream and side-stream smoke of cigarettes and cigars and in environmental tobacco smoke. In this study, 3-vinylpyridine and its isomers 2- and 4-vinylpyridine as well as styrene (vinylbenzene) were bioassayed for mutagenicity in Salmonella typhimurium strains TA 1535, TA 1538, TA 98 and TA 100 and for their genotoxicity in the rat hepatocyte DNA-repair test. In both in vitro assays-all three vinylpyridines and styrene were inactive. In a test for tumorigenicity in which the test compounds were injected intraperitoneally into A/J mice (total dose 200 mumol/animal) there was no significant incidence of lung adenoma nor of any other type of tumors.

Animals↗
PubMed1992

Induction of proliferative lesions of ventral prostate, seminal vesicle, and other accessory sex glands in rats by N-methyl-N-nitrosourea: effect of castration, pretreatment with cyproterone acetate and testosterone propionate and rat strain.

Wistar (Cpb:WU), F344 or Sprague-Dawley rats were sequentially treated with cyproterone acetate (CA) for 21 days, testosterone propionate (TP) for 3 days, followed by a single i.v. injection of N-methyl-N-nitrosourea (MNU). One group of Wistar rats was castrated 4 weeks after MNU injection, and another group 58 weeks after MNU, when the first prostatic carcinoma was detected. Control groups received only CA + TP, CA, MNU, or they remained untreated. Early or late castration inhibited the development of atypical hyperplasia of the ventral prostate in Wistar rats. This lesion was induced by the CA + TP + MNU treatment in F344 rats, but not Sprague-Dawley rats; in Wistar rats, it was induced by CA + TP treatment, irrespective of whether MNU was given. Hypertrophic-hyperplastic lesions of the seminal vesicle were induced by MNU, irrespective of pretreatment, and their development was prevented by early castration and inhibited by late orchiectomy. Dorsolateral prostate carcinomas and preneoplasia occurred only in low incidence in Wistar and Sprague-Dawley rats. These lesions were absent in F344 rats that had received treatment with CA + TP + MNU. No dorsolateral prostate (pre)neoplasia was found in Wistar rats subjected to early orchiectomy, but rats castrated at 58 weeks had an incidence similar to that for the intact group treated with CA + TP + MNU. This finding supports the contention that androgens are required for the development of MNU-induced prostatic cancer in rats but that advanced carcinomas are androgen insensitive. Differences in incidence and localization of prostatic proliferative lesions between F344 and Wistar rats and between dorsolateral and ventral prostate could not be explained by differences in epithelial cell proliferative responses to CA + TP treatment at the time of MNU injection, since they were similar in ventral and dorsolateral prostate and were more prominent in F344 rats than in Wistar rats. DNA damage as estimated by MNU-induced unscheduled DNA synthesis also did not differ between dorsolateral and ventral prostate.

Androgens↗
PubMed1992

A study of tobacco carcinogenesis XLVIII. Carcinogenicity of N'-nitrosonornicotine in mink (Mustela vison).

During tobacco processing and smoking, nicotine and nornicotine give rise to N'-nitrosonornicotine (NNN), a highly abundant, strong carcinogen. NNN is known to exert carcinogenic activity in mice, rats and hamsters. Major target organs for NNN carcinogenicity in the rat are the esophagus and the nasal mucosa, and in the Syrian golden hamster trachea and nasal mucosa. In comparison with the rat, the mink (Mustela vison) has a markedly expanded nasal mucosa. Therefore, we explored in this study whether the mink could serve as a non-rodent model for nasal carcinogenesis using NNN as the carcinogen. Twenty random-bred mink, beginning at the age of 3 weeks, received twice weekly s.c. injections of NNN, a total dose of 11.9 mM per animal over a 38 week period. All of the 19 mink at risk developed malignant tumors of both the respiratory and the olfactory region of the nose within 3.5 years. In most animals the malignant tumors, primarily esthesioneuroepithelioma, invaded the brain. Remarkably, NNN induced no other tumors in the mink. None of the control animals developed nasal tumors nor tumors at other sites during the 3.5 years of the assay. The historical data from the farm did not reveal any spontaneous occurrence of nasal tumors in mink at any age. This study supports the concept that NNN is a proven carcinogen for multiple species of mammals and that the mink can serve as a non-rodent, non-inbred animal model for nasal carcinogenesis, especially since NNN induces only tumors in the nasal cavity in this species and not at other sites, as it does in mice, rats and hamsters.

Animals↗
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↗
PubMed1992

Induction of skin and thyroid tumors in male rats by N-methyl-N-nitrosourea after sequential treatment with cyproterone acetate and testosterone propionate: effects of castration, rat strain and time of carcinogen injection.

The purpose of this study was to determine the carcinogenic effect in male rats of a single i.v. injection of N-methyl-N-nitrosourea (MNU) after sequential treatment with cyproterone acetate (for 21 days) and testosterone propionate (for 3 days). This treatment has previously been shown to induce carcinomas of the prostate and other male accessory sex glands. A wide spectrum of non-melanoma skin tumors was found in 38-48% of Wistar (Cpb:WU) rats given this sequential treatment, but only in 5% of rats that received only MNU. Castration long and, particularly, early after MNU markedly reduced this skin tumor response to a 10-13% incidence. The skin tumorigenic efficacy of MNU was dependent on the time between the start of the testosterone propionate treatment and carcinogen administration: MNU injection after 48-50 or 60-63 h induced skin tumors in 17-21% of Wistar rats, whereas injection after 72-74 h induced a 48% incidence. The Fischer F344 and Sprague-Dawley strains were not very sensitive to induction of skin tumors by this approach. Thyroid follicular cell tumors were also induced by MNU only after the hormonal pretreatment, and their induction was influenced by the time of MNU injection as well. The time of MNU injection and rat strain used did not significantly influence the induction of sebaceous-squamous neoplasms of the ear-duct/Zymbal's glands or other tumors. These data indicate that endogenous androgens are critically involved in the later stages of rat skin tumorigenesis and suggest that androgen-induced cell proliferation influences the initiation stage of this process and, possibly, of thyroid tumorigenesis.

