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Biomedical subjects

W Lijinsky

Publications and source records attributed to W Lijinsky.

At least 55 records · Page 3Linked to original sources
PubMed1989

Lack of effect of selenium on induction of tumors of esophagus and bladder in rats by two nitrosamines.

The effect of differences in level of dietary selenium on the induction of esophageal and bladder tumors in rats by two nitrosamines was investigated. Groups of 20 female F344 rats were given a synthetic diet containing less than 0.05 ppm Se to which selenium (as sodium selenite) was added at the concentration of 0.35, 0.7, 1.4 and 2.1 ppm selenium. These four groups, plus one without added Se, were treated with 20 ml per rat per day, 5 days a week, of a solution of nitrosomethylcyclohexylamine containing 5 mg/liter. A parallel five groups were treated in the same way with a solution of nitrosomethyl-3-carboxypropylamine in drinking water containing 600 mg per liter, as drinking water. Treatment lasted 28 weeks, at which time some animals had developed tumors. A group of 20 rats fed 0, 1.4 and 2.1 ppm Se was not treated with carcinogen. Rats consuming 1.4 ppm or 2.1 ppm Se gained weight more slowly than other groups. There was no significant difference in survival between the five groups treated with each carcinogen but receiving different dietary levels of selenium. Neither was there any significant difference between groups receiving each carcinogen in the incidence of tumors of the esophagus induced by nitrosomethylcyclohexylamine or of tumors of the urinary bladder induced by nitrosomethylcarboxypropylamine. Control rats on the synthetic diets did not survive as well as untreated rats eating regular chow diet. In these conditions there was no effect of dietary selenium levels on the induction of tumors in female rats by the two carcinogenic nitrosamines we used.

Animals↗
PubMed1989

Similar carcinogenic actions of nitrosoalkylureas of varying structure given to rats by gavage.

To relate the tumorigenic effects of directly acting alkylating nitrosoalkylureas to their chemical structure, a series of these compounds was given to F344 rats by gavage at approximately equimolar doses. In some cases, more than one dose rate was used. Potency, as measured by time to death with tumors, was similar for nitrosomethylurea and nitrosoethylurea, although the tumor pattern was different between the two. Nitrosoallylurea was of similar potency, and induced a spectrum of tumors similar to nitroethylurea. Nitroso-n-butyl-, n-amyl- and n-hexyl-ureas were less potent than nitrosoethylurea, but induced a similar pattern of tumors. All of the nitrosoureas induced tumors of the forestomach, usually in high incidence, except nitroso-2-hydroxypropylurea, which caused death of the rats with thymic lymphoma within 6 months. Nitroso-3-hydroxypropylurea was much less potent than its 2-isomer, but induced no tumors of the thymus and was the only one of this group to induce tumors of the glandular stomach. Only nitrosomethylurea induced a high incidence of tumors of the nervous system, but no mammary carcinomas, which most of the other nitrosoureas induced in high incidence in females. Tumors of the lung, duodenum, colon and intestines were induced by several of the compounds, more commonly in males than in females, but a high incidence of liver tumors was found only in rats of both sexes given nitroso-2-phenylethylurea.

Animals↗
PubMed1989

Carcinogenesis by nitrosamines and azoxyalkanes by different routes of administration to rats.

The effects of administering similar doses of some simple alkylating agents to rats by different regimens have been compared. Two of the compounds were methylating agents, nitrosodimethylamine and azoxymethane; two were ethylating agents, nitrosodiethylamine and azoxyethane; and nitrosomethylethylamine was both a methylating and an ethylating agent. The treatments gave rise to tumors in almost all treated rats. The results indicate the importance of pharmacokinetics in determining which organs are the targets of the alkylating carcinogens.

Administration, Intravesical↗
PubMed1989

The uniform carcinogenic action of alkylnitrosoureas in Syrian hamsters.

The carcinogenic effects of a number of alkylnitrosoureas in Syrian golden hamsters have been compared by administering them by gavage as solutions in corn oil/ethyl acetate. The compounds were methyl-, ethyl-, 2-hydroxyethyl-, 2-oxopropyl-, and 2-phenylethylnitrosourea and the dialkylnitrosoureas dimethyl- and diethylnitrosourea, ethylnitrosohydroxyethylurea, ethylnitroso-2-oxopropylurea, 2-oxopropylnitrosochloroethylurea, and hydroxyethylnitrosoethylurea. All were given at approximately equimolar doses and, in most cases, to male and female hamsters. Most of the hamsters died with tumors associated with the treatments. Methylnitrosourea, ethylnitrosourea, and hydroxyethylnitrosourea, but not oxopropylnitrosourea, gave rise to a high incidence of tumors of the forestomach, while the dialkylnitrosoureas produced smaller numbers of forestomach tumors. All of the alkylnitrosoureas induced hemangiosarcomas of the spleen, which was the most common tumor produced by these carcinogens. Tumors of other types were uncommon, except that ethylnitrosourea and ethylnitrosohydroxyethylurea induced tumors of the cervix in about half of the animals and ethylnitrosooxopropylurea induced some nervous system tumors. The small number of common target organs of alkylnitrosoureas in hamsters contrasted sharply with the broad spectrum of tumors they induced in rats, depending on the nature of the alkyl groups, and with a quite different order of potency in the latter species.

Animals↗
PubMed1988

Comparative carcinogenesis by nitrosomethylalkylamines in Syrian hamsters.

Six homologous nitrosomethyl-n-alkylamines, from n-propyl (C-3) to n-octyl (C-8), were administered by gavage to groups of 12 male and 12 female Syrian golden hamsters as solutions in corn oil:ethyl acetate (2:1). The solutions of C-8 to C-4 were equimolar; nitrosomethyl-n-butylamine (C-4) and nitrosomethyl-n-propylamine (C-3) were given at a lower concentration. Treatment with 0.2 ml of solution lasted 23 to 50 wk, being stopped when several hamsters had died. Additional groups of hamsters were treated similarly with nitrosomethylaniline and nitrosomethylcyclohexylamine. Excepting hamsters given the latter, treated animals had reduced survival compared with controls. The incidence of tumors in hamsters given nitrosomethylaniline and nitrosomethylcyclohexylamine was low and occurred in the liver, lungs, and spleen. Hamsters treated with nitrosomethyl-n-propylamine and nitrosomethyl-n-butylamine suffered the greatest decrease in survival. Potency judged by this criterion decreased as the size of the molecule increased in the homologous series. Virtually all of these treated hamsters died with tumors not seen in controls. These tumors, which were common in hamsters given all of the nitrosomethyl-n-alkylamines, were in the liver, lung, forestomach, and nasal mucosa, but the incidences varied somewhat between the compounds and between sexes. Bladder tumors were seen only in hamsters given nitrosamines containing even numbers of carbon atoms in the chain, namely, nitrosomethyl-n-hexylamine and nitrosomethyl-n-octylamine.

Animals↗
PubMed1988

Lack of binding of methapyrilene and similar antihistamines to rat liver DNA examined by 32P postlabeling.

The nonmutagenic carcinogen methapyrilene, together with several noncarcinogenic analogues, was administered to rats p.o. for as long as 4 wk at concentrations of 0.1%. DNA was isolated from the liver and other organs and hydrolyzed, and the identification of covalent adducts was made using the 32P postlabeling method of Randerath. Some modified procedures were also used to deal with the possibility of very mobile adducts being formed from these hydrophilic amines. Although the rats had received as much as 2 g of amine per kg of body weight, no evidence of formation of DNA adducts in liver or other organs was seen; the level of detection was between 1 in 10(8) and 1 in 10(9) nucleotides. Adduct formation from much lower doses of the mutagenic food pyrolysis product 2-amino-3-methylimidaz(4, 5f)quinoline was detectable at a level of 1 in 10(6) nucleotides in parallel analyses. These results add to the evidence that carcinogenesis by methapyrilene is through an indirect or nonmutagenic mechanism.

Aminopyridines↗
PubMed1988

Strain comparison of systemic N-nitrosohexamethyleneimine carcinogenesis in BALB/c, SENCAR and CD-1 mice.