Animals↗
PubMed1991

A study of betel quid carcinogenesis. IX. Comparative carcinogenicity of 3-(methylnitrosamino)propionitrile and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone upon local application to mouse skin and rat oral mucosa.

The Areca-derived 3-(methylnitrosamino)propionitrile (MNPN) was tested for its tumor initiating activity on mouse skin and for its tumorigenic potential in the oral mucosa of rats. On mouse skin, like the otherwise strongly carcinogenic, tobacco-specific 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), MNPN showed only weak local tumor initiator activity. However, the application of MNPN to mouse skin led also to multiple distant tumors in the lungs of the animals. Twice daily swabbing of the oral cavity of rats with aqueous solutions of MNPN or NNK for up to 61 weeks led only to one oral tumor in each group of 30 animals. Yet, these N-nitrosamines proved again to be strong organ-specific carcinogens. Thus, MNPN induced nasal tumors in 80% of the rats and lung adenomas in 13%, liver tumors in 10% and papillomas of the esophagus in 7%. NNK induced lung adenoma and/or adenocarcinoma in 90%, nasal tumors in 43% and liver adenomas/adenocarcinomas in 30% of the rats. These results confirm previous observations that, independent of the site and mode of application, MNPN and NNK remain strong organ-specific carcinogens in laboratory animals.

Administration, Topical↗
PubMed1991

Nicotine-derived N-nitrosamines (TSNA) and their relevance in tobacco carcinogenesis.

Biochemical studies and bioassays support the concept that the increased risk for cancer of the oral cavity in snuff dippers and cancer of the lung, upper aerodigestive tract, and pancreas in smokers is most likely associated with the exposure to tobacco-specific N-nitrosamines. The doses of TSNA required to induce tumors in the oral cavity in rats and tumors in the lungs of rats and hamsters are comparable to the total doses of TSNA to which a long-term snuff dipper, respectively a cigarette smoker, are exposed over 4 decades. The carcinogenic NNN and NNK are metabolized to highly reactive electrophiles which react with nucleophilic centers of DNA and with proteins. The DNA-adducts are known to cause miscoding which can activate K-ras proto-oncogenes. K-ras oncogenes have been detected in adenocarcinomas of the lung of smokers. TSNA also form globin adducts in the blood of laboratory animals as well as of snuff dippers and smokers. Such adducts are currently being evaluated for their significance as biochemical markers of exposure to TSNA. These biomarkers may also serve as indicators for the possible endogenous formation of TSNA in tobacco chewers and smokers. Additional research needs in TSNA carcinogenesis include the development of modified methods for the reduction of TSNA in tobacco and smoke, inhibition of TSNA carcinogenesis by nutrients and micro-nutrients and the testing of chemopreventive agents.

Animals↗
PubMed1991

Extensive spontaneous occlusive arteriosclerosis of the lingual arteries in Fischer rats, a model for the study of human occlusive arteriosclerosis of medium- and small-sized arteries.

Spontaneous occlusive arteriosclerosis is rarely present in rats or other laboratory rodents. Instead, the common vascular lesion in these animals is a mineralization resembling Mönkeberg's medial calcinosis, or non-atheromatous and non-obstructive arteriosclerosis. For reasons yet unknown, the lingual arteries of Fischer rats behave differently; they develop extensive sclerotic lesions with progressive narrowing of the lumen, leading to complete occlusion and sometimes recanalization, comparable to lesions seen in human coronaries, carotids, tibials, etc. The spontaneous plaque-forming, thrombotic, occlusive arteriosclerosis of the lingual artery in Fischer rats can serve as an experimental model for the same lesion of medium- and small-sized arteries in man. As such, it can considerably facilitate the testing of nutritional, hormonal, immunological and other chemical or physical factors for a possible role in promoting or inhibiting the thrombotic-occlusive arteriopathy in man.

Animals↗
PubMed1989

A study of tobacco carcinogenesis XLIV. Bioassay in A/J mice of some N-nitrosamines.

The evaluation of the tumorigenic activity in A/J mouse lung of certain tobacco N-nitrosamines, namely 3-(methylnitrosamino)propionic acid (NMPA), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and 4-(methylnitrosamino)-4-(3-pyridyl)-butyric acid (iso-NNAC), had the following results (total dose in micromol per mouse/lung tumors per mouse): NMPA (200/7.1 +/- 2.9); NNK (2/15.7 +/- 4.1); iso-NNAC (200/0.24 +/- 0.43); saline control (0.2 +/- 0.4). The tumorigenic activity of NMPA was not surprising since its lower homologue, N-nitrososarcosine, as well as its higher homologue, 4-(methylnitrosamino)-butyric acid, are known carcinogens. The high tumorigenic activity of NNK in strain A/J mice confirms earlier findings as to its carcinogenic potency in rats and hamsters. The lack of tumorigenic activity of iso-NNAC supports the observation that the pyridyl rest adjacent to the nitrosamino group inhibits the activity of some tobacco-specific N-nitrosamines (TSNA). Iso-NNAC is most likely formed endogenously from the nicotine metabolites cotinine and 4-(methylamino)-4-(3-pyridyl)butyric acid.

Animals↗