SENCAR mice have been selectively bred for hypersusceptibility to 2-stage chemical skin carcinogenesis. In this study the relative susceptibilities of SENCAR, BALB/c and CD-1 mice to systemic carcinogenesis by N-nitrosohexamethyleneimine (NHEX) were examined. NHEX was administered twice weekly (1 mg/mouse) in corn oil by gavage for 30 weeks. NHEX caused primarily liver and lung tumors in all 3 strains of mice. Hemangiosarcomas (but not other liver tumors) were more common in CD-1 mice than BALB/c or SENCAR mice. Lung tumors (adenomas and adenocarcinomas) and forestomach tumors (squamous carcinomas) were more common in SENCAR mice than BALB/c or CD-1 mice. Survival was better in SENCAR mice dosed with NHEX than in the other 2 strains. These results indicate that SENCAR mice are not unusually sensitive to liver carcinogenesis by NHEX, but are relatively sensitive to tumorigenesis in 2 epithelial tissues, lung and forestomach.

Animals↗
PubMed1988

Carcinogenesis by nitroso-2-hydroxyethylurea in splenectomized hamsters.

Several nitrosoalkylureas tested for carcinogenic activity in Syrian hamsters have as their main effect the induction of hemangiosarcomas of the spleen, many of which appear to metastasize to the liver. To investigate whether any of these lesions in the liver might not be metastases, a group of female Syrian hamsters was surgically splenectomized and treated with nitroso-2-hydroxyethylurea (NHEU) dissolved in corn oil/ethyl acetate once a week for 22 weeks. The animals survived much longer (median 45 weeks) than a comparable group of unsplenectomized female hamsters given identical treatment (median 24 weeks). The absence of hemangiosarcomas of the liver in the splenectomized hamsters showed that the presumed metastases seen in intact animals were, in fact, just that. A second interesting conclusion is that the compound did not produce a concomitant increase in tumors of other types.

Animals↗
PubMed1988

Dose-response study with N-nitrosomorpholine in drinking water of F-344 rats.

A dose-response study in carcinogenesis was carried out with N-nitrosomorpholine in female F344 rats. The compound was administered in drinking water, which was supplied in controlled amounts of 20 ml per day per rat, 5 days a wk. At the two highest dose rates, 100 mg/liter and 40 mg/liter, treatment lasted 25 and 40 wk, respectively. At the other dose rates, which differed by a factor of 2.5, treatment lasted 50 or 100 wk. The average total dose received by each rat ranged from 250 mg to 0.7 mg. There were 100 animals per group at the lowest dose rates and 24 animals per group at the highest dose rates. Total doses of nitrosomorpholine above approximately 30 mg per rat caused a statistically significant decrease in survival, but at lower doses survival was similar to that of untreated controls. In nearly all of the treated groups there was a statistically significant increase in the incidence of benign or malignant hepatocellular neoplasms, with a highly significant dose-related trend. At the higher doses there was a significant incidence of hemangiosarcomas of the liver. Both hepatocellular carcinomas and hemangiosarcomas metastasized to the lungs and other organs. At the highest doses there was a significant incidence of neoplasms of the tongue and esophagus, which were rarely seen at the lower doses. The results suggest that even the lowest dose of nitrosomorpholine received by the rats, 0.7 mg or approximately 3 mg/kg body weight, was not a no-effect dose during the 2-yr lifetime of a rat. Probit analysis of the results indicate a dose estimated to cause tumors in 50% of the population of 25 mg nitrosomorpholine for liver neoplasms.

Animals↗
PubMed1988

Neoplasms of the skin and other organs observed in Swiss mice treated with nitrosoalkylureas.

A number of nitrosoalkylureas, nitrosoalkylcarbamates, and chlorinated nitrosotrialkylureas were painted twice a week on the skin of female Swiss mice at a concentration of 40 mM. Of the 29 compounds, 16 induced skin tumors in 4 or more of 20 mice; 9 compounds produced tumors in 10 or more mice. Most of the skin tumors were squamous cell or basal cell carcinomas, and some sarcomas. These carcinomas and sarcomas of the skin were large, invasive, and in several animals there were multiple large metastases to the lungs and lymph nodes. Treatment with several of the compounds was associated with poor survival. The median survival in many other groups was reduced considerably below the 2-year survival of acetone-treated controls. Many of the treatments led to development of tumors of internal organs, including mammary carcinomas, adenocarcinomas and squamous cell carcinomas of the lung, and tumors of the stomach. The stomach tumors might have arisen through exposure to the compound licked from the skin. It appears that several of the compounds were absorbed through the skin of the mice and exerted their effect systemically.

Administration, Topical↗
PubMed1988

Carcinogenesis and nucleic acid alkylation by some oxygenated nitrosamines in rats and hamsters.

A comparison has been made of the carcinogenic effects of nitroso-2,6-dimethylmorpholine and several hydroxylated acyclic nitrosodialkylamines derived from it or related to it in rats and Syrian hamsters. In rats nitrosodimethylmorpholine was the most potent, inducing mainly esophageal tumors. Nitrosodiethanolamine was the weakest of the five nitrosamines in both rats and hamsters. Tumors of the pancreas ducts were induced by four of the five compounds, but only in hamsters, and esophageal tumors appeared only in rats. Most of the nitrosamines induced tumors of liver and lung in both rats and hamsters. A study of alkylation of nucleic acids of the liver following treatment of rats and hamsters with the radiolabeled nitrosamines showed that nitrosodiethanolamine alkylated liver nucleic acids in rats to only a very small extent. The other four nitrosamines all gave rise to 7-methylation and O6-methylation of guanine residues in DNA of hamster liver and all but nitrosodimethylmorpholine in rat liver DNA, which corresponded quite well with the induction of liver tumors in the two species. Quantitatively, however, there was not a good correlation between liver DNA alkylation and the potency of the nitrosamine in inducing tumors.

Administration, Oral↗
PubMed1988

Effects of feminization of male F344 rats on induction of tumors and on nucleic acid alkylation by nitrosobis-(2-oxopropyl)amine.

Groups of male and female F344 rats were treated twice weekly by gavage with 2.5 mg of nitrosobis-(2-oxopropyl)amine (BOP) for 35 weeks. Additional groups given the same treatment were male rats castrated at birth, male rats bearing an implant of a pellet containing estradiol and castrated male rats bearing an estradiol pellet. Most rats died with tumors related to the treatment; intact male rats survived the least well of the five groups. Most rats in all groups had alveolar/bronchiolar neoplasms of the lung. Many of the male rats also had follicular cell neoplasms of the thyroid and transitional cell neoplasms of the urinary bladder and kidney pelvis; there were no liver tumors in intact male rats. Almost all female rats and castrated male rats had liver neoplasms, including hepatocellular, cholangiocellular and hemangiosarcomatous neoplasms, but few neoplasms of the thyroid, kidney or bladder. The male rats feminized with estradiol, intact or castrated, had liver neoplasms, mainly cholangiocellular, and also neoplasms of the thyroid. Two rats of each of the five groups were treated at 20 weeks of age with [14C]BOP. As measured by respiration of 14CO2, metabolism of BOP was faster in the two groups of male rats with the estradiol implant than in the other groups. DNA and RNA of the liver were isolated 6 h after treatment. The extent of methylation of liver DNA as 7-methylguanine and O6-methylguanine was higher in the females and in the feminized males than in the intact male rats, but when normalized to the dose of nitrosamine per unit body weight there was little difference among the five groups.

Alkylation↗
PubMed1988

Carcinogenesis in rats by cyclic N-nitrosamines containing sulphur.

The effects of chronic exposure to three sulphur-containing heterocyclic N-nitrosamines were determined after repeated oral administration to female Fischer 344 rats. Nitrosothiazolidine did not significantly affect the survival of the rats or the incidence of tumours at a total dose of 3.5 mmol. Nitrosodithiazine, an analogue of nitrosothiazolidine which contains an extra sulphur atom inserted between the carbons of its CH2-CH2 moiety, produced only three tumours (two of the nasal mucosa) in a group of 20 rats at a total dose of 1.75 mmol/rat. Nitrosothialdine, the all-cis 2,4,6-trimethyl analogue of nitrosodithiazine, was a potent carcinogen that significantly shortened the lifespan and produced oesophageal tumours in 70% of treated rats as well as numerous tumours of the tongue and liver; this outcome was unexpected because alpha-methyl substitution in other heterocyclic nitrosamines usually reduces or eliminates tumorigenicity. The results extend the data base on the carcinogenic activity of molecules containing both divalent sulphur and the nitrosamino function. The lack of significant carcinogenicity of nitrosothiazolidine in this study suggests that its presence in the human food supply presents a relatively minor risk.

Animals↗
PubMed1988

Carcinogenic effect of N-nitrosotriethylurea in single administration to female rats.

N-Nitrosotriethylurea (NTEU) was administered once into the stomach or intravenously to outbred female rats. The rats given NTEU by oral administration developed malignant tumours of the mammary gland, uterus and liver. The rats exposed to NTEU by i.v. administration developed tumours of the mammary gland and ovaries. NTEU accelerated the appearance of tumours which are normally characteristic of the rat stock used (tumours of the pituitary, thyroid, adrenal cortex, fibroadenoma of the mammary gland, endometrial polyps.

Animals↗
PubMed1988

DNA alkylation by nitrosobis-(2-oxopropyl)amine in rats of different ages.

We have examined the methylation of liver DNA (O6- and N7-methylguanine) by nitrosobis-(2-oxopropyl)amine (BOP) in male and female rats at various ages, following treatment with 2.5 mg of BOP; this dose given twice weekly for 30 weeks induces tumors in all animals. Except in young rats there was more methylation in female rat liver than in male rat liver, when adjusted for different sizes of the animals. There were differences in the extent of methylation between young (4 weeks) and older rats, but not between young adult (20 weeks) and old adult (65 weeks) males; the latter developed liver tumors when treated with BOP, and the former did not. There was no obvious relation between increased susceptibility to liver tumor induction by BOP and the extent of alkylation of liver DNA. Methylation of DNA was lower in the kidney than in the liver and, here, there was little difference between the sexes. In the testis there was N7-methylation of guanine in DNA, but no O6-methylguanine was detected.

Aging↗
PubMed1988

Carcinogenesis by nitrosohydroxyethylurea and nitrosomethoxyethylurea in F344 rats.

Nitroso-2-hydroxyethylurea and its methyl ether, nitroso-2-methoxyethylurea, were administered to male and female rats by gavage, each at two dose rates. The highest dose rate of nitrosohydroxyethylurea was 14 mg twice a week for 18 weeks, which led to death of all animals by week 34 with a variety of neoplasms, which have been observed in earlier experiments at lower doses, and included those in lung, colon, thyroid, forestomach, tongue, duodenum, jejunum, Zymbal's gland, thymus and mammary gland adenocarcinomas. At a dose 10 times smaller, the animals survived much longer, but the distribution of tumors was similar, except that there were few of the duodenum and jejunum. At an equimolar dose of nitrosomethoxyethylurea (1.6 mg, twice a week), the pattern of tumors was similar to that seen with nitrosohydroxyethylurea, including the absence of tumors in the duodenum and jejunum, although there were tumors of the colon. The rats treated with the methyl ether died earlier than those given nitrosohydroxyethylurea, indicating a greater potency of the former. At a dose of 3.2 mg twice a week, nitrosomethoxyethylurea produced the same pattern of tumors as the lower dose, but the animals died earlier. In all groups, there were more lung tumors in males than in females, and this was true to a lesser extent of the colon. The main effect of methylation of the hydroxyl group in nitrosohydroxyethylurea was to increase the potency of the carcinogen, but there was no effect on the target organ specificity of the nitrosourea.

Animals↗
PubMed1988

The induction of bladder tumors in F344 rats by intravesicular administration of some nitrosamines.

Three nitrosamines, metabolically related and formed in vivo from the bladder carcinogen nitrosomethyl-n-octylamine, were administered to groups of 12 female F344 rats by intraurethral instillation twice a week for 30 weeks. All three compounds induced tumors in the urinary bladder. Nitrosomethyl-2-oxopropylamine at 10 mg/ml was the most potent, causing death of half of the animals with tumors at 43 weeks, following a total dose of 1.0 mmol; most of the rats also had tumors of the nasal mucosa, and there were some tumors of the kidney and kidney pelvis. Nitrosomethyl-2-hydroxypropylamine at 10 mg/ml (total dose 1.0 mmol) was much less effective, the median week of death being 83 weeks. In addition to bladder tumors, this group had tumors of the nasal mucosa, esophagus, and kidney. Nitrosomethyl-3-carboxypropylamine at 75 mg/ml and a total dose of 6.2 mmol per rat induced a high incidence of bladder tumors and tumors of the kidney pelvis, but not tumors of the nasal mucosa; the median week of death for this group was 55 weeks. It is concluded that nitrosomethyl-n-alkylamines that induce bladder tumors by oral administration to rats are metabolized to nitrosomethyl-3-carboxypropylamine, which is excreted in the urine and further metabolized to nitrosomethyl-2-oxopropylamine, the proximate bladder carcinogen.

Administration, Intravesical↗